Deciphering Host–Virus Interactions and Advancing Therapeutics for Chronic Viral Infection
Majid Eslami, Neda Arjmand, Fatemeh Mahmoudian, Ali Babaeizad, Hamed Tahmasebi, Fahimeh Fattahi, Valentyn Oksenych
Abstract
Chronic viral infections like HIV, HBV, and HCV establish persistent interactions with the host immune system, resulting in immune evasion and long-term immune dysfunction. These viruses use a range of strategies to limit host defenses, such as downregulating MHC class I, disrupting interferon signaling, altering apoptosis pathways, and suppressing cytotoxic T-cell activity. Key viral proteins, including HIV Nef, HBV X protein, and HCV NS5A, interfere with antigen presentation and JAK/STAT signaling, thereby reducing antiviral immune responses. Chronic infections induce immune exhaustion due to persistent antigen exposure, which leads to the expression of inhibitory receptors like PD-1 and CTLA-4 on T cells. Viral epigenetic changes, such as N6-methyladenosine modifications and histone deacetylation, enhance immune evasion by modulating gene expression in infected cells. Viruses further manipulate host cytokine networks by promoting an immunosuppressive environment through IL-10 and TGF-β secretion, which suppress inflammatory responses and inhibit T-cell activation. This review examines the molecular/cellular mechanisms that enable chronic viruses to escape host immunity, focusing on antigenic variation, cytokine disruption, and control of apoptotic pathways. It also addresses how host genetic factors, such as HLA polymorphisms, influence disease progression. Lastly, we discuss host-targeted therapies, including immune checkpoint inhibitors, cytokine treatments, and CRISPR.