The STAT Signaling Pathway in HIV-1 Infection: Roles and Dysregulation

The STAT (Signal Transducer and Activator of Transcription) signaling pathway plays a central role in immune regulation by mediating cytokine responses and orchestrating both innate and adaptive immunity. Although CD4+ T cell depletion is the main driver of HIV-1-induced immunodeficiency, the virus also exerts a significant and often underestimated impact by disrupting the function of STAT family members, thereby exacerbating immune imbalance and accelerating disease progression. Specifically, HIV-1 suppresses STAT1 activation, impairing the induction of antiviral genes; inhibits IL-23-driven STAT3 activation in CD4+ Th17 cells with a reduction in IL-17; alters STAT3-dependent functions in antigen-presenting cells; and imposes profound-and at times opposing-dysregulations of STAT5, including the induction of a truncated isoform that contributes to latency. Notably, pharmacological inhibition of the JAK/STAT axis, particularly with JAK2 inhibitors, has been shown to reduce integrated proviral DNA and viral replication in vitro and in early clinical studies. This review provides an updated overview of the roles of individual STAT proteins in HIV-1 infection and pathogenesis, emphasizing the intricate interplay between viral factors and host signaling, highlighting the potential therapeutic implications, and suggesting that immunological assessment in HIV-1 patients should extend beyond CD4+ T cell counts and the CD4/CD8 ratio to include functional analysis of STAT signaling for deeper insights into immune dysfunction and chronic inflammation.