{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,20]],"date-time":"2026-09-20T16:39:11Z","timestamp":1789922351134,"version":"4.0.1"},"reference-count":102,"publisher":"MDPI AG","issue":"3","license":[{"start":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T00:00:00Z","timestamp":1741564800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Viruses"],"abstract":"<jats:p>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-\u03b2 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.<\/jats:p>","DOI":"10.3390\/v17030390","type":"journal-article","created":{"date-parts":[[2025,3,10]],"date-time":"2025-03-10T08:46:41Z","timestamp":1741596401000},"page":"390","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":24,"title":["Deciphering Host\u2013Virus Interactions and Advancing Therapeutics for Chronic Viral Infection"],"prefix":"10.3390","volume":"17","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-5118-678X","authenticated-orcid":false,"given":"Majid","family":"Eslami","sequence":"first","affiliation":[{"name":"Cancer Research Center, Semnan University of Medical Sciences, Semnan 35147-99442, Iran"},{"name":"Department of Bacteriology and Virology, Faculty of Medicine, Semnan University of Medical Sciences, Semnan 35147-99442, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Neda","family":"Arjmand","sequence":"additional","affiliation":[{"name":"Department of Obstetrics and Gynecology, Tehran Medical University, Tehran 14167-53955, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Fatemeh","family":"Mahmoudian","sequence":"additional","affiliation":[{"name":"Cancer Research Center, Semnan University of Medical Sciences, Semnan 35147-99442, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ali","family":"Babaeizad","sequence":"additional","affiliation":[{"name":"Student Research Committee, Semnan University of Medical Sciences, Semnan 35147-99442, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9257-4479","authenticated-orcid":false,"given":"Hamed","family":"Tahmasebi","sequence":"additional","affiliation":[{"name":"School of Medicine, Shahroud University of Medical Sciences, Shahroud 36147-73943, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2563-0004","authenticated-orcid":false,"given":"Fahimeh","family":"Fattahi","sequence":"additional","affiliation":[{"name":"Clinical Research Development Unit of Ayatollah-Khansari Hospital, Arak University of Medical Sciences, Arak 38186-49433, Iran"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5088-3791","authenticated-orcid":false,"given":"Valentyn","family":"Oksenych","sequence":"additional","affiliation":[{"name":"Faculty of Medicine, University of Bergen, 5020 Bergen, Norway"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,3,10]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"30","DOI":"10.1016\/j.cell.2009.06.036","article-title":"Redefining chronic viral infection","volume":"138","author":"Virgin","year":"2009","journal-title":"Cell"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"573","DOI":"10.1146\/annurev-virology-100114-055226","article-title":"Innate and Adaptive Immune Regulation During Chronic Viral Infections","volume":"2","author":"Zuniga","year":"2015","journal-title":"Annu. 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