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During acute infection, robust IFN signaling is critical in controlling viral replication, activating innate immunity, and limiting reservoir establishment. However, sustained IFN-I activation during chronic infection fuels systemic inflammation, immune exhaustion, and fibrosis, particularly in lymphoid tissues such as gut-associated lymphoid tissue (GALT). Prolonged IFN-I exposure upregulates inhibitory receptors on T cells, impairs metabolic fitness, and fosters an immunosuppressive cytokine milieu that weakens overall immune responses. In contrast to natural SIV (Simian immunodeficiency virus) hosts, IFN-I responses are tightly regulated to prevent chronic immune activation and tissue damage. However, humans and non-natural hosts experience persistent Interferon Stimulated Gene (ISG) expression and IFN-I driven inflammation. Emerging therapeutic strategies seek to harness the antiviral benefits of IFN-I while mitigating its pathogenic effects. Approaches such as the IFNAR blockade, autophagy induction, JAK-STAT inhibition, and combined immune inhibitory blockade therapy show promise in restoring immune balance and enhancing T cell function. This review examines the mechanisms of IFN-I dysregulation in chronic HIV-1 infection and highlights novel interventions aimed at finetuning IFN-I signaling for therapeutic benefit.<\/jats:p>","DOI":"10.3390\/v17060774","type":"journal-article","created":{"date-parts":[[2025,5,29]],"date-time":"2025-05-29T04:46:38Z","timestamp":1748493998000},"page":"774","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":11,"title":["Finetuning Type I Interferon Signaling to Enhance T Cell Immunity in HIV Infection"],"prefix":"10.3390","volume":"17","author":[{"given":"Wenli","family":"Mu","sequence":"first","affiliation":[{"name":"Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nandita","family":"Kedia","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anjie","family":"Zhen","sequence":"additional","affiliation":[{"name":"Division of Hematology and Oncology, David Geffen School of Medicine, University of California, Los Angeles, CA 90095, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2025,5,29]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"1205","DOI":"10.1097\/QAD.0b013e328354622a","article-title":"The evolving epidemiology of HIV\/AIDS","volume":"26","author":"Jaffe","year":"2012","journal-title":"AIDS"},{"key":"ref_2","doi-asserted-by":"crossref","first-page":"15035","DOI":"10.1038\/nrdp.2015.35","article-title":"HIV infection","volume":"1","author":"Deeks","year":"2015","journal-title":"Nat. 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