The majority of HIV infected individuals fail to produce protective antibodies and have diminished responses to immunization1–3. We report that even though there is an expansion of T follicular helper (Tfh) cells in HIV infected individuals, these are unable to provide adequate B cell help. A higher frequency of PD-L1+ germinal center (GC) B cells from lymph nodes of HIV infected individuals suggested a potential role for PD-1/PD-L1 interaction in regulating Tfh cell function. In fact, engagement of PD-1 on Tfh cells led to a reduction in cell proliferation, activation, ICOS expression and IL-21 cytokine secretion. Importantly, blocking PD-1 signaling enhanced HIV-specific immunoglobulin production in vitro. We further show that at least part of this defect involves IL-21 as addition of this cytokine rescued antibody responses and plasma cell generation. Our results suggest that deregulation of Tfh-mediated B cell help diminishes B cell responses during HIV infection and may be related to PD-1 triggering on Tfh cells. These results show, for the first time, a role for Tfh cell function in HIV pathogenesis and suggest that an alteration in their function could have a significant impact on the outcome and control of HIV infection, future infections and vaccinations.

Viral replication and microbial translocation from the gut to the blood during HIV infection lead to hyperimmune activation, which contributes to the decline in CD4+ T cell numbers during HIV infection. Programmed death-1 (PD-1) and interleukin-10 (IL-10) are both upregulated during HIV infection. Blocking interactions between PD-1 and programmed death ligand-1 (PD-L1) and between IL-10 and IL-10 receptor (IL-10R) results in viral clearance and improves T cell function in animal models of chronic viral infections. Here we show that high amounts of microbial products and inflammatory cytokines in the plasma of HIV-infected subjects lead to upregulation of PD-1 expression on monocytes that correlates with high plasma concentrations of IL-10. Triggering of PD-1 expressed on monocytes by PD-L1 expressed on various cell types induced IL-10 production and led to reversible CD4+ T cell dysfunction. We describe a new function for PD-1 whereby microbial products inhibit T cell expansion and function by upregulating PD-1 levels and IL-10 production by monocytes after binding of PD-1 by PD-L1.

Human T cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T cell leukemia and HTLV-1-associated myelopathies. In addition to T cells, HTLV-1 infects cells of the myeloid lineage, which play critical roles in the host innate response to viral infection. Investigating the monocyte depletion observed during HTLV-1 infection, we discovered that primary human monocytes infected with HTLV-1 undergo abortive infection accompanied by apoptosis dependent on SAMHD1, a host restriction factor that hydrolyzes endogenous dNTPs to below the levels required for productive reverse transcription. Reverse transcription intermediates (RTI) produced in the presence of SAMHD1 induced IRF3-mediated antiviral and apoptotic responses. Viral RTIs complexed with the DNA sensor STING to trigger formation of an IRF3-Bax complex leading to apoptosis. This study provides a mechanistic explanation for abortive HTLV-1 infection of monocytes and reports a link between SAMHD1 restriction, HTLV-1 RTI sensing by STING, and initiation of IRF3-Bax driven apoptosis.