(1) Background: The HIV subtype D is generally associated with a faster decline in CD4+ T cell counts, a higher viral load, and a faster progression to AIDS. However, it is still poorly characterized in Brazil. In this study, we used genomics and epidemiological data to investigate the transmission dynamics of HIV subtype D in the state of Bahia, Northeast Brazil. (2) Methods: to achieve this goal, we obtained four novel HIV-1 subtype D partial pol genome sequences using the Sanger method. To understand the emergence of this novel subtype in the state of Bahia, we used phylodynamic analysis on a dataset comprising 3,704 pol genome sequences downloaded from the Los Alamos database. (3) Results: Our analysis revealed three branching patterns, indicating multiple introductions of the HIV-1 subtype D in Brazil from the late 1980s to the late 2000s and a single introduction event in the state of Bahia. Our data further suggest that these introductions most likely originated from European, Eastern African, Western African and Southern African countries. (4) Conclusion: Understanding the distribution of HIV-1 viral strains and their temporal dynamics is crucial for monitoring the real-time evolution of circulating subtypes and recombinant forms, as well as for designing novel diagnostic and vaccination strategies. We advocate for a shift to active surveillance, to ensure adequate preparedness for future epidemics mediated by emerging viral strains.

We report the characterization of phenotype, genotype, and functional parameters such as CD4+ T cell, viral load, HIV-1 genotype, class I HLA genotype, CCR5 polymorphism, and IFN-γ producing cells from a cohort of 37 people living with HIV-1 (PLWH) (viremic controllers, were compared those on antiretroviral therapy (ART) from two sites in São Paulo, Brazil. Half the PLWH (51.4%) were classified as viremic controllers (Controller group - CG), compared to 48.6% were on ART. As expected, controllers showed baseline higher levels of CD4+ T cells and nadir compared to those under ART, confirming the ability of HIV-1 controllers to preserve these cells even in the absence of ART. IFN-γ-producing cells showed greater magnitude to the HIV peptides Gag in controllers (p<0.03). Our results demonstrated that HLA protective alleles are associated with strong production of IFN-γ to Gag, Nef and RT epitopes in people living with HIV controllers.

Adipose tissue is a crucial organ in energy metabolism and thermoregulation. Adipose tissue phenotype is controlled by various signaling mechanisms under pathophysiological conditions. Type II transmembrane serine proteases (TTSPs) are a group of trypsin-like enzymes anchoring on the cell surface. These proteases act in diverse tissues to regulate physiological processes, such as food digestion, salt-water balance, iron metabolism, epithelial integrity, and auditory nerve development. More recently, several members of the TTSP family, namely, hepsin, matriptase-2, and corin, have been shown to play a role in regulating lipid metabolism, adipose tissue phenotype, and thermogenesis, via direct growth factor activation or indirect hormonal mechanisms. In mice, hepsin deficiency increases adipose browning and protects from high-fat diet-induced hyperglycemia, hyperlipidemia, and obesity. Similarly, matriptase-2 deficiency increases fat lipolysis and reduces obesity and hepatic steatosis in high-fat diet-fed mice. In contrast, corin deficiency increases white adipose weights and cell sizes, suppresses adipocyte browning and thermogenic responses, and causes cold intolerance in mice. These findings highlight an important role of TTSPs in modifying cellular phenotype and function in adipose tissue. In this review, we provide a brief description about TTSPs and discuss recent findings regarding the role of hepsin, matriptase-2, and corin in regulating adipose tissue phenotype, energy metabolism, and thermogenic responses.

Cryptococcosis is a leading cause of death among people with HIV in sub-Saharan Africa. Limited diagnostic and therapeutic options significantly impair treatment options in Africa. We investigated the burden of cryptococcosis and related mortality among people with HIV and suspected sepsis in Ethiopia. We conducted a prospective cohort at 1) Adama Hospital Medical College and 2) Asella Referral and Teaching Hospital from September 2019 to November 2020. We enrolled adult HIV-infected patients presenting with suspected sepsis and assessed 28-day survival. We performed blood cultures and cryptococcal antigen (CrAg) testing. In total, 82 participants were enrolled with a median age of 35 years and 61% being female. Overall, 11(13%) had positive CrAg tests, of which 5 had Cryptococcus detected in blood cultures. Despite high-dose fluconazole (1200mg/d) monotherapy in patients with positive CrAg tests, the 28-day mortality was 64%(7/11), being significantly higher than in CrAg-negative patients (9%(6/71); p&lt;0.001). Cryptococcosis is the leading cause of mortality among HIV-infected sepsis patients. CrAg screening in HIV-infected patients attending emergency department can minimize the cryptococcosis missing case irrespective of CD4 count and viral load. These findings warrant the need of a bundle approach for diagnosis of HIV-infected persons presenting with sepsis in low- and middle-income countries.

Increasing quality of life (QoL) is both an end in itself and a means to optimize the impact of treatment in HIV-infected persons. Possibly due to cultural and social influences, the predictors of QoL vary across studies, which highlights the importance of studying specific populations. In the present study, we wanted to determine the sociodemographic (age, sex, schooling) and psychosocial correlates (meaning in life, social support, positive and negative affect) of QoL in HIV-infected patients living in Mozambique, a country with high prevalence of HIV, but also with well-structured strategies to fight the disease. To that end, we made correlational analyses followed by regression models, and we examined potential mediation processes among predictors. All correlates were relevant except sex. Meaning in life was the strongest predictor, while social support was the weakest. Schooling was both directly and indirectly related with QoL - in the latter case, it was mediated by meaning in life, social support and positive affect. Our findings suggest that investments in education may be highly rewarding to Mozambicans, and that satisfying needs of self-actualization and purpose may be more urgent than improving social connections.

Potato (Solanum tuberosum L) gradually becomes a stable food worldwide since it can be treated as practical nutritional supplement and antioxidant, as well as energy provider for human beings. Financially and nutritionally, cultivation and utility of potatoes is worthy enough attention of the world. To further explore functionality and maximize utilization of component parts, also to develop new products based on potato still be an ongoing issue. To maximize the benefits of potato and induce new high-value products while avoiding unfavorable properties of the crop has been a growing trend in food and medical areas. This review intends to summarize the factors that influence the changes in the key functional components of potatoes and discuss referred research focuses, then help further researchers to make efforts into. Afterwards, it summarizes the application of the latest commercial products and potential value of components existing in potato. Particularly, there are several main tasks for the next potato research: preparing starchy foods for special group of people and developing fiber-rich products to supply the dietary fiber intake as well as manufacturing bio-friendly and specific design films/coating in packaging industry; extracting bioactive proteins and potato protease inhibitors with high biological activity, and continue to build new commercial products based on potato protein and examine their health benefits. Noteworthy, the preservation methods play a key role in phytochemicals contents left in foods and potato performs superior to many common vegetables when meeting demand of mineral daily intake and alleviating mineral deficiencies.

Pre-exposure prophylaxis (PrEP) is a highly effective HIV prevention strategy that involves the continuous administration of antiretroviral drugs to HIV-negative individuals wit a substantial risk of contracting an HIV infection. The use of PrEP has shown a reduction in the risk of HIV acquisition through sexual intercourse by up to 99%. Despite its effectiveness, PrEP uptake remains low among populations at high risk of HIV infection. This highlights the need for further research in stratetegies to enhance awareness and uptake of PrEP amongst these specific populations

The Virus HIV-1 infection still represents a serious disease even if actually it is transformed in chronic pathology. Considering the crucial role of the enzyme Protease in life cycle of HIV many efforts have been made in the research of new organic compounds showing inhibitory activity. After development of several series of non peptidic inhibitors we report here the synthesis of novel simple HIV-Protease inhibitors containing heteroaryl carboxamides and their antiviral activity in vitro and in HEK293 cells. Benzofuryl- benzothienyl- and indolyl rings as well as aryl sulfonamides with different electronic properties have been introduced by efficient synthetic procedures. All compounds showed inhibitory activity similar to the commercial drug Darunavir, effective against both wild-type HIV-1 protease and that containing the V32I or V82A mutations. ADME properties were also evaluated, showing the potential of such compounds to be developed as drugs.

Soil enzyme activity can be affected by both production and degradation, as enzymes can be degraded by proteases. However, the impact of nutrient addition on enzyme activity is often solely attributed to changes in enzyme production without fully considering degradation. Here, we demonstrated that the activities of β-1,4-glucosidase (BG), β-D-cellobiohydrolase (CBH), β-1,4-Xylosidase (BX), and β-1,4-N-acetyl-glucosaminnidase (NAG) were comparable in nitrogen (N) and phosphorus (P) fertilized soils and the unfertilized control under field conditions, but the reduction in activity was substantially greater in the fertilized soils during short-term laboratory incubation. The results show that the interruption of the natural, continuous supply of organic matter or non-soil microbial-derived enzymes, which typically occurs under field conditions, leads to a more significant reduction in apparent enzyme activities in fertilized soils compared to unfertilized control. This may be attributed to the higher abundance of protease in fertilized soils, resulting in faster enzyme degradation. Interestingly, P fertilization alone did not have a similar effect, indicating that N fertilization is likely the main cause of the larger decreases in enzyme activity during incubation in fertilized soils compared to unfertilized control soils, despite our study site being poor in P and rich in N. These findings highlight the importance of considering enzyme degradation when investigating material dynamics in forest ecosystems, including the impact of nutrient addition on enzyme activity, as enzyme production alone may not fully explain changes in apparent enzyme activity.

Background and Objectives: HIV infection is a global public health problem that can lead to the progression of AIDS. Nutritional status and biochemical markers can significantly contribute to the progression of AIDS in HIV/AIDS patients. The main objective of this study is to examine the association between the nutritional and biochemical markers as well as BMI in HIV/AIDS patients in the kingdom of Bahrain. Methods: A retrospective cohort study, including 300 patients (248 males and 52 females) with HIV/AIDS in Bahrain. Various biochemical markers were collected from patients’ medical records including CD4^+ T cells counts, albumin, Hb, HCT, MCV, WBC, and creatinine. A semi-structured questionnaire using of a standardized food frequency questionnaire (FFQ) was used from which total energy and total macronutrients were calculate. Results: the mean BMI of participants was 27.20 kg/m2 with none of the participants had a BMI lower than 18.5 kg/m2 (underweight). The majority of patients’ dietary intake of macronutrients and total calories intake were either within or above the recommended RDA levels. The results also showed that all mean values of the nutritional and biochemical markers (CD4^+ T cells counts, albumin, Hb, HCT, MCV, WBC, and creatinine) are within the referenced normal ranges. A significant positive correlation of CD4^+ T cells counts, Hb, HCT and albumin at <0.05 level was found. There was no significant correlation between CD4^+ T cells counts and MCV, WBC and creatinine. A positive significant correlation was found between BMI, CD4^+ T cells counts, and WBC at <0.01 level. Conclusion: BMI values significantly correlated to biochemical markers of AIDS progression. Dietary pattern of participants was undiversified among participants, with high prevalence of obesity and overweight. Malnutrition among this study population was not present.

An essential metric for determining the efficacy of tuberculosis (TB) control programs is the evaluation of TB treatment outcomes. Assessing treatment outcomes is fundamental to facilitating the End TB Strategy set target. Clinic records from 457 patients with DR-TB were examined for data collection while 101 patients were followed up prospectively. Data were analyzed using Stata version 17.0. The odds ratio and 95% confidence interval were calculated to check the association between variables. P ≤ 0.05 was con-sidered statistically significant. Of the 427 participants, 65.8% had successful treatment whilst 34.2% had unsuccessful TB treatment. A total of 61.2% and 39% of the HIV-positive and HIV-negative participants had a successful TB treatment whilst 66% and 34% of both HIV-negative and positive participants had unsuccessful TB treatment. From 101 patients that were followed up, smokers had longer treatment outcomes compared to non-smokers. In the study with HIV/TB co-infection, men predominated. HIV and tuberculosis co-infection made therapy difficult with unfavorable effects on TB management. The treatment success rate (65.8%) is lower than the WHO threshold standard with a high proportion of patients lost to follow-up. The co-infection of tuberculosis and HIV resulted in undesirable treatment outcomes. Strengthening TB surveillance and control is recommended.

The Infectious and Tropical Diseases Department of University of Brescia organized free rapid screening tests for HIV and HCV as part of the Fast Track City commitment. A cross-sectional study was conducted, consisting of an anonymous, multiple-choice questionnaire that was administered to individuals who underwent the screening or consultation. The study aimed to compare knowledge and attitudes towards HIV and HCV between age groups (18-40 vs. >40) and sexual orientations (heterosexual vs. LGBTQ+). Overall, 333 questionnaires were completed. Individuals over the age of 40 and those who identified as heterosexual had the lowest level of knowledge about HIV transmission (7.9% and 30% respectively), undetectable=untransmittable (19.7% and 39.4% respectively) and PrEP (9.2% and 18.2% respectively). They were also less willing to cohabit with people with HIV (PLHIV). Only 9.6% of the population demonstrated high levels of knowledge for both HIV and HCV. People over the age of 40 had the largest gaps in knowledge and would benefit the most from educational and prevention interventions.

World Health Organization (WHO) has announced the monkeypox (MPX) epidemic a global public health emergency due to its re-emergence, remarkable increase in the number of MPX cases worldwide, and its potential spread. This paper introduces the symptoms, complications, and features of MPX; its transmission, diagnosis and testing, vaccines and treatment; MPX and sexually transmitted diseases, especially the human immunodeficiency virus (HIV); possible natural hosts or reservoirs of the monkeypox virus (MPXV). A useful tool for MPX and surgical safety recommendations are presented. The challenges in fighting the MPX epidemic, One Health strategy, and future research are discussed.

PG16 is a broadly neutralizing antibody that binds to the gp120 subunit of the HIV-1 Env protein. The major interaction site is formed by the unusually long complementarity determining region (CDR) H3. The CDRH3 residue Tyr100H is known to represent a tyrosine sulfation site; however, this modification is not present in the experimental complex structure of PG16 with full-length HIV-1 Env. To investigate the role of sulfation for this complex, we modeled the sulfation of Tyr100H and compared the dynamics and energetics of the modified and unmodified complex by atomistic molecular dynamics simulations. Our results show that sulfation does not affect the overall conformation of CDRH3, but still enhances gp120 interactions both at the site of mutation and for the neighboring residues. This stabilization affects not only protein-protein contacts, but also the interactions between PG16 and the gp120 glycan shield. Further, we also investigated whether PG16-CDRH3 is a suitable template for the development of peptide mimetics. For a peptide spanning residues 93-105 of PG16 we obtained an experimental EC50 value of 3nM for the binding of gp120 to the peptide. This affinity can be enhanced by almost one order of magnitude by artificial disulfide bonding between residues 99 and 100F. In contrast, any truncation results in significantly lower affinity, suggesting that the entire peptide segment is involved in gp120 recognition. Their high affinity makes PG16-derived peptides useful building blocks for further optimization to obtain a potent inhibitor that efficiently blocks HIV-1 infection.

There is a significant overlap between HIV infection and substance use disorders. Dopamine (DA) is the most abundantly upregulated neurotransmitter in Methamphetamine abuse, with receptors (DRD1-5) that are expressed by neurons as well as by a large diversity of cell types, including innate immune cells that are targets of HIV infection, making them responsive to the hyperdopaminergic environment that is characteristic of stimulant drugs. Therefore, the presence of high levels of dopamine may affect the pathogenesis of HIV, particularly in the brain. The stimulation of HIV-latently infected U1 promonocytes with DA significantly increased viral p24 levels in the supernatant at 24 hrs, suggesting effects on activation and replication. Using selective agonists to different DRDs, we found that DRD1 played a major role in activating viral transcription, followed by DRD4, which increased p24 with a slower kinetic. Transcriptome and systems biology analyses led to the identification of a cluster of genes responsive to DA, where S100A8 and S100A9 were most significantly correlated with the early increase of p24 levels following DA stimulation. Conversely, DA increased the expression of these genes’ transcripts at the protein level, respectively MRP8 and MRP14, which form a complex also known as Calprotectin. Interestingly, MRP8/14 was able to stimulate HIV transcription in latent U1 cells, and this occurred via binding to the receptor for advanced glycosylation end-product (RAGE). Using selective agonists, both DRD1 and DRD4 increased MRP8/14 on the surface and in the cytoplasm, as well as secreted in the supernatants. On the other hand, while DRD1/5 did not affect the expression of RAGE, DRD4 stimulation caused its downregulation, offering a mechanistic for the delayed effect via DRD4 on p24 increase. To cross-validate MRP8/14 as a DA signature with biomarker value, we tested its expression in HIV+ Meth users’ brains and peripheral cells. MRP8/14+ cells were more frequently identified in mesolimbic areas such as basal ganglia of HIV+ Meth+ cases compared to HIV+ non-Meth users or to controls. Likewise, MRP8/14+ CD11b+ monocytes were more frequent in HIV+ Meth users, particularly in participants with detectable viral load in the CSF. Overall, our results suggest that the MRP8 and MRP14 complex may serve as a signature to distinguish subjects using addictive substances in the context of HIV, and that this may play a role in aggravating HIV pathology by promoting viral replication in people with HIV who use Meth.

Background: Histoplasmosis is a systemic mycosis, present globally. We aimed to describe cases of histoplasmosis (Hc) and to establish a risk profile associated to Hc in HIV-infected patients (HIV+). Methods: This was a retrospective study of patients with a clinical-. laboratorial diagnosis of Hc. Data was fed into REDCap and statistical analysis was done with R . Results: We included 99 records, 65 HIV+ and 34 HIV-. Average age was 39 years. Median time from onset to diagnosis was 8 weeks in HIV- and 22 weeks in HIV+. Disseminated histoplasmosis occurred in 79.4% HIV+, vs 36.4% HIV-. Median CD4 count was 70. Co-infection with tuberculosis was present in 20% of HIV+. Blood cultures were positive in 32.3% of HIV+ vs 11.8% of HIV- (p=0.025); bone marrow culture was positive in 36.9% vs 8.8%(p=0.003). Most HIV+ patients (71.4%) were hospitalized. On univariate analysis, anemia, leukopenia, intensive care, use of vasopressors and mechanical ventilation were associated with death in HIV+. Conclusions: Most of our patients with histoplasmosis were HIV+, presenting advanced AIDS. Diagnosis was late in HIV+ patients, and they frequently presented disseminated Hc, required hospitalization, and died. Early screening for Hc in HIV+ and drug induced immunosuppressed patients is crucial.

The COVID-19 pandemic and associated lockdown measures have been associated with substantial disruptions to health care services, including screening for human immunodeficiency virus (HIV) and management of people living with HIV (PLWH). Methods: Data from 3265 patients were examined in a retrospective cohort study. We compared outpatient follow-up for PLWH, the number of new patients, treatment adherence, hospitalizations, and deaths during the “pandemic period” (March 2020 to February 2021) to the “pre-pandemic period” (the equivalent timeframe in 2019) and the “post-pandemic period” (March to September 2021). Results: During the pandemic period, the number of new patients seen at the HIV clinic (116), as well as the requested viral load tests (2414), decreased significantly compared to the pre-pandemic (204 and 2831, respectively) and post-pandemic periods (146 and 2640, respectively)(p<0.01 for all the comparisons). However, across the three study periods, the number of drug refills (1385, 1330, 1411, respectively), the number of patients with undetectable viral loads (85%, 90%, 93%, respectively), and the number of hospital admissions among PLWH remained constant. Conclusions: Despite the COVID-19 pandemic impact, our findings show stability in the retention of clinical care, adherence to treatment, and viral suppression of PLWH, with no significant impact on hospitalization rates and all-cause mortality.

Antiretroviral therapy has effectively suppressed HIV infection and replication and prolonged the lifespan of HIV-infected individuals. In the meantime, various complications including type 2 diabetes associated with long-term antiviral therapy have shown steady increases. Metformin has been the front-line anti-hyperglycemic drug of choice and the most widely prescribed medication for the treatment of type 2 diabetes. However, little is known about the effects of Metformin on HIV infection and replication. In this study, we showed that Metformin treatment enhanced HIV gene expression and transcription in HIV-transfected 293T and HIV-infected Jurkat and human PBMC. Moreover, we demonstrated that Metformin treatment resulted in increased CREB expression and phosphorylation, and TBP expression. Furthermore, we showed that Metformin treatment increased the recruitment of phosphorylated CREB and TBP to the HIV LTR promoter. Lastly, we showed that inhibition of CREB activation significantly abrogated Metformin-enhanced HIV gene expression. Taken together, these results demonstrated that Metformin treatment increased HIV transcription, gene expression, and production though increased CREB phosphorylation and recruitment to the HIV LTR promoter. These findings may help design the clinical management plan and HIV cure strategy of using metformin to treat type 2 diabetes, a comorbidity with an increasing prevalence, in people living with HIV.

Essential oils have demonstrated antiviral activity, but their toxicity can hinder their use as therapeutic agents. Recently, some essential oil components have been used within safe levels of acceptable daily intake limits without causing toxicity. The "ImmunoDefender," a novel antiviral compound made from a well-known mixture of essential oils, is considered highly effective in treating SARS-CoV-2 infections. The components and doses were chosen based on existing information about their structure and toxicity. Blocking the Main Protease (Mpro) of SARS-CoV-2 with high affinity and capacity is critical for inhibiting the virus's pathogenesis and transmission. In-silico studies were conducted to examine the molecular interactions between the main essential oil components in "ImmunoDefender" and SARS-CoV-2 Mpro. The screening results showed that six key components of ImmunoDefender formed stable complexes with Mpro via its active catalytic site with binding energies ranging from -8.75 to -10.30 kcal/mol, respectively for Cinnamtannin B1, Cinnamtannin B2, Pavetannin C1, Syzyginin B, Procyanidin C1, and Tenuifolin. Furthermore, three essential oil bioactive inhibitors, Cinnamtannin B1, Cinnamtannin B2, and Pavetannin C, have a significant ability to bind to the allosteric site of the main protease with binding energies of -11.12, -10.74, and -10.79 kcal/mol, These results suggest that these essential oil bioactive compounds may play a role in preventing the attachment of the translated polyprotein to Mpro, inhibiting the virus's pathogenesis and transmission. These components also had drug-like characteristics similar to approved and effective drugs, suggesting further pre-clinical and clinical studies are needed to confirm the generated in-silico outcomes.

Few studies have examined the pros and cons of integrated TB and HIV service delivery in public healthcare facilities, and even fewer have proposed conceptual models for improved integration. This study intends to fill that vacuum by outlining the development of a facility-based paradigm for integrating TB, HIV and patients services. The design of the proposed model were in stages that involved the evaluation of existing TB-HIV integration model and synthesis of both quantitative and qualitative data from the study sites which were selected public healthcare facilities at both rural and peri-urban settings in Oliver Reginald (O.R) Tambo District Municipality in Eastern Cape, South Africa. Secondary data on 2009-2013 TB-HIV clinical outcomes were obtained from multiple sources for quantitative analysis. Qualitative data involved focus group discussions among patient and heath care staff, which was thematically analysed. The development of a possibly better model and validation of this model show that the district's health system was reinforced by the model's guiding principles, which placed a strong emphasis on inputs, processes, outcomes, and integration effects.The model is adaptable to different healthcare delivery systems but will require support from healthcare stakeholders and professionals to be successful.

Background: Human papillomavirus (HPV) is responsible for most cervical cancer cases globally, with women living with HIV at higher risk of persistent HPV infection and HPV-associated disease. The HPV vaccine is a promising solution to reducing cervical cancer rates, but its uptake among women living with HIV in Nigeria is unknown. Methods: A facility-based, cross-sectional survey was conducted with 1,371 women living with HIV to assess their knowledge of HPV, cervical cancer, and the HPV vaccine, as well as their willingness to pay for the vaccine at the HIV treatment clinic, Nigerian Institute of Medical Research, Lagos. Willingness to pay for the HPV vaccine was also assessed. Multivariable logistic regression models were developed to identify factors associated with willingness to pay for the HPV vaccine. Results: The study found that 79.1% of participants had not heard of the vaccine, and only 29.0% knew of its efficacy in preventing cervical cancer. Moreover, 68.3% of participants were unwilling to pay for the vaccine, and the average amount they were willing to pay was low. Knowledge of HPV, the HPV vaccine, cervical cancer, and income were factors associated with willingness to pay for the vaccine. Health workers were the primary source of information. Conclusion: The study found that 79.1% of participants had not heard of the vaccine, and only 29.0% knew of its efficacy in preventing cervical cancer. Moreover, 68.3% of participants were unwilling to pay for the vaccine, and the average amount they were willing to pay was low. Knowledge of HPV, the HPV vaccine, cervical cancer, and income were factors associated with willingness to pay for the vaccine. Health workers were the primary source of information.

Abstract: The SARS-CoV-2 pandemic has significantly impacted world health and economic status. In response, much work has been undertaken to provide effective, safe vaccines, antibodies and antiviral drugs with which to address this pandemic. Treatment of a pandemic population presents multiple challenges in addition to the primary issue of drug efficacy and safety, such as large scale drug manufacture and distribution, drug stability, oral dosing and pharmacoeconomic considerations. Ideally, these factors must be addressed if new candidate drugs are to be advanced for treatment of large (pandemic) populations. Subsequently, new antivirals have reached the market but choices are few. According to the NIH Covid Treatment Guidelines, only three small molecule antiviral drugs are available to treat COVID-19 disease. As such, a significant part of the research towards discovery of new antiviral drugs has focused on screening and evaluation of ‘repurposed drugs’ or previously approved or clinical stage drugs. Yet, in spite of this increased research activity, one promising clinical stage candidate drug has received little attention regarding its potential as a monotherapy or component of combination therapy for treatment of COVID-19 disease. Tucaresol, with documented human safety and pharmacokinetic data, is an orally active, stable, small molecule amenable to large scale manufacture by a proprietary two-step synthesis developed by us. Tucaresol functions as a host-targeted antiviral by selective protection/reconstitution of CD4+ T helper cells as demonstrated in HIV patients and SIV macaques. In view of similarities between HIV and SARS-CoV-2, especially with respect to host CD4+ T helper cells, and the suitability of Tucaresol for facile treatment of pandemic populations, Tucaresol is presented herein for treatment of mild-to-moderate COVID-19 patients but may also be useful for treatment of advanced disease accompanied by lymphopenia.

Background: Pregnancy can be a period of increased psychological susceptibility for women living with HIV. This study aimed to determine the prevalence and factors associated with depression and psychological stress among women living with HIV during their perinatal period in Ibadan, Nigeria. Methods: This study was a facility-based cross-sectional survey conducted in three HIV treatment centers. The study population consisted of women living with HIV 18 years and above who were pregnant or had given birth within the last two years. Data obtained were analyzed using Statistical Package for Social Science version 25. Results: A total of 402 participants were eligible for this study. About 69.0% and 78.0% of the participants were depressed and had perceived stress respectively. Women who had positive partners (OR=0.60, 95% CI=0.20-1.30) were found to be significantly associated with perceived depression. Women who reported having a gestational age between 29-40 weeks (OR=0.054 95% CI = 0.006, 0.500) were found to be significantly associated with perceived stress. Factors associated with the co-occurrence of symptoms of depression and perceived stress were partner status, income level, family support, gestational age, and years on ART. Conclusions: Given the high prevalence of major depression, perceived stress, and the co-occurrence of depression and perceived stress among women living with HIV, mental health care should be incorporated into the routine maternal healthcare for all women, especially those living with HIV.

The enzymatic activities of bacterial isolates have been widely studied, but a spatial distribution of this activity is rarely focused. New antibiotic-producing microorganisms can be discovered in a more efficient manner if spatial statistical techniques are applied to the distribution of the activity of bacterial isolates in different terrains. This study is focused to generate a series of maps illustrating the spatial distribution of different soil parameters and the inhibition against relative-safe pathogens (like Escherichia coli, Staphylococcus aureus, Klebsiella pneumoniae, Salmonella, Pseudomonas fluorencens and Enterobacter cloacae) in an urban park in València (Spain). This spatial data has demonstrated a higher proportion of isolates was specifically allocated. This routine of data presentation is valuable for understanding bacterial population dynamics at a local level.

The human immunodeficiency virus 1 (HIV-1) viral protease (PR) is one of the most studied viral enzymes, and approval of drugs targeting its catalytic activity opened the door to the develop-ment of highly active antiretroviral therapy (HAART). Despite the fact that its crucial role in viri-on maturation is well characterized, an increasing body of research is starting to focus on its abil-ity to cleave host cell proteins, based on recent advances in proteomics and genomics technologies. Such findings are apparently in contrast with the dogma of HIV-1 PR activity being restricted to the interior of nascent virions, and suggest catalytic activity within the host cell environment. Given the limited amount of PR present in the virion at the time of infection, it is tempting to specu-late that such events mainly occur during viral late gene expression, mediated by newly synthe-sized Gag-Pol polyprotein precursors, rather than at a very early stage of infection, before pro-viral integration. Among cellular targets of HIV-1 PR, three major clusters can be identified: pro-teins involved in viral and cellular translation, those controlling cell survival, and restriction fac-tors responsible for innate/intrinsic antiviral responses. Indeed, by cleaving host cell translation initiation factors HIV-1 PR can impair cap-dependent translation, thus promoting IRES-mediated translation of late viral transcripts and viral production, while by targeting several apoptotic fac-tors it modulates cell survival, thus promoting immune evasion and viral dissemination. Addi-tionally, HIV-1 PR counteracts restriction factors incorporated in the virion that would otherwise interfere with nascent virus vitality. Thus, HIV-1 PR appears to modulate host cell function at dif-ferent times and locations during its life cycle, to ensure efficient viral persistency and propaga-tion. This kind of PR-mediated host cell modulation is found in a plethora of different viruses and HIV-1 is no exception, and although we are far from having a complete picture, it is clear that the PR has a multifaceted role in interfering with host machineries to better suit viral replication, and is a field that needs to be explored further.

In this review, we present several extracellular proteases, enzymes, membrane permeases, and transporters as essential accessories proteins for nutrient assimilation, conservation, and transportation as determined by nutrient repletion or depletion. As an obligate aerobic pathogen, it is crucial for invading Cryptococcus (C.) neoformans to negotiate its adaptation to human internal organs like the brain and spinal cord, where the oxygen level is low compared to peripheral organs. Besides, essential metals like copper and iron are important cofactors to functional proteins; however, these metals are not usually freely available to invading human pathogens. Again, the phagolysosome low pH with glucose paucity, internal temperature, immune response, and complex extracellular matrixes are challenging environments that must be circumvented by C. neoformans in the systemic tissues for survival, adaptation, and infection in humans. We review extensive works on several extracellular proteases, enzymes, membrane permeases and transporters orchestrated by different transcription factors and present these proteins as weapons needed to outwit systemic resistance to invading pathogens. Lastly, we examine the extracellular secretory vesicles of C. neoformans as “an exosomal virulence bag” that harbours urease, laccase, phosphatase, and capsular components as additional secretory weapons for tissue invasion and persistence.

Vaccines against SARS-CoV-2 have been pivotal in overcoming the Covid-19 pandemic yet understanding the subsequent outcomes and immunological effects remain crucial, especially for at-risk groups e.g. people living with human immunodeficiency virus (HIV) (PLWH). In this study we report the longitudinal IgA and IgG antibody titers, as well as antibody-mediated angiotensin converting enzyme 2 (ACE2) binding blockade, against the SARS-CoV-2 spike (S) proteins after 1 and 2 doses of the ChAdOx1 nCoV-19 vaccine in a population of Black PLWH. Here, we report that PLWH (N = 103) did not produce an anti-S IgA response after infection or vaccination, however, anti-S IgG was detected in response to vaccination and infection, with the highest level detected for infected vaccinated participants. The anti-IgG and ACE2 blockade assays revealed that both vaccination and infection resulted in IgG production, however, only vaccination resulted in a moderate increase in ACE2 binding blockade to the ancestral S protein. Vaccination with a previous infection results in the greatest anti-S IgG and ACE2 blockade for the ancestral S protein. In conclusion, PLWH produce an anti-S IgG response to the ChAdOx1 nCoV-19 vaccine and/or infection, and ChAdOx1 nCoV-19 vaccination with a previous infection produced more neutralizing antibodies than vaccination alone.

Rapid progress in gene editing based on clustered regularly interspaced short palindromic repeats/CRISPR-associated protein (CRISPR/Cas) has revolutionized the study of gene and genome function and genetic disease correction. While numerous genetically modified cellular and animal models have been created to understand biological processes, the clinical application of CRISPR/Cas tools has been impeded by off-targeting and delivery problems. It is generally accepted that the delivery of CRISPR in the form of a ribonucleoprotein complex (RNP) substantially reduces the time of DNA exposure to the effector nuclease, minimizing off-target effects and facilitating clinical usage. This review focuses on CRISPR/Cas RNP delivery with retro/lentiviral particles and exosomes, whose parallel production by cells transfected with viral vectors is underestimated. We critically evaluate specific mechanisms of extracellular particle formation and loading with CRISPR/Cas for each system. Additionally, the details of Cas-nanoparticle entry and uncoating, previously unappreciated in the context of gene editing efficiency, are discussed. Based on existing knowledge about the consequences of intervention in retroviral assembly, entry, or exosome formation, we outline the potential problems with CRISPR/Cas delivery using extracellular nanoparticles and ways to address them.

Proprotein convertases activate various envelope glycoproteins and participate in cellular entry of many viruses. We recently showed that the convertase furin is critical for the infectivity of SARS-CoV-2. This study investigated the implication of the two cholesterol-regulating convertases SKI-1 and PCSK9 in SARS-CoV-2 entry. We used cell-to-cell fusion assays in HeLa cells and pseudoparticle entry into Calu-3 cells. SKI-1 increases cell-to-cell fusion by enhancing the activation of SREBP-2, whereas PCSK9 reduces cell-to-cell fusion by promoting the cellular degradation of ACE2. Metalloprotease activation is sensitive to enhanced cholesterol levels resulting from SKI-1-activated SREBP-2 that leads to enhanced S2’ formation. However, high metalloprotease activity results in S2’ shedding into a new C-terminal fragment (S2”), leading to reduced cell-to-cell fusion. Indeed, S-mutants that increase S2’’ formation, abolish S2’ and cell-to-cell fusion, as well as pseudoparticles entry, indicating that the formation of S2’’ prevents SARS-CoV-2 cell-to-cell fusion and entry. We next demonstrated that PCSK9 enhanced the cellular degradation of ACE2, thereby reducing cell-to-cell fusion. However, different from the LDLR, a canonical target of PCSK9, the C-terminal CHRD domain of PCSK9 is dispensable for the PCSK9-induced degradation of ACE2. Molecular modeling suggested binding of ACE2 to the Pro/Catalytic domains of mature PCSK9. Thus, both cholesterol-regulating convertases SKI-1 and PCSK9 can modulate SARS-CoV-2 entry via two independent mechanisms.

The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has forced the development of direct-acting antiviral drugs due to the coronavirus disease 2019 (COVID-19) pandemic. The main protease of SARS-CoV-2 is a crucial enzyme that breaks down polyproteins synthesized from the viral RNA, making it a validated target for the development of SARS-CoV-2 therapeutics. New chemical phenotypes are frequently discovered in natural goods. In the current study, we used a fluorogenic assay to test a variety of natural products for their ability to inhibit SARS-CoV-2 Mpro. Several compounds were discovered to inhibit the Mpro at low micromolar concentrations. It was possible to crystallize robinetin together with SARS-CoV-2 Mpro, and the X-ray structure revealed covalent interaction with the protease's catalytic Cys145 site. Selected potent molecules also exhibited antiviral properties without cytotoxicity. Some of these powerful inhibitors might be utilized as lead compounds for COVID-19 research.

Globally, non-communicable diseases like hypertension are on the rise, existing concurrently with the human immunodeficiency virus (HIV) in populations, especially those in low- to middle-income countries. The introduction of antiretroviral treatment (ART) for people living with HIV was welcomed with great enthu-siasm across populations. A cross-sectional study of 100 purposively selected adult participants on an-tiretroviral treatment living in the OR Tambo district was conducted to determine factors associated with treatment outcomes among patients living with HIV and hypertension comorbidity. The data was analyzed using the Statistical Package for Social Sciences, with a p-value of 0.05 considered significant. A total of 86% of the female population, with a mean age of 39.76, was studied. Participants with improved viral load and CD4 cell count after initiation of ART increased from 63% to 68% and 74% to 90%, respectively whilst viral load suppression increased from 45.1% to 90.2%. Hypertension post-ART initiation increased from 9% to 34%, exacerbated by smoking (12%), alcohol (14%), vegetable consumption (39%), skipping breakfast (50%), sugar use (62%), and vigorous physical activity (12%). The onset of hypertension was linked to the start of ART, and risky behaviors influenced treatment outcomes. Primordial prevention, like strong health promotion inter-ventions for risk factors, is needed to improve life expectancy.

HIV-1, like other viruses, represents an open thermodynamic system. This is why it is important to know its thermodynamic properties. Virus-host interactions are performed at the membrane as antigen-receptor binding. Antigen-receptor binding represents a chemical reaction, similar to protein-ligand interactions. The driving force for antigen-receptor binding is Gibbs energy of binding. Knowing Gibbs energy of binding, it is possible to estimate the rate of virus binding and entry into host cells. In this paper, binding equilibrium constants and standard Gibbs energies of binding between the HIV-1 gp120 antigen and the CD4 receptor have been reported at 4°C, 22°C and 37°C.

Abstract: Tuberculosis (TB) and human immunodeficiency virus (HIV) epidemics in South Africa have been closely related and persistent, posing a significant burden for healthcare provision. We explored the patients perspectives on challenges and barriers of scaling up TB and HIV integrated services. A descriptive cross-sectional study applying a qualitive research approach was used. Through focus group discusssions (FGDs), we interviewed 29 patients accessing TB and HIV services at the study sites which were selected at primary health care (PHC) clinics in the O.R Tambo district in Eastern Cape, South Africa. Anonymised data was analysed using both content and thematic analysis technique. Challenges and barriers identified included a lack of health education about TB and HIV; an inadequate counselling for antiretroviral drugs (ARVs) and HIV; a lack of awareness of the National TB control program; and poor quality of services provided by the health care facilities. These findings suggest that the O.R. Tambo district needs to strengthen its TB-HIV integration immediately. Keywords: TB-HIV integration; Challenges and barriers; Patients; O.R Tambo District; Eastern Cape; South Africa

TB and HIV continue to increase and constitute major public health concerns worldwide, mainly in resource-limited countries, showing that we are not going to end HIV if we do not also end TB. Herein, we investigated the risk factors related to HIV infection among TB patients in Luanda, the capital city of Angola. This was a retrospective cohort study conducted on the medical records of 117 TB patients from January to September 2016. Overall, the HIV/TB co-infection rate was 12%. The mean age of coinfected patients was 37.7±10.1 years. No statistically significant relationship was observed between sociodemographic or clinical features with HIV/TB co-infection (p>0.05). TB patients aged 30 years or older (OR: 4.13, p=0.072), female (OR: 1.08, p=0.898), residing in urbanized areas (OR: 1.90, p=0.578), with a history of treatment abandonment (OR: 3.74, p=0.083), with polyresistance (OR: 1.62, p=0.603), and MDR-TB (OR: 2.00, p=0.454), were more likely to have HIV/TB co-infection, while latent TB infection (OR: 0.63, p=0.559) and treatment-susceptible TB patients (OR: 0.56, p=0.616), presented a lower chance of HIV/TB coinfection. Our finding showed a slightly high HIV/TB coinfected rate, which suggests that the dual HIV/TB epidemic keeps evolving and poses a huge concern to the public health in Angola. Further studies on features related to HIV/TB coinfection and its impact on disease progression and clinical outcome in adults from high-risk Angolan communities, should be carried out to intensify and strengthen collaborative activities between national TB and HIV programs in Angola.

At the end of 2019, while the world was being hit by the COVID-19 virus and, consequently, was living a global health crisis, many other pandemics were putting humankind in danger. The role of social media is of paramount importance in these kinds of contexts since they help health systems to cope with emergencies by contributing to conducting some activities such as the identification of public concerns, the detection of infections’ symptoms, and the traceability of the virus diffusion. In this paper, we have analyzed comments on events related to cholera, ebola, HIV/AIDS, influenza, malaria, Spanish influenza, swine flu, tuberculosis, typhus, yellow fever, and zika, collecting 369,472 tweets from the 3rd of March to the 15th of September, 2022. Our analysis has started with the collection of comments composed of unstructured texts on which we have applied natural language processing solutions. Afterward, we have employed topic modelling and sentiment analysis techniques to obtain a collection of people’s concerns and attitudes toward these pandemics. According to our findings, people's discussions were mostly about malaria, influenza, and tuberculosis and the focus was on the diseases themselves. As regards emotions, the most popular were fear, trust, and disgust where trust is mainly regarding HIV/AIDS tweets.

In this paper mathematical analysis of the HIV/AIDS deterministic model exposed in [Espitia, C. et. al. Mathematical Model of HIV/AIDS Considering Sexual Preferences Under Antiretroviral Therapy, a Case Study in San Juan de Pasto, Colombia, Journal of Computational Biology 29 (2022) 483–493] is made. The objective is to gain insight into the qualitative dynamics of the model determining the conditions for the persistence or effective control of the disease in the community through the study of basic properties such as positiveness and boundedness, calculus of basic reproduction number, stationary points such as disease free equilibrium (DFE), boundary equilibrium (BE) and endemic equilibrium (EE) are calculated, local stability (LAS) of disease free equilibrium. It research allow to conclude that the best way to reduce contagion and consequently to reach a DFE is thought to be the reduction of homosexual partners rate as they are the most affected population by the virus, and are therefore the most likely to become infected and to spread the infection. Increasing the departure rate of infected individuals, leads to a decrease in untreated infected heterosexual men and untreated infected women.

The Centers for Disease Control and Prevention recommends everyone between 13-64 years be tested for HIV at least once as a routine procedure. HIV routine screening is reimbursable by Medicare, Medicaid, expanded Medicaid, and most commercial insurance plans. Yet, scaling-up HIV routine screening remains a challenge. We conducted a scoping review for studies on financial benefits and barriers associated with HIV screening in clinical settings in the U.S. to inform an evidence-based strategy to scale-up HIV routine screening. We searched Ovid MEDLINE®, Cochrane, and Scopus for studies published between 2006 - 2020 in English. The search identified 383 Citations; we screened 220 and excluded 163 (outside the time limit, irrelevant, or outside the U.S.). Of the 220 screened articles, we included 35 and disqualified 155 (did not meet the eligibility criteria). We organized eligible articles under two themes: financial benefits/barriers in healthcare settings (9 articles); and Cost-effectiveness in healthcare settings (26 articles). The review concluded recommendations in three areas: (1) Finance: Incentivize healthcare providers/systems for implementing HIV routine screening and/or separate its reimbursement from bundle payments; (2) Personnel: Encourage nurse-initiated HIV screening programs in primary care settings and educate providers on CDC recommendations; and (3) Approach: Use opt-out approach.

Background: Sexualized substance use (SSU) is the practice of psychotropic substance usage, before or during sexual intercourse in order to increase sexual pleasure and arousal. It has a strong association with sexually transmitted infections (STIs). The present study aimed to assess the knowledge gaps regarding SSUs among the community health mobilizers by interviewing them regarding their knowledge, attitudes, and practices through qualitative approach. Methodology: In-depth interviews (IDIs) were conducted with a total of nineteen community health mobilizers engaged in counselling of sexualized substance users. A semi-structured open-ended questionnaire with socio-demographic information and probes related to SSU was administered. Informed consent was taken from each participant prior to data collection. Results: Gender-wise distribution indicated that 47% of the community mobilizers are men, followed by transgender persons (32%), and women (21%). Responses of participants highlighted that alcohol consumption was the most observed form of SSU. The findings indicated that drug administration through injection was most common, followed by sniffing and swallowing. Sources of drug pro-curement enlisted by participants included peddlers, peer groups, sexual parties, medical and liquor stores. Only 63% of participants had fair knowledge about STIs such as HIV, viral hepatitis, syphilis, and gonorrhoea. All were familiar with the administration of naloxone injections and the locations of nearby hospitals where patients could be transported in the event of an overdose. Conclusions: The in-depth interviews among the study participants reflected substantial know-ledge gaps related to various areas associated with SSU, which highlights the need for periodic workshops and training for upgradation of existing knowledge and practices among community health mobilizers. This will help to broaden their knowledge of different types of SSUs, the latest substances of abuse, the diseases caused by high-risk sexual practices, and additional health and psychological issues associated with SSUs, which would ultimately help in better counseling and management of sexualized substance users. It may also play a crucial role in the strengthening of capacity-building systems and engagements at the community level. This study may be used as formative research by researchers and policy makers to develop study protocols for multi-centric community-based studies among community health mobilizers and sexualized substance users across the country for further validation and exploration.

Africa is expected to have a lion’s Share in the world’s population growth by 2050. At the same time, the World Health Organisation (WHO) reported that roughly 3.4 percent (1/25) of African adults live with HIV making the contient the most severely affected by the HIV pandemic. Consequently, this study, the first of its kind, investigates the impact of population growth and HIV incidence on economic growth and economic development in Africa by utilizing the Pooled Mean Group (PMG) estimator on data from 1990 to 2020 across 29 countries. The results show that population growth has a postive long run impact on Gross Domestic Product (GDP) but has a negative long run impact on per capita GDP, albeit the effects are insignificant in the short run. The incidence of HIV has a negative long run impact on both GDP and per capita GDP although its effect is not significant in the short run. The study, therefore, calls for the advancement of family planning practices and the usage of contraceptives to simultaneously control population growth and curb the spread of HIV incidence. The study futher calls for African governments to increase budgetary allocations to the health and education sectors, as these policy perspectives have the potential of increasing the human capital stock and at the same time enhancing the health status of the work force for sustained growth and development.

People with HIV (PWH) experience higher rates of cardiovascular events (CVEs) compared with the general population. A substantial body of evidence supports that select biomarkers of inflammation (soluble CD14 [sCD14], soluble CD163 [sCD163], highly sensitive C-reactive protein [hs-CRP], interleukin-6 [IL-6]), and coagulation (D-dimer) are elevated in PWH and related to increased rates of CVEs. Our previous work showed that smoking compared with nonsmoking was associated with significantly elevated sCD14, a biomarker of monocyte activation. We aimed to explore the effect of electronic cigarette (EC) provision on inflammatory biomarkers in PWH who smoked daily and then switched to an EC. Nineteen PWH were enrolled in a pilot study in which an EC and e-liquid were provided weekly or 8 weeks. Blood specimens for inflammatory biomarker analysis were obtained at baseline (BL) and at week 8. Biomarker levels were high at BL and did not differ significantly at week 8. There were small nonsignificant reductions in sCD163 and CRP levels. Non-significant increases in IL-6, D-dimer and sCD14 levels were also noted. Use of ECs for 8 weeks does not appear to significantly increase or decrease inflammatory biomarker levels in SWH. Further research with larger samples and a control group is needed.

Medium-Long term impacts of Antiretroviral drugs on arterial blood pressure in people living with HIV in Malawi.SAGNO Jean Bpatiste², Loenardo Palombi¹ , Giuseppe Liotta¹, Victor T Tolno², Sangare H Mamary², Jere Haswel ².1= University of Tor vergata Roma, 2= Dream Health center MalawiKey Words: HIV, hypertension ABSTRACTIntroduction: We aimed to explore the medium-long term impacts of Anti-Retroviral Treatment (ART) on Hypertension in a sample of HIV-positive in Malawi. Methodology: This was a retrospective case control study carried out at DREAM health Centre in Blantyre/Malawi on patients who were enrolled from 2005 to 2019, Information about age, gender, blood pressure, ART regimen, BMI, CD4 count, Viral load, Biochemistry, hemoglobin, marital status, education level, survival and period on ARVs were retrieved from data base from 01/01/2006 to 31/12/2015.. In total, we enrolled (alive and on HAART)1350 patients > 18 years (mean age: 43.4 and the SD was ±10.7 with 1031 (65.9%) females and 534 (34.1%) males who were taking (or have taken) ARVs for more than 6 months at the date of enrollment and who were not affected by hypertension or potentially related diseases like Renal failure at the enrollment. The mean observation time, from the HAART initiation was 77 months per person (SD±40). Results: The sample was made up by two groups of patients, 675 who developed hypertension and 675 who did not, with similar age and gender composition. Among patients with hypertension, 30/675 (4.4%) developed a stage 3 hypertension, 154 a stage 2 (22.8%) and 491 a stage 1 (72.8%). Hypertension stages were not associated to statistic significant differences of age and/or gender ( p=0.422, p=0.281 respectively). At baseline, patients who developed hypertension showed higher hemoglobin, higher CD4 count and lower VL ( P<0.001). Patients on AZT-based regimen and TDF based regimen were at high risk to develop hypertension while PI-based regimen was protective to hypertension (P<0.001). In a multivariate analysis, factors independently associated to Hypertension were higher CD4 count and Body Mass Index at the visit date, while Baseline Viral Load and PI-Including regimes were protective factors. Education level was inversely associated with risk of hypertension, while being married was associated of risk of hypertension (p<0.001). Mortality rate among hypertensive patients was 1.6% for those treated for hypertension against the 3.6% for those not treated. Conclusion: this study shows a protective action of PI-including regimens compared with AZT based regimen that is associated to an increased risk of hypertension. Factors related to a better general health status are associated to an higher risk of hypertension as well as lower education, older age and male gender. Treatment should be started as soon as Hypertension stages 2-3 are reached and control by behavioral factors is no longer effective.

Mutations within the hepatitis B virus (HBV) genome have been associated with rapid progres-sion to hepatocellular carcinoma (HCC); however, there is limited information regarding the prevalence and impact of these mutations in most of sub-Saharan Africa, including Botswana. We aimed to determine the prevalence of HBV mutations known to be associated with progression to HCC using a retrospective, cross-sectional analysis of 48 previously generated HBV sequences from adults with concomitant HBV/HIV initiating HIV antiretroviral therapy in Botswana. The sequences were aligned with reference sequences, and HCC-associated mutations were manually identified using BioEdit. Sixteen (33.3 %) of 48 participant samples had 20 HCC-associated mu-tations. Seven HCC mutations were present in the core region, 4 in the preCore region, 7 in the X region, and one mutation in the surface region, as well as deletions within the preSurface 1 region. Seven of the 16 participants (43.8%) had multiple HCC-associated mutations. There were also previously uncharacterized mutations at positions with known HCC-associated mutations. HCC-associated mutations were common in this cohort; hence, some participants may require close clinical monitoring as they might be more prone to rapid disease progression. Other functionally uncharacterized polymorphisms were also detected and require characterization in future studies.

Young people living with perinatal infections of Human Immunodeficiency Virus (YLPHIV) face a chronic disease, with treatment including adherence to life-long antiretroviral treatment (ART). The aim of this QES was to explore adherence to ART for YLPHIV as an assemblage within the framework of the BPS model with a new materialist perspective. We searched up to November 2021 and followed the ENTREQ and Cochrane guidelines for QES. All screening, data extraction and critical appraisal was done in duplicate. We analysed and interpreted the findings innovatively, by creating images of meaning, a storyboard, and storylines. We then reported the findings in a narrative first person story. We included 47 studies and identified 9 storylines. We found that treatment adherence has less to do with humans’ preferences, motivations, needs and dispositions, and more to do with how bodies, viruses, things, ideas, institutions, environments, social processes, and social structures assemble. This QES highlights that adherence to ART for YLPHIV is a multisensorial experience in a multi agentic world. Future research into rethinking the linear and casual inferences we are accustomed too in evidence-based health care is needed if we are to adopt multidisciplinary approaches to address pressing issues such as adherence to ART.

Cerebrospinal fluid (CSF) viral escape has been poorly described among people with HIV-associated cryptococcal meningitis. We determined the prevalence of CSF viral escape and HIV-1 viral load (VL) trajectories in individuals treated for HIV-associated cryptococcal meningitis. A retrospective longitudinal study was performed using paired CSF and plasma collected prior to and during the antifungal treatment of 83 participants recruited at the Botswana site of the phase-3 AMBITION-cm trial (2018-2021). HIV-1 RNA levels were quantified then CSF viral escape (CSF HIV-1 RNA ≥ 0.5 log10 higher than plasma) and HIV-1 VL trajectories were assessed. CSF viral escape occurred in 20/62 (32.3%; 95% confidence interval [CI]: 21.9%-44.6%), 13/52 (25.0%; 95% CI: 15.2%-38.2%) and 1/33 (3.0%; 95% CI: 0.16%-15.3%) participants at days 1, 7 and 14 respectively. CSF viral escape was significantly lower on day 14 compared to days 1 and 7, p=0.003 and p=0.02, respectively. HIV-1 VL de-creased significantly from day 1 to day 14 post antifungal therapy in the CSF but not in the plasma (OR, 0.56; 95% CI: 0.41-0.77; p<0.001). CSF viral escape is high among individuals presenting with HIV-associated cryptococcal meningitis; however, antifungal therapy may reverse this, highlighting the importance of rapid initiation of antifungal therapy in these patients.

HIV-1 protease (PR) is a viral enzyme that cleaves viral polyprotein precursors to convert them into functional forms, a process essential to generate infectious viral particles. Due to its broad substrate specificity, HIV-1 PR can also cleave certain host cell proteins. Several studies have identified host cell substrates of HIV-1 PR and described the potential impact of their cleavage on HIV-1-infected cells. Of particular interest is the interaction between PR and the caspase recruitment domain-containing protein 8 (CARD8) inflammasome. While PR typically has low levels of intracellular activity prior to viral budding, induction of premature PR activation to trigger CARD8-mediated cell killing may help eliminate latent reservoirs in people living with HIV. In this review, we discuss the viral and host substrates of HIV-1 protease and highlight potential applications and advantages of targeting CARD8 sensing of HIV-1 PR.

PrEP uptake in the Netherlands is growing but remains at suboptimal levels. Hence, the analysis of hurdles is paramount. Given the initial focus of PrEP provision among men-who-have-sex-with-men (MSM) via a demonstration project that was launched in June 2015, AmPrEP in Amsterdam, and pharmacies in the main urban areas (so called “Randstad”, entailing Amsterdam, Utrecht, Leiden, The Hague and Rotterdam), investigating regional differences is necessary. This study seeks to unravel regional differences jointly with psycho-social determinants of PrEP uptake. This cross-sectional study included 3,232 HIV-negative Dutch MSM recruited via the EMIS survey in late 2017. Prevalence and standardized prevalence ratio (SPR) of PrEP awareness, intention and uptake were measured on a regional level (Randstad vs. the rest of the country). Multilevel logistic modelling was conducted to identify the association of PrEP uptake with PrEP awareness and intention, sociodemographic, psycho-social determinants, and random effects from regional differences. MSM from the Randstad used more PrEP (SPR=1.4 vs. 0.7) compared to the rest of the country, but there were minor differences for awareness and intention. The regional distinction was estimated to explain 4.6% of the PrEP use variance. We observed a greater influence from PrEP intention (OR=4.5, 95%CI 2.0-10.1), while there was limited influence from the awareness of PrEP (OR=0.4, 95%CI 0.04-4.4). Lower education (OR=0.4, 95%CI 0.2-0.9) was negatively associated with PrEP uptake, however, no significant difference was found between middle and high education (OR=1.2, 95%CI 0.7-2.0). We showed that regional differences – MSM in non-urban regions – and other psycho-social determinants account for lower PrEP uptake. Based on these findings, more fine-tuned PrEP access with a focus on non-urban regions can be implemented, and tailored campaigns increasing intention/use can be conducted among target populations.

Introduction. Self-sampling has the potential to increase cervical cancer screening (CCS) among women living with HIV (WLWH) in low and middle-income countries (LMICs). However, our understanding of how HPV self-collection studies have been conducted in WLWH is limited. The purpose of this scoping review was to examine the extent to which the HPV self-sampling has been applied among WLWH in LMICs. Method: We conducted multiple searches in several databases for articles published between 2000 and January 2022. With the combination of keywords relating to HPV self-sampling, LMICs, and WLWH, we retrieved over 9,000 articles. We used pre-defined inclusion and exclusion criteria to select relevant studies for this review. Once a study met the inclusion criteria, we created a table to extract each study’s characteristics and classified them under common themes. We used a qualitative descriptive approach to summarize the scoping results. Results: A total of 12 articles were included in the final review. Overall, 3,178 women were enrolled in those studies and 2,105 (66%) of them were WLWH. The self-sampling participation rate was 92.6%. The findings of our study show that 43% of the WLWH in 8 of the studies reviewed tested positive for high-risk HPV (hr-HPV) genotypes, indicating 4 out of 10 WLWH in the studies are at risk of cervical cancer. The prevalence of the hr-HPV in WLWH was 18% higher than that of HIV-negative women. Most women in the study found the self-sampling experience acceptable, easy to use, convenient, and comfortable. Self-sampling performance in detecting hr HPV genotypes is comparable to clinician-performed sampling. However, limited access (i.e., affordability, availability, transportation), limited knowledge about self-screening, doubts about the credibility of self-sampling results, and stigma remain barriers to wide acceptance and implementation of self-sampling. In conclusion, the findings of this review highlight that (a) cervical cancer is a threat to every sexually active woman but for WLWH the threat increases, (b) self-sampling laboratory performance is similar to clinician performed sampling, (c) self-sampling is associated with an increase in cervical cancer screening uptake and (d) WLWH reported a positive experience with self-sampling. However, personal, environmental, and structural barriers challenge the application of self-sampling in LMICs, and these need to be addressed. Keywords: keyword 1; keyword 2; keyword 3 (List three to ten pertinent keywords specific to the article yet reasonably common within the subject discipline.)

Introduction: Established predictors for COVID-19 related mortalities are diverse, with cytokine release syndrome (CRS), a key intermediator to the case fatalities being dominant and multi-faceted. The impact of these several risk factors on coronavirus mortality have been previously reported in several meta‐analyses limited by small sample sizes and premature data, and CRS not fully being accounted for. The objective of this systematic review and meta-analysis was to evaluate the evidence on the risk of COVID-19 related CRS and mortality with HIV serostatus using published data, and a meta-regression to account for possible covariates. Method: Electronic databases including Google Scholar, Cochrane Library, Web of Sciences (WOS), EMBASE, Medline/PubMed, COVID-19 Research Database, and Scopus, were systematically searched till 30th February, 2022. All human studies were included irrespective of publication date or region. Twenty-two studies with a total of 19,783,097 patients detailing COVID-related mortality and eleven with a total of 2,005,274 were included. To pool the estimate, a random-effects model with risk ration as the effect measure was used. Moreover, publication bias and sensitivity analysis were evaluated followed by meta-regression. The trial was registered (CRD42021264761) on the PROSPERO register. Results: The findings were consistent in stating the contribution of HIV infection for COVID-19 related CRS and mortality. The cumulative COVID-19 related mortality and CRS was 110270 (0.6%) and 48863 (2.4%) with total events of 2010 (3.6%), 108260 (0.5%) and 837(4.6%), 48026 (2.4%) among HIV-positive and negative persons respectively. HIV infection showed an increased risk of COVID-19 related CRS and mortality [RR= 1.48, 95% CI (1.16, 1.88) (P=0.002)] and [RR =1.19, 95% CI (1.02 -1.39) (P=0.00001)] respectively, both with substantial heterogeneity (I² > 80%). The true effects size in 95% of all the comparable populations fell between 0.64 to 2.22 and 0.67 to 3.29 for mortality and CRS respectively. MC studies and COVID-19 mortality with HIV infection showed a significant association [RR = 1.305, 95% CI (1.092 -1.559) (P = 0.003)], similar to studies conducted in America (RR = 1.422, 95% CI 1.233–1.639) and South Africa (RR = 1.123, 95% CI 1.052–1.198). HIV infection showed a risk for ICU admission [(P=0.00001) (I² = 0%)] and mechanical ventilation [(P=0.04) (I² = 0%)] as parameters of CRS. Furthermore, risk of COVID-19 related CRS is influenced by the year a study was conducted (R² = 0.55) and the region (R² = 0.11) same for mortality (R² = 0.60). The variance proportion explained by covariates was significant for CRS (I² = 86.5%, Q = 73.99, df = 10, P = 0.0000) (R² = 0.78) and mortality (I² = 87.5%, Q = 168.02, df = 21, p = 0.0000) (R² = 0.67). Conclusion: Our updated meta-analysis indicated that HIV infection was significantly associated with an increased risk for both COVID-19 – CRS and mortality, which might be modulated by regions, study setting and year. Risk for ICU admission and mechanical ventilation are the key indicators of CRS. We believe the updated data further anchoring CRS will contribute to more substantiation of the findings reported by similar earlier studies (Dong et al., 2021; K. W. Lee et al., 2021; Massarvva, 2021; Mellor et al., 2021; Ssentongo et al., 2021)

Proteases or peptidases are hydrolases that catalyze the breakdown of polypeptide chains into smaller peptide subunits. Proteases exist in all life forms, including archaea, bacteria, protozoa, insects, animals, and plants, due to their vital functions in cellular processing and regulation. There are several classes of proteases in the MEROPS database based on their catalytic mecha-nisms. This review focuses on the post-proline cleaving enzymes (PPCEs), especially the prolyl endoprotease/oligopeptidase (PEP/POP). To date, most PPCEs studied are of microbial and ani-mal origins. Recently, there are reports of new plant PPCEs. The most common PEP/POP are members of the S9 family that comprise two conserved domains. The substrate-limiting β-propeller domain prevents unwanted digestion, while the α/β hydrolase catalyzes reaction at the carboxyl-terminal of proline residues. PPCEs have diverse applications, are widely used in the beer brewing industry, and have potential as therapeutic agents for Alzheimer’s disease and celiac disease by targeting proline-rich substrates. Protein engineering via mutagenesis has been performed to improve heat resistance, pepsin-resistant capability, specificity, and protein turno-ver of PPCEs for pharmacological applications. This is the first comprehensive review to cover the biotechnological applications of PPCEs and discuss the unique prolyl cleaving activity of dif-ferent enzymes based on the recent structure-function studies from diverse taxa.

Since the outbreak of COVID-19, one of the strategies used to search for new drugs has been to find inhibitors of the main protease (Mpro) of virus SARS-CoV-2. Initially, previously reported inhibitors of related proteases like the main proteases of SARS-CoV and MERS-CoV were tested. Then a huge effort has been done by the scientific community to design, synthesize and test new small molecules acting as inactivators of SARS-CoV-2 Mpro. From the structure view, these compounds can be classified into two main groups: one corresponds to modified peptides displaying an adequate sequence for high affinity and a reactive warhead, and the second one is a diverse group including chemical compounds which do not have a peptide framework. Although a drug including a SARS-CoV-2 main protease has already been commercialized, denoting the importance of this field, more compounds have been demonstrated to be promising potent inhibitors as potential antiviral drugs.

The COVID-19 pandemic affects all parameters, especially health care professionals, drugs and medical supplies. The KERRA is a mixed medicinal plant capsule that is used for the treatment of patients with high fever with food and drug administration approved by FDA Thailand. Recently, KERRA showed quicker recovery for COVID-19 patients. Therefore, it is possible that some ingredients in KERRA could inhibit SARS-CoV-2. In this study, two important replication-related enzymes in SARS-CoV-2, a main protease and an RNA-dependent RNA polymerase (RdRp), were used to study the effect of KERRA. The results showed that KERRA inhibited the SARS-CoV-2 main protease and SARS-CoV-2 RdRp with IC50 values of 49.91 ± 1.75 ng/mL and 36.23 ± 5.23 µg/mL, respectively. KERRA displayed no cytotoxic activity on macrophage cells at concentrations lower than 1 mg/mL and exhibited anti-inflammatory activity. Additionally, KERRA was against a feline coronavirus (feline infectious peritonitis [FIP]) infection with an EC50 value of 134.3 g/mL. This study supports the potential use of KERRA as a candidate drug for COVID-19.

Despite intensive HIV education and prevention efforts in the past years, stigmatizing attitudes toward people living with HIV (PLWH) remain a major barrier to HIV prevention and treatment efforts in Vietnam. The purpose of this study was to examine the prevalence of stigmatizing attitudes regarding HIV and identifying correlative factors that impact perceptions of PLWH among women migrant workers working in the industrial zones (IZ) in Hanoi, Vietnam. A cross-sectional study was conducted among 1061 women migrant workers aged 18 to 29 from January to November 2020 in Hanoi, Vietnam. Stigmatizing attitudes toward PLWH were measured using a four-item scale. Multiple logistic regression was conducted to examine factors associated with stigmatizing attitudes. Over seventy-six (76.2 %) of the participants reported having at least one of the four stigmatizing attitudes. Greater levels of stigmatizing attitudes toward PLH were significantly associated with lower HIV knowledge, lower education and being Kinh (the ethnic majority in Vietnam). A high level of stigmatizing attitudes toward PWH among the study participants suggests that there is an urgent need for the development of appropriate culturally interventions and outreach education activities to reduce stigmatizing attitudes toward PWH among women migrant workers working in the IZs in Vietnam.Despite intensive HIV education and prevention efforts in the past years, stigmatizing attitudes toward people living with HIV (PLWH) remain a major barrier to HIV prevention and treatment efforts in Vietnam. The purpose of this study was to examine the prevalence of stigmatizing attitudes regarding HIV and identifying correlative factors that impact perceptions of PLWH among women migrant workers working in the industrial zones (IZ) in Hanoi, Vietnam. A cross-sectional study was conducted among 1061 women migrant workers aged 18 to 29 from January to November 2020 in Hanoi, Vietnam. Stigmatizing attitudes toward PLWH were measured using a four-item scale. Multiple logistic regression was conducted to examine factors associated with stigmatizing attitudes. Over seventy-six (76.2 %) of the participants reported having at least one of the four stigmatizing attitudes. Greater levels of stigmatizing attitudes toward PLH were significantly associated with lower HIV knowledge, lower education and being Kinh (the ethnic majority in Vietnam). A high level of stigmatizing attitudes toward PWH among the study participants suggests that there is an urgent need for the development of appropriate culturally interventions and outreach education activities to reduce stigmatizing attitudes toward PWH among women migrant workers working in the IZs in Vietnam.

HIV-associated neurocognitive disorder (HAND) is an array of neurocognitive changes associated with HIV infection, and the roles of microRNAs in HAND are not completely revealed yet. Based on published data and publicly available databases, we constructed an integrated miRNA-mRNA network involved in HAND. Bioinformatics analyses, including gene ontology, network analysis, and KEGG pathway analysis, were applied for further study of the network and the genes of the network. The axon guidance KEGG pathway, three genes NTNG1, EFNB2, CXCL12, and 17 miRNAs which regulates them, are spotlighted in our study. This study provides new perspectives to the knowledge of miRNAs’ roles in the process of HAND, and our findings provided potential therapeutic targets and clues of HAND.

HIV-1 Nef is a multifunctional protein with well-known lethal properties. HIV infects various cells from the brain compartment and expressed nef is responsible for developing neuropathogenic potential. HIV-infected glial cells express nefvirotoxinand stimulate the cascade of various pathways to activate uninfected cells to release neurotoxic elements damaging cells themselves. A lot of genetic variabilities of this protein have been reported from patients with HIV-associated neurocognitive disorders. To determine the neurotoxic potential of subtype-specific nef plasmids and nef plasmids of clinical samples with and without HAND were transfected in normal human astrocytes (NHA) and monocyte-derived macrophages (MDM) using nef-pCMV-HA plasmid constructs. Supernatants from subtype-specific Nef plasmids indicated the upregulation of proinflammatory cytokines. The induced expression might be due to the nef genetic variability or variations in the transfection efficiency and expression levels of nef.The mRNA expression of IL-6, IP-10, and TNF-α indicated upregulation of 5.0-fold in NHA and 3-fold in MDM with respect to empty vector control transfection. Further, the kynurenine metabolites were also assessed from culture supernatants of NHA and MDM indicating the upregulation of IDO and KYNU in NHA by 3.0-fold and 3.2-fold in MDM.The expression levels of nef and cytokines at the translational level were confirmed by western blotting and bio-plex Pro cytokine estimation assay respectively along with controls expressing green fluorescent protein (GFP).The oxidative stress was also found to be elevated as compared to control cells as determined by the estimation of nitric oxide from the culture supernatant to confirm the neurotoxic potential of HIV nef plasmids. The downregulation in the levels of cytokines, as well as kynurenine metabolites, was observed in culture supernatants after blocking the expression of nef using HIV nef siRNA. Phylogenetic analysis of Nef sequences indicated subtype C predominance except one sequence showing the partial sequence of HIV-1 subtype B sequence forming BC recombinantThe upregulation in the cytokine and pathway-specific metabolites might be linked with the neurotoxic potential of HIV-1 Nef leading to neuropathogenesis. In conclusion, the variation in the transfection efficiency, nef expression levels, and the genetic variability of Nef might be responsible for upregulating the expression levels of cytokines and kynurenine metabolites in astrocytes and MDM.

Improving access to sexual health services is critical in light of rising sexually transmitted infections (STIs). We evaluated a Hub and Spoke model for improving access to sexual health services in three general practices in Victoria, Australia. The primary outcome was the impact on HIV and STI (chlamydia, gonorrhoea, syphilis) testing. Segmented linear regression analysis was conducted to examine the trends in the total HIV/STI tests before (from January 2019 to June 2020) and post-implementation (from July 2020 to July 2021). We evaluated the feasibility and acceptability of integrating this model into the general practices using semi-structured individual interviews. There was a statistically significant rise in testing for HIV and STIs in all general practices: post-implementation, there was an increase of an average of 11.2 chlamydia tests per month (p=0.026), 10.5 gonorrhoea tests per month (p=0.001), 4.3 syphilis tests per month (p=0.010), and 5.6 HIV tests per month (p=0.010). Participants reported increases in knowledge level and confidence in offering STI testing and managing more variety of sexual health cases. This study demonstrated the feasibility of implementing a hub and spoke model to enable GPs to deliver sexual health care with support from a sexual health specialist service.

Background: Objectives were to determine the real-life effectiveness and safety of DT with dolutegravir (50 mg/QD) plus lamivudine (300 mg/QD) in multiple-tablet regimen (MTR) in naïve PLHIV followed up for 48 weeks and to evaluate the compliance and satisfaction of patients. Material and methods: Open, single-arm, multicenter, non-randomized clinical trial from May 2019 through September 2020 with 48-week follow-up. Results: The study included 88 PLHIV (91% male) with mean age of 35.9 years; 76.1% were MSM. Mean baseline CD4 was 516.4 cells/uL, with viral load (VL) of 104,828 cop/mL, and 11.4% were in AIDS stage. DT started within 7 days of first specialist consultation in all patients and the same day in 84.1%; 3.4% had baseline resistance mutations (K103N, V106I+E138A, and V108I); 12.5% were lost to follow-up. At week 48, 86.3% had VL< 50 cop/uL by intention-to-treat analysis and 98.7% by per-protocol (PP) analysis. Virological failure (VF) was recorded in 1.1%, with no resistance mutation. One blip was detected in 5.2%, without VF. Three reported anxiety, dizziness, and cephalgia, respectively, at week 4 and one insomnia at week 24; none reported adverse events at week 48. Mean weight was 4 kg higher at 48 weeks (p=0.0001) and abdominal circumference 3 cm larger at 24 weeks (p=0.022). No forgetfulness occurred in 98.7% of patients. Patient satisfaction was 90/100 at 4, 24, and 48 weeks. Conclusion: Real-world data demonstrate that dolutegravir plus lamivudine in MTR is effective, safe, and satisfactory, moderately increasing weight and abdominal circumference and administrable on a test-and-treat strategy.

HIV infection invariably attracts the attention of medical staff in complex medical specialties. To achieve the goal of elimination by 2020, various approaches are required, including the establishment of prevention, diagnosis, monitoring, treatment, control measures. These should be supported by statistical studies that report on restricted or extended geographical areas, to the level of social class and age. Such an approach, combing the medical and social science perspectives (medicosocial) can prove useful for developing control measures. Due to the complexity of this immunodeficiency pathology, the condition also attracts comorbidities (most notably tuberculosis). Hence, prospective strategies need to be developed and oriented towards the goal of eradicating HIV infection. This paper presents strategies for consideration.

The purpose of this study was to identify the factors that affect the mortality among adult HIV/TB co-infected patients and to see the nutritional difference among mortality in residence level. Retrospective cohort studies of 417 patients which fulfill our criteria were included. Multilevel logistic regression models were used. MLwiN and SPSS software are used to estimate the parameter. The variance of the random factor in the empty model was significant which indicates that there were residential differences in TB-HIV co-infected mortality and it shows multilevel analysis was an appropriate approach for further analysis. The prevalence of HIV/TB co-infected patients' death was 12.9% in study time. Functional status, age of patients, WHO clinical stages, nutritional status, CD4 counts, regimen, and BMI were found to be significant determinants of HIV/TB co-infected mortality. In our study, patients with the bedridden category of functional status, the fourth stages of WHO clinical stages (stage IV), patients with higher age, patients whose treatments were second-line regimen and low CD4 cell counts were more at risk of death. The study also revealed that; poor nutritional status increased the risk of mortality among HIV/TB co-infected patients and it varies among the residence of the patients (rural area were more at risk).

Background: Vertical transmission of HIV infection can occur during pregnancy, during childbirth or through breastfeeding. The recommendations issued by the various international guidelines (WHO 2010, EACS 2017, DHHS 2017) on the safety of breastfeeding of HIV-infected women in effective antiretroviral treatment do not provide univocal indications referring to individual countries the choice to advise or advise against such procedure. Methods: A retrospective study was conducted in a small cohort of HIV-infected pregnant women who, despite the information received, decided to breastfeed their children. The observation was carried out in the period between March 2017 and June 2021. In all newborns, prophylaxis therapy was initiated at birth, according to the treatment guidelines, the scheme adopted involved the administration of zidovudine (AZT) orally for 4 weeks, started immediately after the childbirth. Breastfeeding time was, on average, 5 months. Results: No contagion was diagnosed. All infants were tested for HIV-RNA at birth, 1, 3, and 6 months after birth, and 1, 3 and 3 months after stopping breastfeeding. Conclusions: The data obtained represent, in our opinion, a solicitation to discuss and re-evaluate scientific evidence that starting from "Undetectable Equals Untransmittable" (U = U) can open a scientific and cultural review of breastfeeding.

In addition to CD4+ T lymphocytes, myeloid cells, and, particularly, differentiated macrophages, are targets of the human immunodeficiency virus type-1 (HIV-1) infection via interaction of gp120Env with CD4 and CCR5 or CXCR4. Both T cells and macrophages support virus replication although with substantial differences. In contrast to activated CD4+ T lymphocytes, HIV-1 replication in macrophages occurs in nondividing cells and it is characterized by virtual absence of cytopathicity both in vitro and in vivo. These general features should be considered in evaluating the role of cell-associated restriction factors aiming at preventing of curtailing virus replication in macrophages and T cells particularly in the context of designing strategies to tackle the viral reservoir in infected individuals receiving combination antiretroviral therapy. In this regard, we will here also discuss a model of reversible HIV-1 latency in primary human macrophages and the role of host factor determining restriction or reactivation of virus replication in myeloid cells.

Among people with HIV, histoplasmosis represents an important cause of mortality. Previous studies have provided estimates of the disease incidence. Here, we compared those estimates with the results obtained from a screening program implemented in Guatemala, which included histoplasmosis detection for people with HIV. To compare the results of this program, with previous estimations, a literature search was done and reports about histoplasmosis incidence were analyzed. The screening program enrolled 6,366 patients. The overall histoplasmosis incidence in the screening program was 7.4%, which was almost double than those estimated by the previous studies. From 2017 to 2019, the screening program showed an upward trend in histoplasmosis cases from 6.5% to 8.8%. Histoplasmosis overall mortality among those who were newly HIV diagnosed showed a decrease at 180 days from 32.8% in 2017 to 21.2% in 2019. The screening approach using rapid diagnostic assays detects quickly more cases of histoplasmosis, allowing a specific treatment, which decreases the mortality of the disease. Therefore, the use of these new techniques, especially in endemic areas of histoplasmosis, must be implemented.

Introduction: Pre-Exposure Prophylaxis (PrEP) for HIV prevention has been implemented in several countries. Previous literature has shown that its cost-effectiveness (and, under some specifications, cost-saving character) is dependent on the reduction in price due to generics, the time-horizon and its effectiveness. The intervention has never been studied in Catalonia, a territory with extensive implementation. Methods: Economic evaluation of the implementation of HIV pre-exposition prophylaxis using administrative data from Men who have Sex with Men (MSM) who receive the treatment (at the generic price). A deterministic compartmental model and a social perspective with a micro-costing approach over the time horizon 2022-2062 are used. A baseline 86% effectiveness of PrEP is assumed. Results: Daily oral PrEP is found to be cost-saving: discounted savings in costs are attained after 16 years, and after 40 years they reach 81 million euros. In terms of health indicators, 10,322 additional discounted QALYs are generated by the intervention. Results are sensitive to sexual behavioral patterns among MSM, the price of PrEP (reduced if offered on-demand), its effectiveness and the discount rate. Conclusions: The use and promotion of PrEP in Catalonia is predicted to result in substantial health and monetary benefits because of reductions in HIV infections. Short-term investments in the promotion of PrEP will result in important cost-savings in the long term.

The acquired immunodeficiency syndrome (AIDS) caused by the human immunodeficiency virus (HIV) continues to be a public health problem. In 2020, 680,000 people died from HIV-related causes, and 1.5 million people were infected. Antiretrovirals are only a way to control HIV infection but not to cure AIDS. As such, effective treatment must be developed to control AIDS. Developing a drug is not an easy task, and there is an enormous amount of work and economic resources invested. For this reason, it is highly convenient to employ computer-aided drug design methods, which can help generate and identify novel molecules. Using the de novo design, new novel molecules can be developed using fragments as building blocks. In this work, we develop a virtual-focused compound library of HIV-1 viral protease inhibitors from natural product fragments. Natural products are characterized by a large diversity of functional groups, many sp3 atoms, and chiral centers. Pseudo-natural products are a combination of natural products fragments that keep the desired structural characteristics from different natural products. An interactive version of chemical space visualization of virtual compounds focused on HIV-1 viral protease inhibitors from natural product fragments is freely available at https://figshare.com/s/ceb58d58e8f5585ce67e.

Infection by human immunodeficiency virus type I (HIV-1) requires virus particle binding to host cell-surface receptor CD4 via the viral envelope glycoprotein gp120. HIV-1 therapy and prevention efforts involve development of mimetic or recombinant gp120 vaccines or deployment of antiviral agents that target specific epitopes of gp120. The unliganded conformational state of gp120 is closed, whereas the CD4-bound state is open. However, in between, there exist dynamic conformational states, indicating intrinsically flexible region(s) of structural dynamics, imposing a structural challenge for developing drug or antibody targets. Known conformational states of gp120 were determined by X-ray crystallographic and cryo-electron microscopy, and neither method captures the population of gp120 species arising from conformational plasticity, motions, and transitions. gp120 plasticity brings up several important questions. How will differences in conformation affect receptor binding, antibody recognition, and neutralization? Which regions are crucial for gp120 structural plasticity? How could structural dynamics influence HIV-1 evasiveness against host immunity and drugs or vaccines, and facilitate the viral entry into its host? This review explores the structural constraints presented by conformational states of the glycoprotein to antibodies or drugs and how these conformational states provide structural avenues for the virus to escape neutralizing agents and evade host immunity.

There are scarce data regarding flu vaccination among people with HIV infection (PWHIV). The goal of this explorative study is to assess hesitancy toward influenza vaccination in a group of PWHIV during the pandemic. A questionnaire was administered to 219 patients vaccinated at our clinic during the 2020-2021 campaign. It evaluated subjects’ adherence over the last 3 seasonal vaccination campaigns, vaccine confidence, complacency and convenience, and the effect of the pandemic on the choice to vaccinate. The population was divided into two groups: fully adherent (all 3 campaigns, 117 patients) and non-fully adherent (1 or 2 campaigns, 102 patients). Adherence increased in non-fully adherent group in 2020-2021, but the pandemic did not affect the choice. Misbelieves emerged: influenza vaccine was considered protective SARS-CoV-2 (22.8% of total population); almost half of all patients thought influenza vaccine could improve their CD4+ cell level (57.3% in fully adherent, 40.2% in non-fully adherent, p<0.05). A quarter of the non-fully adherent group would not have vaccinated in a location other than our clinic (24.5% vs 11.9% in fully adherent group, p<0.05). Conclusively, offering a secure and private space for vaccination seems to encourage vaccination; healthcare professionals should improve counselling to increase adherence and correct misbeliefs.

Malassezia are lipid-dependent basidiomycetous yeast of the normal skin microbiome, although Malassezia DNA has been recently detected in other body sites and has been associated with cer-tain chronic human diseases. This new perspective raises many questions. Are these yeasts truly present in the investigated body site or were they contaminated by other body sites, adjacent or not? Does this DNA contamination come from living or dead yeast? If these yeasts are alive, do they belong to the resident mycobiota or are they transient colonizers which are not permanently established within these niches? And, finally, are these yeasts associated with certain chronic diseases or not? In an attempt to shed light on this knowledge gap, we critically re-viewed the 31 published studies focusing on the association of Malassezia spp. with chronic human diseases, including psoriasis, atopic dermatitis (AD), chronic rhinosinusitis (CRS), asthma, cystic fibrosis (CF), HIV infection, inflammatory bowel disease (IBD), colorectal cancer (CRC), and neurodegenerative diseases.

New series of compounds containing both heterocycle moieties and pseudo-symmetric hydroxyethylamine core were obtained using a simple synthetic path that can provide a library of compounds in few steps and high yields. Furthermore, diversity-oriented synthesis was studied to change different functionalities according to needs. The in vitro inhibition activity against recombinant HIV-1 protease was evaluated. A beneficial effect of this class of compounds can be obtained either for the presence of a bis-benzyl group into the core and for the heterocyclic moiety in P1, specifically the indole ring. Docking analysis was also reported.

Several factors enhance the possibility of vertical HIV transmission in the pediatric population. Unfortunately, the data of the prevalence of HIV and associated risk factors in these populations remain limited in Rwanda. The study aimed to assess HIV prevalence and risk factors for infants born to mothers on ARV treatment at CHUB/Rwanda. MethodsA cross-sectional study was carried out on infants who were born to mothers under ARV treatment at CHUB. The associated risk factors were retrospectively assessed using prevention vertical HIV transmission records, and Dried Blood spots (DBS) were prospectively tested using Polymerase Chain Reaction (PCR). Data were analyzed by logistic regression. Ethical clearance (Ref: CMHS/IRB/198/2017) was issued by University of Rwanda to fulfill research ethical consideration.ResultsAmong 185(100%) infants born to HIV-positive mothers under ARV treatment, 5(2.7%) were HIV positive. The most associated risk factors were increased to over 1log copies/ml mother’s viral load (OR 9.3, 95% CI 1.01-85.45, P= 0.04) and mother’s CD4 count lower than 350 cells/µl (OR 6.4, 95% CI 1.03-40.06, P=0.04). The factors found to reduce the rate of vertical transmission of HIV were health facility as a delivery place (P=0.03), exclusive breastfeeding for 6 months (P= 0.006), and attending the antenatal care (P=0.01) while feeding children and vaginal delivery were associated risks but not statistically significant.ConclusionThe current study supports that the more mothers’ viral load and CD4 count decrease, so does the risk of HIV to their infants. A fact which indicates that both prevalence and risk factors remain an alarming issue. Much effort and multi-disciplinary approach are highly recommended.

Despite widespread use of combined antiretroviral therapy (cART) and increased life expectancy in people living with HIV (PLWH), HIV-related lymphomas (HRL) remain a leading cause of cancer morbidity and mortality for PLWH, even in patients optimally treated with cART. While incidence of aggressive forms of non-Hodgkin lymphoma decreased after cART advent, incidence of Hodgkin lymphoma (HL) has increased among PLWH in recent decades. The coinfection of Epstein Barr virus plays a crucial role in the pathogenesis of HL in the HIV setting. Currently, PLWH with HRL, including HL, are treated similarly to HIV-negative patients and, importantly, the prognosis of HL in PLWH is approaching to that of the general population. In this regard, effective chem-otherapy is strongly recommended since it has been shown to improve survival rates in all lymphoma subtypes, including HL. As a consequence, interdisciplinary collaboration between HIV specialists and hemato-oncologists for the management of potential drug-drug interactions and overlapping toxicities between antiretroviral and antineoplastic drugs is crucial for the op-timal treatment of PLWH with HL. In this article the authors review and update the epidemio-logical, clinical and biological aspects of HL presenting in PLWH with special emphasis in the improvement on prognosis and the factors that have contributed to it.

HIV-1 Tat protein interacts with TAR RNA and recruits CDK9/cyclin T1 and other host factors to induce HIV-1 transcription. Thus Tat-TAR RNA interaction, which is unique for HIV-1, represents an attractive target for anti-HIV-1 therapeutics. To target Tat-TAR RNA interaction, we used a crystal structure of TAR RNA with acetylpromazine bound to the bulge of TAR RNA, to dock compounds from Enamine database containing 1.6 million individual compounds. Docking identified 173 compounds that were analyzed for the inhibition of HIV-1 infection. Top ten inhibitory compounds with IC50 ≤ 6 µM were selected and the three least toxic compounds, T6780107 (IC50=2.97 μM), T0516-4834 (IC50=0.2 μM) and T5628834 (IC50=3.46 μM), were further tested for HIV-1 transcription inhibition. Only T0516-4834 compound showed selective inhibition of Tat-induced HIV-1 transcription, whereas T6780107 compound inhibited equally basal and Tat-induced transcription and T5628834 compound only inhibited basal HIV-1 transcription. The T0516-4834 compound also showed strongest inhibition of HIV-1 gag RNA expression and p24 production in CEM T cells infected with HIV-1 IIIB. Of the three compounds, only the T0516-4834 compound disrupted Tat-TAR RNA interaction indicating that it might target TAR RNA. Also, of the three tested compounds, T5628834 but not T6780107 or T0516-4834 disrupted Tat-CDK9/cyclin T1 interaction. Taken together, our study identified novel compound T0516-4834 that disrupted Tat-TAR RNA interaction and inhibited Tat-induced transcription and HIV-1 infection suggesting that this compound might serve as a new lead for anti-HIV-1 therapeutics.

Background: HIV self-testing (HIVST) is one of the recommended approaches for HIV testing services, particularly for helping reach populations who would not normally access facility-based HIV testing. HIVST must be tailored to different populations to ensure uptake. Objective: The main objective of this study was to develop an acceptable HIVST delivery strategy to help improve urban men’s engagement with HIV services. Methods: We invited key stakeholders for urban men’s HIV services to participate in a co-creation workshop aimed at developing HIVST delivery approaches for urban men, using eThekwini municipality as a study setting. We conducted purposive sampling to include health care users and health care providers, representing a range of views across the public sector and voluntary sector. We employed the Nominal Group Technique (NGT) method for data collection. The NGT workshop was conducted in two consecutive phases: phase one was focused on determining barriers for men’s engagement with the current/facility-based HIV testing services; phase two was aimed at determining HIVST delivery strategies. We used the results of the NGT to design a tailored HIVST strategy for urban men in eThekwini District. Results: Participants identified the following psychological factors as the most important barriers to uptake of HIV testing services by urban men: stigma, ignorance about the importance of testing and testing process as well as fear of positive test results. Key stakeholders suggested internal motivation strategies as a potentially effective approach to support HIVST delivery strategy. Guided by the NGT results, we designed a HIVST delivery strategy that is supported by a risk communication approach Conclusion: We designed an evidence-based risk communication mobile health (mHealth) strategy coupled with SARS COV-2 self-testing tailored to improve men’s uptake of HIVST. A follow-up study to evaluate the feasibility of implementing these approaches is recommended.

Despite widespread use of combined antiretroviral therapy (ART) and increased life expectancy in people living with HIV (PLWH), HIV-related lymphomas (HRL) remain a leading cause of cancer morbidity and mortality for PLWH, even in patients optimally treated with ART. While incidence of aggressive forms of non-Hodgkin lymphoma decreased after ART advent, incidence of Hodgkin lymphoma (HL) has increased among PLWH in recent decades. The coinfection of Epstein Barr virus plays a crucial role in the pathogenesis of HL in the HIV setting. Currently, PLWH with HRL, including HL, are treated similarly to HIV-negative patients and, importantly, the prognosis of HL in PLWH is approaching to that of the general population. In this regard, effective chemotherapy is strongly recommended since it has been shown to improve survival rates in all lymphoma subtypes, including HL. As a consequence, interdisciplinary collaboration between HIV specialists and hemato-oncologists for the management of potential drug-drug interactions and overlapping toxicities between antiretroviral and antineoplastic drugs is crucial for the optimal treatment of PLWH with HL. In this article the authors review and update the epidemiological, clinical and biological aspects of HL presenting in PLWH with special emphasis in the improvement on prognosis and the factors that have contributed to it.

Aims: Spironolactone is a steroidal mineralocoricosteroid receptor antagonist (MRA) used for treatment of resistant hypertension, heart failure and edema. It exerts class specific adverse effects that are shared by other MRAs. Additionally, it exerts unique “off target” steroidal effects that include gynecomastia, impotence and loss of libido in males and menstrual irregularity in females. Together, these have led to a poor tolerability and limited use despite positive results in many randomized, controlled clinical trials. We review the off-target effects of spironolactone that may summate with its MRA action to provide an advantageous profile for prevention or treatment of patients with COVID-19. Methods: Literature review using PubMed Central. Results: The blockade by spironolactone of the androgen receptor should diminish the expression of transmembrane protease serine 2 (TMPRSS2) that has an androgen promoter while its MRA action should enhance the expression of protease nexin1 (PN1) that inhibits furin and plasmin. TMPRSS2, furin and plasmin cooperated to process the SARS-CoV-2 spike protein to increase its high affinity binding to the angiotensin converting enzyme 2 (ACE2) and thereby promote viral cell entry. Its actions as an MRA may reduce inflammation and preserve pulmonary, cardiac and vascular functions. Its anti-plasmin action may combat hemostatic dysfunction. Conclusion: The hypothesis that the off-target effects of spironolactone summate with its MRA actions to provide special benefits for COVID-19 is worthy of direct investigation and clinical trial.

Host ribosome-associated scaffold protein Receptor for Activated C Kinase 1 (RACK1) is utilized by a diverse group of human viruses for Internal Ribosomal Entry Sites (IRES) – mediated translation of viral mRNAs. We recently reported inhibition of herpes virus by small molecules targeting the RACK1 functional site. Here, we tested these molecules against HIV-1 and HCV, as HIV-1 contains two potential IRES sites and HCV translation occurs exclusively through IRES. Compounds significantly downregulated activities of HIV-1- and HCV-related dicistronic reporter constructs in transfected HEK293T cells. The compounds also strongly downregulated production of the HIV-1 capsid protein p24 in HIV-infected cells, as well as production of HIV-1 Gag precursor p55 and p55-derived proteins p24 and p17 in cells infected with the HIV-1 virus. Hepatitis C virus (HCV) IRES activities were also significantly inhibited by RACK1 inhibitor compounds. Since a number of human and plant pathogenic viruses are reported to use IRES, the RACK1 compounds can be established as broad host-targeted antivirals.

ABSTRACTIntroduction:Human Immunodeficiency Virus (HIV) is a global health problem that is almost recorded in every country. The long-term and long-term negative impacts of HIV cases are stigma and discrimination in people with HIV (PLHIV). The purpose of this study is to find out the stigma and discrimination felt by PLHIV.Method:This study design of systematic review from 4 electronic databases namely Scopus ScienceDirect, Sage and ProQuest by using keywords tailored to Medical Subject Headings (MeSH) including "Stress", "covid", "nursing", "hospital". This study uses PICOS framework to prevent research bias and analysed using descriptive analysis.Results:The results of the analysis of the article showed from 761 articles have been identified title, abstract and full-text so that recorded 15 articles that can be reviewed. The article consists of various designs, namely RCT, cross sectional and qualitative studies. Analysis shows that stigma and discrimination are social phenomena that manifest in several social areas.Conclusion:Stigma and discrimination in people with HIV (PLHIV) is still common, stigma is carried out by the wider community to their own families. The family approach is necessary to improve well-being as well as improve the social community of the family.

Background: A person living with HIV / AIDS bargains with stressors such as discrimination, stigma depression, and several psychological impacts. The stressors experienced by people with HIV/ AIDS will certainly have an impact on daily activities, welfare, and management of medications which in general will have an impact on the quality of life. To deal with these stressors, it is necessary to have good and proper coping from within the PLWHA. Coping strategies need to be owned and carried out by PLWHA in order to respond adaptively to the stressor conditions experienced. Purpose: The aim of this review is to describe the stress experienced and the coping strategies used among PLWHA. Methods: This literature review used keywords in the search for international references are coping strategy, stressor, HIV-AIDS. Inclusion criteria: selection of titles that are relevant to the formulation of the problem and objectives, full-text articles in English, articles published from 2019 to 2021. The exclusion criteria used were coping strategy articles that did not involve HIV patients. Search references from electronic database sources namely ProQuest, CINAHL, and ScienceDirect.Six articles that are deemed worthy of analysis are then discussed or analyzed. Results: Age, gender and sexual orientation have contributed to the emerging stressor among PLWHA. The internal and external coping strategies focusing on the problem are important for PLWHA in handling the stressor. Conclusion: People with HIV-AIDS have many stressors in their lives, but they also have proper coping strategies depending on their internal and external conditions.

A multiscale mathematical model is proposed seeking to study the propagation dynamics of the Human Immunodeficiency Virus (HIV) in a group of young people between 15 and 24 years of age, through sexual contact without protection, considering the use of antiretroviral therapy (ART) and therapeutic failure. The model consists in a scale-free complex network that follows a power law, coupled with the immunological dynamics of each individual, that is, it considers the infection by the virus in the immune system of each HIV carrier, through a system of non-linear differential equations that govern the infection’s behavior in the immune system. Propagation of the virus in the network is modelled by taking into account information from the immunological status of each person. The study found that for a population to have high HIV prevalence, it is not necessary at the beginning of the simulation time for the virus to propagate rapidly. In addition, the study proves that with a higher number of sexual partners, there will be greater prevalence of HIV in the population and that the use of ART helps to control the propagation of the infection in the population. As an interesting result, it was also found that there is a higher number of HIV carriers who abandon ART than those who have access to it.

SARS-CoV-2 and HIV are zoonotic viruses that rapidly reached pandemic scale causing global losses and fear. The COVID-19 and AIDS pandemics ignited massive efforts worldwide to develop antiviral strategies and characterize viral architectures, biological and immunological properties, and clinical outcomes. Although both viruses have a comparable appearance as enveloped viruses with positive-stranded RNA and envelope spikes mediating cellular entry, the entry process, downstream biological and immunological pathways, clinical outcomes, and disease courses are strikingly different. This review provides a systemic comparison of both viruses’ structural and functional characteristics delineating their distinct strategies for efficient spread.

We aimed to investigate whether the sequence length of HIV-1 increases over time. A longitudinal analysis of full-length coding region sequences (FLs) during an HIV-1 outbreak among pa-tients with hemophilia and local controls infected with the Korean subclade B of HIV-1 (KSB) was performed. Genes were amplified by overlapping RT-PCR or nested PCR and subjected to direct sequencing. Overall, 141 FLs were sequentially determined over 30 years in 62 KSB-infected patients. Phylogenetic analysis indicated that within KSB, two FLs from plasma donors O and P comprised two clusters together with 8 and 12 patients with hemophilia, respectively. Signature pattern analysis for the KSB of HIV-1 revealed 91 signature nucleotide residues (1.05%). In total, 48 and 43 signature nucleotides originated from clusters O and P, respectively. Only six positions contained 100% specific nucleotide(s) in clusters O and P. Additionally, in-depth FL analysis over 30 years indicates that the KSB FL significantly increased over time before combined antiretroviral therapy (cART) and decreased with cART. The increase occurred due to a significant increase in env and nef genes, originating in the variable regions of both genes. The increase in the sequence length of HIV-1 over time suggests that it has an evolutionary direction.

Matrix metalloproteinases (MMPs) have been demonstrated to have both detrimental and protective functions in inflammatory diseases. Several MMP inhibitors, with the exception of Periostat®, have failed in Phase III clinical trials. As an alternative strategy, recent efforts have been focussed on the development of more selective inhibitors or targeting other domains than their active sites (e.g., exosites, ectosites) through specific small molecule inhibitors or monoclonal antibodies. Here, we present some examples that aim to better understand the mechanisms of conformational changes/allosteric control of MMPs functions. In addition to MMP inhibitors, we discuss unbiased global approaches such as proteomics and N-terminomics to identify new MMP substrates and achieve a better understanding of the roles of these proteases in diseases.

The objective of this study is to investigate whether the sequence length of HIV-1 increases over time. A longitudinal analysis of full-length coding region sequences (FLs) in an outbreak of HIV-1 infection among patients with hemophilia and local controls identified as infected with the Korean subclade B of HIV-1 (KSB). Genes amplified by overlapping RT-PCR or nested PCR were subjected to direct sequencing. In total, 141 FLs were sequentially determined over 30 years in 62 KSB-infected patients. Non-KSB sequences were retrieved from the Los Alamos National Laboratory HIV Database. Phylogenetic analysis indicated that within KSB, 2 FLs from plasma donors O and P comprised two clusters together with 8 and 12 patients with hemophilia, respectively. Signature pattern analysis for the KSB of HIV-1 revealed signature nucleotide residues at 1.05%, compared with local controls. Additionally, in-depth FLs sequence analysis over 30 years in KSB indicates that the KSB FL significantly increases over time before combined antiretroviral therapy (cART) and decreases on cART. Furthermore, the increase in FLs over time significantly occurred in the subtypes B, C and G, but, there was no increase in the subtypes D, A, and F1. Consequently, subtypes F1 and D had the shortest sequence length. Our analysis was extended to compare HIV-1 with HIV-2 and SIVs. Essentially, the longer the sequence length (SIVsm > HIV-2 > SIVcpz > HIV-1), the longer the survival period. The increase in the length of the HIV-1 sequence over time suggests that it might be an evolutionary direction toward attenuated pathogenicity.

Current therapeutic protocols for the treatment of HIV infection consist of the combination of diverse anti-retroviral drugs in order to reduce the selection of resistant mutants and to allow for the use of lower doses of each single agent to reduce toxicity. However, avoiding drugs interactions and patient compliance are issues not fully accomplished so far. In this respect the identification of single agents with multitarget potential might represent the ideal solution. Accordingly, a small library of biphenylhydrazo 4-arylthiazoles derivatives has been synthesised and evaluated to investigate the ability of the new derivatives to simultaneously inhibit both associated functions of HIV reverse transcriptase. All compounds were active towards the two functions, although at different concentrations. The substitution pattern on the biphenyl moiety appears relevant to determine the activity.

Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) is the etiological agent of the current pandemic worldwide. The pathological condition induced by this pathogen is known as COVID-19 disease. SARS-CoV-2 associated pandemic has been defined as a “public health emergency of international concern” by the International Health Regulation Emergency Committee of the World Health Organization. To date, considerable efforts are in progress to develop more advanced strategies against SARS-CoV-2. Despite the numerous scientific studies published, our knowledge regarding this pathogen is still incomplete, as this virus has been identified only recently. Therefore, scientific investigation of the SARS-CoV-2 has been possible only for a short period of time and effective management of the serious forms of this disease is still lacking. Considerable efforts are in progress worldwide with the purpose to develop more advanced strategies against this pathogen. In this review, we have analyzed the structural and the biological SARS-CoV-2 characteristics and those of other well-known RNA viruses, with the aim to identify possible similarities and analogies between all these pathogens, may be a very useful approach. These infectious agents have been widely studied since several years ago and, a large series of scientific reports are available in the literature regarding this topic. Therefore, focusing on the Human Immunodeficiency Virus (HIV), Hepatitis C Virus (HCV) and Influenza viruses (IVs), we have collected their historical data, clinical manifestations, pathogenetic mechanisms and related infections. Taking advantage of the results of our research, we have assembled this narrative review, with the aim to get useful insights and lessons from HIV, HCV and IVs characteristics and, consequently, to transfer the obtained knowledge to the study of SARS-CoV-2 biology. There are well known differences between all these pathogens. In particular, they present a distinct mode of transmission, as SARS-CoV-2 and Influenza viruses are airborne pathogens, whereas HIV and HCV are bloodborne infectious agents. However, these viruses exhibit some potential common clinical manifestations and pathogenetic mechanisms and their understanding may contribute to establishing preventive measures and new therapies against SARS-CoV-2. Accordingly, we have analysed and discussed the following points: 1) the biology, the pathogenesis and the clinical manifestations of SARS-CoV-2, HIV, HCV and IVs in mankind; 2) the onset and spreading of pandemics caused by respiratory viruses according to a perspective historical point of view; 3) the possible development of a persistent SARS-CoV-2 reservoir worldwide; 4) the possibility of SARS-CoV-2 reinfection/reactivation; 5) the possible involvement and impact of climatic factors in increasing the risk of SARS-CoV-2 spreading.

Discriminatory attitudes towards people living with HIV/AIDS are prevalent. A Joint United Nations Program on HIV/AIDS report (2019) indicated that more than 50% of the people surveyed in one of the studies spanning 26 countries expressed unfavorable attitudes towards HIV-positive people. The objective of this study was to assess the attitudes of senior Education Studies students at a university in Spain towards people with HIV/AIDS so as to propose specific educational interventions. The study employed a quantitative methodological approach; a questionnaire with a 14-item attitude score served as the analytical instrument. The study sample comprised 613 students from the School of Education at the University of Huelva, Spain. The results showed that more than 50% of the School’s senior students had discriminatory attitudes towards HIV-positive people, some of whom were fellow classmates. This study proposes several formative approaches to reducing the stigma suffered by HIV-positive people, while also improving senior students’ skills and capabilities in the field of health promotion.

The RV144 trial represents the only vaccine trial to demonstrate any protective effect against HIV-1 infection. While the reason(s) for this protection are still being evaluated, it serves as justification for widespread efforts aimed at developing new, more effective HIV-1 vaccines. Advances in our knowledge of HIV-1 immunogens and host antibody responses to these immunogens are crucial to informing vaccine design. While the envelope (Env) protein is the only viral protein present on the surface of virions, it exists in a complex trimeric conformation and is decorated with an array of variable N-linked glycans, making it an important but difficult target for vaccine design. Thus far, efforts to elicit a protective humoral immune response using structural mimics of native Env trimers have been unsuccessful. Notably, the aforementioned N-linked glycans serve as a component of many of the epitopes crucial for the induction of potentially protective broadly neutralizing antibodies (bnAbs). Thus, a greater understanding of Env structural determinants, most critically Env glycosylation, will no doubt be of importance in generating effective immunogens. Recent studies have identified the HIV-1 Env signal peptide (SP) as an important contributor to Env glycosylation. Further investigation into the mechanisms by which the SP directs glycosylation will be important, both in the context of understanding HIV-1 biology and in order to inform HIV-1 vaccine design.

The need for antiserum for immunohistochemical (IHC) detection of enterovirus (EV) in formaldehyde fixed and paraffin-embedded (FFPE) specimens is increasing. The standard monoclonal antibody against EV-envelope protein (VP1), clone 5D8/1, was proven to cross-react with other proteins. Another candidate marker of EV proteins is 2A protease (2Apro), which is coded by the EV gene and translated by host cells during EV replication. We raised polyclonal antiserum by immunizing rabbits with an 18-mer peptide of Coxsackievirus B1 (CVB1)-2A protease (2Apro) and examined the specificity and sensitivity for EV on FFPE tissue samples. ELISA study showed a high titer of antibody for CVB1-2Apro. IHC demonstrated that antiserum against 2Apro reacted with CVB1-infected Vero-cells. Confocal microscopy demonstrated that 2Apro labelled by the antibody located in the same cell with VP1 stained with 5D8/1. IHC demonstrated dense positive reactions pancreatic islets of EV-associated fulminant type 1 diabetes (FT1DM), and located in the same cell stained positive with 5D8/1. Specificity of IHC staining FT1DM pancreas was confirmed by absorption with an excessive concentration of immunized peptide. In conclusion, our study provides a new polyclonal antiserum against CVB1 2Apro which may be useful for detection of EV-infected human tissues stored as archive of FFPE tissue samples.

Cryptosporidiosis is one of the most important causes of gastroenteritis in the world, especially in low- and middle-income countries. It is caused by the Apicomplexan parasite Cryptosporidium spp., and mainly affects children and immunosuppressed people, in whom it can pose a serious risk to their health, or even be life-threatening. In Honduras there are no data on parasite species or on molecular diversity or Cryptosporidium subtypes. Therefore, a cross-sectional study was conducted between September 2019 and March 2020 for the molecular identification of Cryptosporidium spp. in 102 patients living with HIV who attended a national hospital in Tegucigalpa. Stool samples were analysed by direct microscopy, acid-fast stained smears, and a rapid lateral flow immunochromatographic test. All samples that tested positive were molecularly analyzed to identify the species and subtype of the parasite using three different markers: gp60, cowp, and 18Sr. PCR products were also sequenced. Four out of 102 samples (3.92%) were positive for Cryptosporidium parvum, and all were assigned to subtype IIa. These findings suggest a possible zoonotic transmission in this population.

The tiered laboratory framework for HIV viral load monitoring accommodates a range of HIV viral load testing platforms, with quality assessment critical to ensure quality patient testing. HIV plasma viral load testing is challenged by the instability of viral RNA. An approach using an RNA stabilizing buffer is described for the Xpert® HIV-1 Viral Load (Cepheid) assay and was tested in remote laboratories in South Africa. EDTA-plasma panels with known HIV viral titres were prepared in PrimeStore molecular transport medium for per-module verification and per-instrument external quality assessment. The panels were transported at ambient temperatures to 13 testing laboratories during 2017 and 2018, tested according to standard procedures and uploaded to a web portal for analysis. A total of 275 quality assessment specimens (57 verification panels and two EQA cycles) were tested. All participating laboratories met study verification criteria (n=171 specimens) with an overall concordance correlation coefficient (ρ_c) of 0.997 (95% confidence interval [CI]: 0.996 to 0.998) and a mean bias of -0.019 log cp/mL (95% CI: -0.044 to 0.063). The overall EQA ρ_c (n=104 specimens) was 0.999 (95% CI: 0.998 to 0.999), with a mean bias of 0.03 log cp/mL (95% CI: 0.02 to 0.05). These panels are suitable for use in quality monitoring of Xpert® HIV-1 VL and are applicable to laboratories in remote settings.

HIV-1 transcribes only one kind of transcript – the full length genomic RNA. To make the mRNA transcripts for the accessory proteins Tat and Rev, the genomic RNA must completely splice. The mRNA transcripts for Vif, Vpr, and Env must splice but not completely. Genomic RNA (which also functions as mRNA for the Gag and Gag/Pro/Pol precursor polyproteins) must not splice at all. HIV-1 can tolerate a surprising range in the relative abundance of individual transcript types, and a surprising amount of aberrant and even odd splicing; however, it must not over-splice, which results in the loss of full length genomic RNA and has a dramatic fitness cost. Cells typically do not tolerate unspliced/incompletely spliced transcripts, so HIV-1 has to circumvent this cell policing mechanism to allow some splicing while suppressing most. Splicing is controlled by RNA secondary structure, cis-acting regulatory sequences which bind splicing factors, and the viral protein Rev. There is still much work to be done to clarify the combinatorial effects of these splicing regulators. These control mechanisms represent attractive targets to induce over-splicing as an antiviral strategy. Finally, splicing has been implicated in latency, but to date there is little supporting evidence for such a mechanism. In this review we apply what is known of cellular splicing to understand splicing in HIV-1, and also present data from our newer and more sensitive deep sequencing assays quantifying the different HIV-1 transcript types.

Alzheimer's disease (AD) is the most common cause of dementia and affects millions of people around the world. Neuronal death in AD is initiated by the toxic action of oligomeric amyloid-β (Aβ) peptides. The formation of membrane channels by Aβ is a primary molecular action and does not require any other proteins. Channels are formed by short amyloid fragments faster and more frequently than by full-length peptides. The channel formation is dependent on an electrostatic interaction between a positively charged peptide and a negatively charged membrane. Negative membranes can be found in several locations of a cell – the inner leaflet of plasma membrane, mitochondria, and lysosomes, which all are well-known cellular targets in AD. Considering that the amyloid enters a cell by endocytosis and is exposed to lysosomal enzymes, we propose the amyloid degradation toxicity hypothesis. Endopeptidases degrade the endocytosed peptide. Produced fragments form membrane channels, which can transfer various ions (including protons) and even relatively large compounds. The neutralization of lysosomal content inactivates enzymes, which fails the whole system of recycling cellular content, including autophagy. The permeabilization of lysosomes could also lead to cell death through necrotic and apoptotic mechanisms. We discuss several mechanisms that describe how amyloid degradation products reach plasma and mitochondrial membranes, and form membrane channels. The pathogenesis of AD is discussed at various levels in a context of how the primary molecular mechanism of membrane channel formation could progress into the disease state. The discussion starts at the molecular level and extends to why the development of a disease takes years and is closely associated with aging. The proposed hypothesis offers an interpretation to several clinical observations such as the involvement of iron metabolism and an inverse association between developing Alzheimer's disease and cancer. Predictions about potential biomarkers and effectiveness of future treatments are discussed.

Tissue resident memory T cells (TRM) were first described in 2009. While initially the major focus was on CD8 TRM, there has been recently an increased interest in defining the phenotype and the role of CD4 TRM in diseases. Circulating CD4 T cells seed tissue CD4 TRM, but there also appears to be an equilibrium between CD4 TRM and blood CD4 T cells. CD4 TRM are more mobile than CD8 TRM, usually localized deeper within the dermis/lamina propria and yet may exhibit synergy with CD8 TRM in disease control. This has been demonstrated in herpes simplex infections in mice. In human recurrent herpes infections, both CD4 and CD8 TRM persisting between lesions may control asymptomatic shedding through interferon gamma secretion, although this has been more clearly shown for CD8 T cells. The exact role of the CD4/CD8 TRM axis in the trigeminal ganglia and/or cornea in controlling recurrent herpetic keratitis is unknown. In HIV, CD4 TRM have now been shown to be a major target for productive and latent infection in cervix. In HSV and HIV co-infections, CD4 TRM persisting in the dermis support HIV replication. Further understanding of the role of CD4 TRM and their induction by vaccines may help control sexual transmission by both viruses.

Immune complexes (ICs) made of antibody-bound antigens exhibit immunomodulatory activities exploitable in a vaccination strategy to optimize vaccine efficacy. The modulatory effects of ICs are typically attributed to the Fc fragments of the antibody components, which engage Fc receptors, complement and complement receptors on various immune cells. These Fc-mediated functions facilitate the critical interplay between innate and adaptive immune systems to impact the quality and quantity of the elicited adaptive responses. In addition to the Fc contribution, the Fab fragment also plays an immunoregulation role. The antigen-binding domains of the Fab fragment can bind their specific epitopes at high affinity to sterically occlude these antigenic sites from recognition by other antibodies. Moreover, the Fab-mediated binding have been demonstrated to induce allosteric alterations at nearby or distant antigenic sites. In this review article, we survey published studies to illuminate how the immunomodulatory functions of ICs have been investigated or utilized in a vaccination strategy to fight against an array of infectious pathogens, culminating with IC vaccine designs aimed at preventing HIV-1 infection. In particular, we highlight IC vaccine candidates that exploit Fab-mediated steric and allosteric effects to direct antibody responses away or toward the V1V2 domain, the V3 loop, and other antigenic sites on the HIV-1 envelope gp120 glycoprotein. Like other HIV-1 vaccine approaches, the path for IC-based vaccines to reach the clinic faces major hurdles yet to be overcome; however, investigations into this vaccine strategy have provided insights into the multifaceted activities of antibodies beyond their conventional roles in the host defense against HIV-1 and other microbial pathogens.

Immune reconstitution inflammatory syndrome (IRIS) presents as an exaggerated immune reaction that occurs during dysregulated immune restoration in immunocompromised patients in late-stage HIV infection who commenced antiretroviral treatments. Virtually, any opportunistic pathogen can provoke this type of immune restoration disorders. In this review, we focus on recent development in the identification of risk factors for Cryptococcal IRIS and on advancements in our understanding of C-IRIS immunopathogenesis. We overview new findings in blood and cerebrospinal fluid which can potentially be useful in the diagnosis of cryptococcal meningitis IRIS. We assess the utility of these biomarkers to identify putative host-based targets, which may justify a clinical need for improvement in monitoring a patient’s laboratory results and adjusting treatment modalities in AIDS patients co-infected with Cryptococcus.

Background. Predisposition to HIV+ is influenced by a wide range of correlated economic, environmental, demographic, social, and behavioral factors. While evidence among a candidate handful have strong evidence, there is lack of a consensus among the vast array of variables measured in large surveys. Methods. We performed a comprehensive data-driven search for correlates of HIV positivity in >600,000 participants of the Demographic and Health Survey (DHS) across 29 sub-Saharan African countries from 2003 to 2017. We associated a total of 7,251 and of 6,288 unique variables with HIV+ in females and males respectively in each of the 50 surveys. We performed a meta-analysis within countries to attain 29 country-specific associations. Results. We identified 344 (5.4% out possible) and 373 (5.1%) associations with HIV+ in males and females, respectively, with robust statistical support. The identified associations are consistent in directionality across countries and sexes. The association sizes among individual correlates and their predictive capability was low to modest, but comparable to established factors. Among the identified associations, variables identifying being head of household among females was identified in 17 countries with a mean odds ratio (OR) of 2.5 (OR range: 1.1-3.5, R² = 0.01). Other common associations were identified with marital status, education, age, and ownership of land or livestock. Conclusions. Our continent-wide search for variables has identified under-recognized variables associated with HIV+ that are consistent across the continent and sex. Many of the association sizes are as high as established risk factors for HIV+, including male circumcision.

(1) Background: Neglected tropical diseases (NTDs) have been overlooked on the global health agenda and in the priorities of national systems in low- and middle-income countries (LMICs). In 2012, the Sustainable Development Goals (SDGs) were created to ensure healthy lives and promoting well-being for all. This roadmap set out to accelerate work to overcome the global impact of NTDs. Almost a decade has passed since NTDs were re-launched as a global priority. Investment in research and development, as well as the production of scientific literature on NTDs, is expected to have increased significantly. (2) Methods: A bibliometric analysis of the scientific production of Latin America and the Caribbean (LAC) was carried out in relation to 19 endemic NTDs. These data were compared with the scientific production in malaria, tuberculosis and HIV / AIDS. The database available from Thomson Reuters Web of Science (WoS) was used. In addition, the average annual growth percentage was calculated for each disease. (3) Results: In the last decade, the NTDs with the highest number of publications in the world were dengue and leishmaniasis. The United States was the most prolific country in the world in 15 out of 19 NTDs analyzed. In the LAC region, Brazil was the largest contributor for 16 of the 19 NTDs analyzed. Arboviral diseases showed the highest average annual growth. The number of publications for malaria, tuberculosis and HIV /AIDS was considerably higher than for NTDs. The contribution of most LAC countries, especially those considered as LMICs, is inadequate and does not reflect the relevance of NTDs for the public health of the population. (4) Conclusion: This is the first bibliometric analysis to assess the trend of scientific documents on endemic NTDs in LAC. Our results could be used by decision makers both to strengthen investment policies in research and development in NTDs.

Proteases catalyse irreversible posttranslational modifications that often alter a biological function of the substrate. The protease dipeptidyl peptidase 4 (DPP4) is a pharmacological target in type 2 diabetes therapy primarily because it inactivates glucagon-like protein-1. DPP4 also has roles in steatosis, insulin resistance, cancers and inflammatory and fibrotic diseases. In addition, DPP4 binds to the spike protein of MERS virus, causing it to be the human cell surface receptor for that virus. DPP4 has been identified as a potential binding target of SARS-CoV-2 spike protein, so this question requires experimental investigation. Understanding protein structure and function requires reliable protocols for production and purification. We developed such strategies for baculovirus generated soluble recombinant human DPP4 (residues 29-766) produced in insect cells. Purification used differential ammonium sulphate precipitation, hydrophobic interaction chromatography, dye affinity chromatography in series with immobilised metal affinity chromatography, and ion exchange chromatography. The binding affinities of DPP4 to the SARS-CoV-2 full-length spike protein and its receptor binding domain (RBD) were measured using surface plasmon resonance and ELISA. This optimised DPP4 purification procedure yielded 1 to 1.8 mg of pure fully active soluble DPP4 protein per litre of insect cell culture with specific activity >30 U/mg, indicative of high purity. No specific binding between DPP4 and CoV-2 spike protein was detected by surface plasmon resonance or ELISA. In summary, a procedure for high purity high yield soluble human DPP4 was achieved and used to show that, unlike MERS-CoV, SARS-CoV-2 does not bind human DPP4.

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) proteins are a diverse and evolutionarily conserved family of cytidine deaminases that provide a variety of functions from tissue-specific gene expression and immunoglobulin diversity to control of viruses and retrotransposons. APOBEC family expansion has been documented among mammalian species, suggesting a powerful selection for their activity. Enzymes with a duplicated zinc-binding domain often have catalytically active and inactive domains, yet both have antiviral function. Although APOBEC antiviral function was discovered through hypermutation of HIV-1 genomes lacking an active Vif protein, much evidence indicates that APOBECs also inhibit virus replication through mechanisms other than mutagenesis. Multiple steps of the viral replication cycle may be affected, although nucleic acid replication is a primary target. Packaging of APOBECs into virions was first noted with HIV-1, yet is not a prerequisite for viral inhibition. APOBEC antagonism may occur in viral producer and recipient cells. Signatures of APOBEC activity include G-to-A and C-to-T mutations in a particular sequence context. The importance of APOBEC activity for viral inhibition is reflected in the identification of numerous viral factors, including Vif, which are dedicated to antagonism of these deaminases. Such viral antagonists often are only partially successful, leading to selection for viral variants.

Different therapeutic strategies have been investigated to target and eliminate HIV-1-infected cells by using armed antibodies specific to viral proteins, with varying degrees of success. Herein, we propose a new strategy by combining photodynamic therapy (PDT) with HIV Env-targeted immunotherapy, and refer to it as HIV photoimmunotherapy (PIT). A human anti-gp41 antibody (7B2) was conjugated to two photosensitizers with different charges through different linking strategies; “Click” conjugation by using an azide-bearing porphyrin attached via a disulfide bridge linker with a drug-to-antibody ratio (DAR) of exactly 4, and “Lysine” conjugation by using phthalocyanine IRDye 700DX dye with average DARs of 2.1, 3.0 and 4.4. These photo-immunoconjugates (PICs) were compared via biochemical and immunological characterizations regarding the dosimetry, solubility, and cell targeting. Photo-induced cytotoxicity of the PICs were compared using assays for apoptosis, reactive oxygen species (ROS), photo-cytotoxicity, and confocal microscopy. Targeted phototoxicity seems to be primarily dependent on the binding of PS-antibody to the HIV antigen on the cell membrane, whilst being independent of the PS type. This is the first report of the application of PIT for HIV immunotherapy by killing HIV Env-expressing cells.

The increasing detection of infections of Trypanosoma cruzi, the etiological agent of Chagas disease, in non-endemic regions beyond Latin America has risen to be a major public health issue. With an impact in the millions of people, current treatments rely on antiquated drugs that produce severe side effects and are considered nearly ineffective for the chronic phase. The minimal progress in the development of new drugs highlights the need for advances in basic research on crucial biochemical pathways in T. cruzi to identify new targets. Here, we report on the T. cruzi presenilin-like transmembrane aspartyl enzyme, a protease of the aspartic class in a unique phylogenetic subgroup with T. vivax separate from protozoans. Computational analyses suggests it contains 9 transmembrane domains and an active site with the characteristic PALP motif of the A22 family. Multiple linear B-cell epitopes were identified by SPOT synthesis analysis with Chagasic patient sera. Two were chosen to generate rabbit antisera, whose signal was primarily localized to the flagellar pocket, intracellular vesicles and endoplasmic reticulum in parasites by whole cell immunofluorescence. The results suggest that the parasitic presenilin-like enzyme could have a role in the secretory pathway and serve as a biomarker for infections.

Background: HIV poses a threat to global health. With effective treatment options available, education and testing strategies are essential in preventing transmission. Text messaging is an effective tool for health promotion and can be used to target higher risk populations. This study reports on the design, delivery and testing of a mobile text messaging SMS intervention for HIV prevention and awareness, aimed at adults in the construction industry and delivered during the COVID-19 pandemic. Method: Participants were recruited at Test@Work workplace health promotion events (21 sites, n=464 employees), including health checks with HIV testing. Message development was based on a participatory design and included a focus group (n=9) and message fidelity testing (n=291) with assessment of intervention uptake, reach, acceptability, and engagement. Barriers to HIV testing were identified and mapped to the COM-B behavioural model. 23 one-way push SMS messages (19 included short web links) were generated and fidelity tested, then sent via automated SMS to two employee cohorts over a 10-week period during the COVID-19 pandemic. Engagement metrics measured were; opt-outs, SMS delivered/read, number of clicks per web link, and four two-way pull messages exploring repeat HIV testing, learning new information, perceived usefulness and behaviour change. Results: 291 people participated (68.3% of eligible attendees). A total of 7,726 messages were sent between March and June 2020, with 91.6% successfully delivered (100% read). 12.4% of participants opted out over 10 weeks. Of delivered messages, links were clicked an average of 14.4%, max 24.1% for HIV related links. The number of clicks on web links declined over time (r= -6.24, p=0.01). Response rate for two-way pull messages was 13.7% of participants. Since the workplace HIV test offer at recruitment, 21.6% reported having taken a further HIV test. Qualitative replies indicated behavioural influence of messaging on exercise, lifestyle behaviours and intention to HIV test. Conclusion: SMS messaging for HIV prevention and awareness is acceptable to adults in the construction industry, has high uptake, low attrition and good engagement with message content, when delivered during a global pandemic. Data collection methods may need refinement for audience and effect of COVID-19 on results is yet to be understood.