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However, despite ART, many PLWH experience chronic immune activation, which contributes to premature aging and non\u2010AIDS\u2010related comorbidities. One reason for this chronic immune activation (CIA) is HIV and its reservoir. There is, however, accumulating evidence for an unexpected contributor: the nucleoside\/nucleotide reverse transcriptase inhibitor (NRTI) class of drugs, particularly tenofovir, which can independently induce interferon (IFN) signaling in mucosal tissues. This CIA\u2010driving effect of tenofovir and other NRTIs warrants further study, as these therapies are taken lifelong and PLWH suffer disproportionately from inflammation\u2010related comorbidities.<\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec>\n                    <jats:title>Objective<\/jats:title>\n                    <jats:p>\n                      This review synthesizes evidence demonstrating that tenofovir contributes to CIA across multiple mucosal compartments (rectum, duodenum, and vagina) in both HIV\u2010uninfected and infected individuals. We detail the known mechanisms that likely underlie NRTI\u2010induced CIA: (1) Suppression of interleukin 10 (IL\u201010), and induction of interleukin 12 (IL\u201012) and interferon\u2010stimulated genes (ISGs), through inhibition of the protein kinase AKT, and (2) interferon response\u2010enhancing interactions with endogenous retroelements. Tenofovir also increases the number of specialized ISG\n                      <jats:sup>high<\/jats:sup>\n                      epithelial cells in the gut. We further discuss the hypothesis that the chronic interferon signaling driven by NRTIs exacerbates HIV reservoir persistence and T\u2010cell exhaustion. Finally, we propose emerging therapeutic strategies, including NRTI\u2010sparing antiretroviral regimens and targeted immunomodulatory treatments, to reduce CIA and improve clinical outcomes for PLWH.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1111\/aji.70255","type":"journal-article","created":{"date-parts":[[2026,5,11]],"date-time":"2026-05-11T15:15:37Z","timestamp":1778512537000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":1,"title":["Tenofovir, Interferon Pathways, and Mucosal Immunity: Implications for People Living With HIV"],"prefix":"10.1111","volume":"95","author":[{"given":"Florian","family":"Hladik","sequence":"first","affiliation":[{"name":"Department of Obstetrics and Gynecology, Division of Research University of Washington  Seattle Washington USA"},{"name":"Department of Medicine, Division of Allergy and Infectious Diseases University of Washington  Seattle Washington 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