Manifestations of viral infections can differ between women and men 1 , and significant sex differences have been described in the course of HIV-1 disease. HIV-1-infected women tend to have lower viral load levels early in HIV-1 infection, but progress faster to AIDS for a given viral load than men 2-7 . Here we demonstrate substantial sex differences in the response of plasmacytoid dendritic cells (pDCs) to HIV-1. pDCs derived from women produce significantly more interferon-α (IFN-α) in response to HIV-1-encoded TLR7 ligands than pDCs derived from men, resulting in stronger secondary activation of CD8+ T cells. In line with these in vitro studies, treatment-naïve chronically HIV-1-infected women had significantly higher levels of CD8+ T cell activation than men after adjusting for viral load. These data show that sex differences in TLR-mediated activation of pDCs can account for higher immune activation in women compared to men at a given HIV-1 viral load, and provide a mechanism by which the same level of viral replication might result in faster HIV-1 disease progression in women compared to men. Modulation of the TLR7 pathway in pDCs may therefore represent a novel approach to reduce HIV-1-associated pathology. According to UNAIDS, almost half of all HIV-1-infected individuals worldwide are women. Studies comparing the course of HIV-1 infection between women and men have demonstrated significant sex differences in the manifestations of HIV-1 disease. While HIV-1-infected women present with lower viral load early in HIV-1 infection, women with the same HIV-1 viral load as men have a 1.6-fold higher risk of developing AIDS 2-7 . The mechanisms underlying these significant sex differences in the manifestation of HIV-1 disease are not understood. NIH Public AccessThere is increasing consensus that the level of immune activation in HIV-1-infected subjects is a strong independent predictor for HIV-1 disease progression [8][9][10][11][12][13][14][15][16] . Plasmacytoid dendritic cells (pDCs) play a central role in this HIV-1-induced activation of the immune system, as they can sense HIV-1 ssRNA via Toll-like receptor (TLR)7 [17][18][19][20] . Interestingly, PBMCs derived from women have been shown to produce significantly more IFN-α in response to the synthetic TLR7 ligand Imiquimod than PBMCs derived from men 21 . We therefore reasoned that sex differences in HIV-1-induced immune activation might be responsible for the observed differences in HIV-1 disease, and investigated differences in cytokine production by PBMC in response to HIV-1 between men and women, and their consequences for T cell activation.Intracellular cytokine staining (ICS) using multiparameter flow cytometry was performed to quantify the percentage of pDCs producing IFN-α or TNF-α after stimulation with HIV-1-derived TLR7/8 ligands, TLR9 ligand ODN2216 (CpG-A), or inactivated HIV-1 virus (AT-2 virus) (Fig. 1). A significantly higher percentage of pDCs derived from women produced IFN-α in response to HIV-1-derived TLR ligands or AT-2 viru...

Decline of peak viremia during acute HIV-1 infection occurs before the development of vigorous adaptive immunity, and the level of decline correlates inversely with the rate of AIDS progression, implicating a potential role for the innate immune response in determining disease outcome. The combined expression of an activating natural killer (NK) cell receptor, the killer immunoglobulin-like receptor (KIR) 3DS1, and its presumed ligand, human leukocyte antigen (HLA)–B Bw4-80I, has been associated in epidemiological studies with a slow progression to AIDS. We examined the functional ability of NK cells to differentially control HIV-1 replication in vitro based on their KIR and HLA types. NK cells expressing KIR3DS1 showed strong, significant dose- and cell contact–dependent inhibition of HIV-1 replication in target cells expressing HLA-B Bw4-80I compared with NK cells that did not express KIR3DS1. Furthermore, KIR3DS1+ NK cells and NKLs were preferentially activated, and lysed HIV-1 infected target cells in an HLA-B Bw4-80I–dependent manner. These data provide the first functional evidence that variation at the KIR locus influences the effectiveness of NK cell activity in the containment of viral replication.

BackgroundVery little is known about the immunodominance patterns of HIV-1-specific T cell responses during primary HIV-1 infection and the reasons for human lymphocyte antigen (HLA) modulation of disease progression.Methods and FindingsIn a cohort of 104 individuals with primary HIV-1 infection, we demonstrate that a subset of CD8+ T cell epitopes within HIV-1 are consistently targeted early after infection, while other epitopes subsequently targeted through the same HLA class I alleles are rarely recognized. Certain HLA alleles consistently contributed more than others to the total virus-specific CD8+ T cell response during primary infection, and also reduced the absolute magnitude of responses restricted by other alleles if coexpressed in the same individual, consistent with immunodomination. Furthermore, individual HLA class I alleles that have been associated with slower HIV-1 disease progression contributed strongly to the total HIV-1-specific CD8+ T cell response during primary infection.ConclusionsThese data demonstrate consistent immunodominance patterns of HIV-1-specific CD8+ T cell responses during primary infection and provide a mechanistic explanation for the protective effect of specific HLA class I alleles on HIV-1 disease progression.