Modulation of Toll-like receptor driven monocyte activation by JAK-STAT inhibitors in people with HIV

Chronic immune activation and systemic inflammation persist in people 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) signalling. 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 signalling and IFN-I-mediated amplification - can be modulated by JAK-STAT inhibition.

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.

Monocytes isolated by negative selection from peripheral blood mononuclear cells (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 h and/or 24 h using flow cytometry, qPCR, and ELISA.

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 h.

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.