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

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: 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.