MAVS signaling in HIV-1 infection: linking innate viral sensing to inflammasome activation, pyroptosis and viral persistence

Despite the remarkable success of antiretroviral therapy, human immunodeficiency virus type 1 (HIV-1) remains incurable because of the persistence of latent viral reservoirs and the chronic immune activation that accompanies infection. While innate immune responses are essential for restricting viral replication, sustained activation of these pathways also contributes to immune dysfunction, CD4 + T-cell loss, and HIV-1-associated comorbidities. Among the molecules involved in antiviral immunity, mitochondrial antiviral signaling protein (MAVS) has emerged as a key regulator that links cytosolic viral RNA sensing to type I interferon production, inflammatory signaling, and inflammasome activation. In this review, we discuss the current evidence on the interplay between MAVS signaling, inflammasome activation, and pyroptosis during HIV-1 infection. We first summarize the molecular mechanisms underlying MAVS activation and its role in coordinating antiviral responses through interferon and NF-κB signaling. We then examine how MAVS contributes to NLRP3 inflammasome activation and the downstream events leading to caspase-1 activation, gasdermin D cleavage, cytokine release, and pyroptotic cell death. Particular attention is given to the different outcomes of these pathways in distinct target cells. In myeloid cells and macrophages, HIV-1 has evolved several mechanisms to dampen MAVS-dependent antiviral responses, thereby promoting viral replication and persistence. In contrast, abortive infection of quiescent CD4 + T cells activates IFI16-dependent, caspase-1-mediated pyroptosis through a MAVS-independent route, which is now recognized as a major driver of CD4 + T-cell depletion and chronic inflammation. We also discuss emerging evidence supporting the role of MAVS-independent pathways, including IFI16- and CARD8-mediated inflammasome activation, highlighting how these mechanisms complement antiviral defense while also influencing HIV-1 pathogenesis. Overall, the available evidence suggests that HIV-1 finely modulates innate immune signaling in a cell type-dependent manner, suppressing antiviral responses where viral persistence is advantageous while promoting inflammatory pathways that contribute to disease progression. We distinguish mechanisms demonstrated in HIV-1 infection models from findings established in other viral systems and from proposed connections that require validation in HIV-1. A better understanding of the MAVS-inflammasome-pyroptosis axis may provide new opportunities for the development of host-directed therapeutic strategies aimed at limiting viral persistence, reducing chronic inflammation, and improving long-term outcomes in people living with HIV.