Tenofovir, Interferon Pathways, and Mucosal Immunity: Implications for People Living With HIV

ABSTRACT Background Antiretroviral therapy (ART) suppresses HIV replication and protects people living with HIV (PLWH) from progressing to AIDS. However, despite ART, many PLWH experience chronic immune activation, which contributes to premature aging and non‐AIDS‐related 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‐driving effect of tenofovir and other NRTIs warrants further study, as these therapies are taken lifelong and PLWH suffer disproportionately from inflammation‐related comorbidities. Objective This review synthesizes evidence demonstrating that tenofovir contributes to CIA across multiple mucosal compartments (rectum, duodenum, and vagina) in both HIV‐uninfected and infected individuals. We detail the known mechanisms that likely underlie NRTI‐induced CIA: (1) Suppression of interleukin 10 (IL‐10), and induction of interleukin 12 (IL‐12) and interferon‐stimulated genes (ISGs), through inhibition of the protein kinase AKT, and (2) interferon response‐enhancing interactions with endogenous retroelements. Tenofovir also increases the number of specialized ISG high epithelial cells in the gut. We further discuss the hypothesis that the chronic interferon signaling driven by NRTIs exacerbates HIV reservoir persistence and T‐cell exhaustion. Finally, we propose emerging therapeutic strategies, including NRTI‐sparing antiretroviral regimens and targeted immunomodulatory treatments, to reduce CIA and improve clinical outcomes for PLWH.