Sensing of HIV-1 nucleic acids by TLR8 in human CD4+ T cells

During HIV-infection, cell-to-cell transmission results in endosomal uptake of the virus by target CD4+ T cells and potential exposure of the viral ssRNA genome to endolysosomal Toll-like receptors (TLRs). TLRs are instrumental in activating inflammatory responses in innate immune cells, but their function in adaptive immune cells is less well understood. Here we show that combined TLR8 ligand and T cell receptor (TCR) stimulation boosted CD4+ T cell activation by enhancing NF-kB and MAPK signaling. This led to increased production of inflammatory cytokines and surface activation marker expression. Adjuvant TLR8 stimulation, but not TLR7 or TLR9, promoted interleukin (IL)-17 and interferon (IFN)-g effector cytokine production, indicating lineage commitment towards the pro-inflammatory T helper (Th)1 and Th17 axis. Using a cell-to-cell transmission model, we found that endosomal HIV-1 induced cytokine secretion from CD4+ T cells, which could be significantly reduced by a TLR8 specific inhibitor. TLR8 engagement also enhanced HIV-1 replication in CD4+ T cells and potentiated the reversal of latency in patient-derived CD4+ T cells. Taken together, our results reveal a previously unknown function of TLR8 in human primary CD4+ T cells in shaping immunity and modulating HIV-1 infection. This adjuvant TLR8 activity can contribute to low-grade inflammation seen in HIV patients and may have broad implications for therapeutic targeting and vaccine development.