Review maps cell-specific MAVS and inflammasome signaling in HIV-1

A review of innate immune signaling in human immunodeficiency virus type 1 (HIV-1) infection identifies mitochondrial antiviral signaling protein (MAVS) as a link between cytosolic viral RNA sensing, type I interferon production, inflammatory signaling and inflammasome activation. The authors argue that this pathway has context-dependent consequences: innate immune responses can restrict viral replication, but their sustained activation can also contribute to immune dysfunction, CD4+ T-cell loss and chronic immune activation. The review was published as an open-access article in the Journal of Translational Medicine on 21 October 2026 and synthesizes evidence from HIV-1 infection models, related findings from other viral systems and proposed links that still require validation in HIV-1.

MAVS operates downstream of cytosolic viral RNA sensing and coordinates antiviral responses through type I interferon and nuclear factor kappa B (NF-κB) signaling. The review examines how this signaling intersects with activation of the NLRP3 inflammasome. In the pathway described, MAVS contributes to inflammasome activation, which is followed by caspase-1 activation, gasdermin D cleavage, cytokine release and pyroptotic cell death. These linked events provide a mechanistic explanation for how viral recognition can generate both antiviral activity and inflammatory responses. Rather than assigning MAVS a single role, the review presents it as a signaling hub whose effects depend on the cellular context and the downstream pathway that becomes engaged.

The clearest HIV-1-specific contrasts in the review emerge from the different outcomes in myeloid cells, macrophages and quiescent CD4+ T cells. In myeloid cells and macrophages, HIV-1 has evolved several mechanisms that dampen MAVS-dependent antiviral responses. This suppression can weaken innate controls on replication and create conditions favorable to viral replication and persistence. The review also emphasizes that mechanisms demonstrated in HIV-1 infection models should not be conflated with findings established in other viral systems. Its central model is therefore not that every viral sensing event converges on MAVS, but that HIV-1 regulates innate pathways in a cell type-dependent manner, suppressing antiviral activity in some compartments while allowing or promoting inflammatory pathways in others.

Abortive infection of quiescent CD4+ T cells follows a distinct route in the evidence summarized by the review. Rather than requiring MAVS, this response uses IFI16-dependent, caspase-1-mediated pyroptosis. The authors describe this MAVS-independent pathway as a major contributor to CD4+ T-cell depletion and chronic inflammation. The distinction matters because it separates MAVS-dependent signaling from inflammasome activation that can occur without MAVS. The review also discusses emerging evidence for CARD8-mediated inflammasome activation, identifying it as another potential route through which innate pathways may complement antiviral defense while influencing HIV-1 pathogenesis. These findings broaden the network under consideration beyond a single MAVS-centered axis and show that different inflammasome pathways can be associated with distinct outcomes.

The review places these mechanistic observations in the broader problem that HIV-1 is not cured by antiretroviral therapy because latent viral reservoirs persist and chronic immune activation continues alongside infection. Its proposed significance is that understanding how MAVS, inflammasomes and pyroptosis interact across different cell types may open possibilities for host-directed approaches intended to limit viral persistence and reduce chronic inflammation. That remains a research direction, not an established treatment or demonstrated clinical benefit. The evidence reviewed is primarily mechanistic and draws on multiple experimental systems; the authors explicitly distinguish observations made in HIV-1 models from evidence derived from other viral infections and from connections that still need validation in HIV-1.

Subject of Research: Cell-specific MAVS-dependent and independent inflammasome signaling in HIV-1 infection

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

Article References: Nesci, S., Glogowski, P. A., Cugliari, A., Trombetti, F., & Algieri, C. (2026). MAVS signaling in HIV-1 infection: linking innate viral sensing to inflammasome activation, pyroptosis and viral persistence. Journal of Translational Medicine. https://doi.org/10.1186/s12967-026-09119-5

Image Credits: AI Generated

DOI: 10.1186/s12967-026-09119-5

Keywords: HIV-1, MAVS, Inflammasomes, Pyroptosis, Innate immunity, CD4+ T cells, NLRP3, IFI16, CARD8, Viral persistence, signaling, infection