Retrovirus-Induced Immunosuppression: A Comprehensive Review

Retroviruses induce immunosuppression in their infected hosts. This phenomenon is well described for the immunodeficiency viruses, with human immunodeficiency virus type 1 (HIV-1) representing the best-studied example, but it also occurs in other retroviral infec-tions. Immunosuppressive properties were first characterized in murine leukemia viruses (MuLV). Additional well-studied examples include feline leukemia virus (FeLV) and koala retrovirus (KoRV). Investigations into the mechanisms underlying retrovirus-induced immunosuppression revealed that not only inactivated viral particles, but also their purified transmembrane envelope (TM) proteins exhibit immunosuppressive activity. However, in certain retroviral infections, additional viral proteins contribute to the immunosup-pression in vivo. Within the TM proteins, a highly conserved region, designated the immunosuppressive (isu) domain, was identified. Synthetic peptides corresponding to this domain suppress a wide range of in vitro immune responses by regulating Ras-Raf-MEK-MAPK and PI3K-AKT-mTOR pathways. They modulate cytokine release and alter gene expression in immune cells, mirroring the activity of the corresponding TM protein. Mutations in the sequence abrogate the effect. Numerous TM proteins have demonstrated immunosuppressive activity in vivo, in a tumor rejection model, and muta-tions within the isu domain also abrogate this function. These studies have important implications for reproduction, particularly through the immunosuppressive syncytins in the placenta; for tumor development, where similar mechanisms may protect cancer cells from the host immune system; as well as for vaccine development and xenotransplantation. Notably, immunization with TM proteins carrying mutations in the isu domain elic-its stronger immune responses compared with the wild-type proteins. Finally, the potential of retroviral TM proteins to protect xenotransplants from immune rejection will be discussed.