OBJECTIVE: Chronic immune activation and systemic inflammation persist in people living with HIV (PWH) despite effective antiretroviral therapy, contributing to increased cardiovascular and cancer risk. Monocytes play a central role in this process, partly through type I interferon (IFN-I) signaling. As Toll-like receptor (TLR) 3 and 7 are key inducers of endogenous IFN-I in response to viral RNA, we investigated how TLR3 and TLR7 stimulation contributes to IFN-I-driven monocyte activation, and whether this response-potentially involving both direct TLR signaling and IFN-I mediated amplification- can be modulated by JAK-STAT inhibition. DESIGN: We assessed IFN-mediated monocyte activation following TLR3 and TLR7 stimulation and evaluated the effect of JAK-STAT inhibition on the expression of activation markers, immune checkpoint ligands, and cytokine production. METHODS: Monocytes isolated by negative selection from PBMCs of PWH were stimulated with the TLR3 agonist Poly(I:C), the TLR7 agonist Imiquimod, or IFN-α2a. Cells were treated with the JAK1/2 inhibitor Baricitinib or the TYK2-selective inhibitor Deucravacitinib. Activation markers, immune checkpoint proteins, and cytokines were analyzed at 4 and/or 24 hours using flow cytometry, qPCR, and ELISA. RESULTS: TLR stimulation induced IFN-mediated activation in monocytes from PWH, with increased PD-L1, CD80 and HLA-DR expression, CXCL10 production, and a shift toward pro-inflammatory subsets. JAK-STAT inhibitors significantly reduced PD-L1 and CXCL10 levels and partially decreased TIM-3 expression, particularly at 24 hours. CONCLUSION: TLR3 and TLR7 agonists induce IFN-driven monocyte activation in PWH, which is effectively modulated by JAK-STAT inhibitors. These findings support their potential as therapeutic agents to mitigate inflammation in chronic HIV infection.
Camard et al. (Mon,) studied this question.