Type I interferon responses in CD14+ monocytes amplify CD4+ T-cell activation in PWH

T-cell activation is a key feature of chronic HIV infection and is predictive of non-AIDS-defining comorbidities in people with HIV (PWH) receiving antiretroviral therapy (ART). Monocytes from PWH display distinct transcriptional programs, yet their role in T-cell activation remains unclear. In this study, we investigated how the response of CD14 + monocytes from PWH to type I interferon (IFN-I) influences T-cell activation. Ex vivo transcriptional profiles and in vitro IFN-I responses of CD14 + monocytes were compared between PWH and uninfected individuals (UI). We identified distinct ex vivo transcriptional signatures in CD14 + monocytes from PWH versus UI, as well as differential responses to IFN-I. T cells from ART-treated PWH exhibited persistent activation, which correlated positively with IFN-I-stimulated gene expression. In vitro IFN-I exposure led to increased proportions of activated CD4 + T cells in PWH - but not in UI – under conditions of TCR engagement, an effect reproduced by the transfer of IFN-I-primed CD14 + monocytes. Finally, JAK inhibitors effectively blocked IFN-I-mediated T-cell activation. Our findings underscore the role of IFN-I-primed CD14 + monocytes in sustaining chronic T-cell activation during HIV infection and highlight JAK inhibitors as a potential therapeutic strategy.