Preprint Article Version 1 Preserved in Portico This version is not peer-reviewed

Deciphering the Role of Post-translational Modifications and Cellular Location of HDV Antigens in HDV-Mediated Liver Damage in Mice

Sheila Maestro
ORCID logo ,
Carla Usai
,
Nahia Gomez-Echarte
ORCID logo ,
Gracian Camps
,
Cristina Olagüe
,
Africa Vales
ORCID logo ,
Rafael Aldabe
,
Gloria Gonzalez-Aseguinolaza
* ORCID logo
Version 1 : Received: 19 January 2024 / Approved: 23 January 2024 / Online: 23 January 2024 (09:49:03 CET)

A peer-reviewed article of this Preprint also exists.

Maestro, S.; Gomez-Echarte, N.; Camps, G.; Usai, C.; Olagüe, C.; Vales, A.; Aldabe, R.; Gonzalez-Aseguinolaza, G. Deciphering the Role of Post-Translational Modifications and Cellular Location of Hepatitis Delta Virus (HDV) Antigens in HDV-Mediated Liver Damage in Mice. Viruses 2024, 16, 379. Maestro, S.; Gomez-Echarte, N.; Camps, G.; Usai, C.; Olagüe, C.; Vales, A.; Aldabe, R.; Gonzalez-Aseguinolaza, G. Deciphering the Role of Post-Translational Modifications and Cellular Location of Hepatitis Delta Virus (HDV) Antigens in HDV-Mediated Liver Damage in Mice. Viruses 2024, 16, 379.

Abstract

Hepatitis D virus (HDV) infection represents the most severe form of chronic viral hepatitis. We have shown that the delivery of HDV replication-competent genomes to the hepatocytes using adenoassociated virus (AAV-HDV) as gene delivery vehicles offers a unique platform to investi-gate the molecular aspects of HDV and associated liver damage. Here, we generated HDV ge-nomes modified by site directed mutagenesis aimed to: i) prevent some post-translational modi-fications of HDV antigens (HDAgs) such as Large-HDAg (L-HDAg) isoprenylation or Short-HDAg (S-HDAg) phosphorylation ii) alter the localization of HDAgs within the subcellular compartments and iii) inhibit the right conformation of the delta ribozyme. First, the different HDV mutants were tested in vitro using plasmid-transfected Huh-7 cells and then in vivo in C57BL/6 mice using AAV vectors. We found that Ser 177 phosphorylation and the ribozymal ac-tivity are essential for HDV replication and HDAg expression. Mutation of the isoprenylation domain prevent the formation of infectious particles and increase cellular toxicity and liver dam-age. Finally, altering the intracellular localization od HDAg have a profound on viral replication in vivo but liver toxicity is maintained. Mutation in the nuclear export signal impair the for-mation of infectious viral particles. These findings contribute valuable insights into the intricate mechanisms of HDV biology and have implications for therapeutic considerations

Keywords

HDV; HDAg post-translational modification; isoprenylation; phosphorylation; ribozyme; intra-cellular localization: cell and mouse models; liver damage

Subject

Biology and Life Sciences, Virology

Copyright: This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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