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Increased PD-L1 expression has been reported in HIV-1-infected individuals, but the mechanisms leading to PD-L1 upregulation remain to be elucidated. Here we demonstrate that HIV-1-derived Toll-like receptor (TLR)7/8 ligands can induce MyD88-dependent upregulation of PD-L1 on plasmacytoid dendritic cells, myeloidic dendritic cells and monocytes. These data suggest a mechanism through which HIV-1-derived TLR ligands might contribute to the functional impairment of virus-specific PD-1-positive T cells by inducing the upregulation of PD-L1 on antigen-presenting cells.

Background Immunodominance and sequence diversity are major hurdles in the development of effective HIV vaccines. We tested the hypothesis that a vaccine candidate composed of strictly Conserved Elements (CE) of the HIV proteome excluding the variable regions would help overcome problems of viral sequence diversity and potential negative effects of immunodominance. Seven CE were identified in p24. Vaccination of macaques with p55DNA failed to elicit cellular or humoral immune responses to the CE, while epitopes outside of the CE were immunogenic.

Understanding the underlying immunological mechanisms of spontaneous HIV control by HIV+ elite controllers (EC) remains an important step in the development of efficient HIV vaccines and functional cures. To understand control mechanisms triggered by CD8+ T cell we established a system in non-activated peripheral blood mononuclear cells (PBMC) using infectious HIV (NL4.3 IRES GFP) carrying the fusion protein Vpr-Beta lactamase (to assess viral entry) and a staining strategy to study the CD8+ T cell response by flow cytometry. First we showed that non-activated CD4+ T cells are permissive for HIV entry but this leads mostly to abortive infection (b-lac+ GFP-). CD8+ T cells from EC were able to recognize these HIV+ cells, became activated (IFNg+, MIP1b+) and underwent degranulation (CD107a+). This activation was initiated by the presentation of HIV peptides from incoming viruses and HLA-I blockade almost abolished this response. We confirmed by mass spectrometry HIV peptides processed in the cytoplasm of CD4+ cells shortly after HIV entry. These results suggest that the ability of CD8+ T cells to form immunological synapses allows them to be activated by low levels of HIV antigens from incoming particles at the surface of early-infected CD4+ T cells. Killing of abortively HIV-infected cells early after HIV entry might avoid inflammation due to pyroptosis and therefore contribute to HIV control.

Background We previously showed that plasmacytoid dendritic cells (pDCs) derived from females can produce significantly more IFN-alpha in response to HIV-1 and HIV-1-encoded TLR7/8 ligands than pDCs derived from males, resulting in stronger secondary activation of CD8+ T cells (Meier et al., Nat Med 2009). Given the crucial role of interferon regulatory factor 7 (IRF7) in the regulation of type I IFN production by pDCs, the goal of the current study was to investigate its impact on the observed differences.

Background: We previously showed that plasmacytoid dendritic cells (pDCs) derived from females can produce significantly more IFNα in response to HIV-1 and HIV-1-encoded TLR7/8 ligands than pDCs derived from males, resulting in stronger secondary activation of CD8+ T cells. Given the crucial role of interferon regulatory factor 7 (IRF7) in the regulation of type I IFN production by pDCs, we hypothesized that IRF7is involved in the differences observed in IFNα production. Methods: Fresh PBMC were isolated from HIV-1-negative subjects enrolled at Massachusetts General Hospital. Levels of IRF7 were measured in pDCs by phospho-flow cytometry, In-Cell Western blotting and qRT-PCR at baseline and at different time-points after TLR7 stimulation. IFNα levels were quantified by flow cytometry, ELISA and qRT-PCR Results: We observed a higher percentage of pDCs expressing phosphorylated IRF7 at baseline in females than in males using flow cytometry (p