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. 2009 Aug;15(8):955-9.
doi: 10.1038/nm.2004. Epub 2009 Jul 13.

Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1

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Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1

Angela Meier et al. Nat Med. 2009 Aug.

Abstract

Manifestations of viral infections can differ between women and men, and marked sex differences have been described in the course of HIV-1 disease. HIV-1-infected women tend to have lower viral loads early in HIV-1 infection but progress faster to AIDS for a given viral load than men. Here we show substantial sex differences in the response of plasmacytoid dendritic cells (pDCs) to HIV-1. pDCs derived from women produce markedly more interferon-alpha (IFN-alpha) in response to HIV-1-encoded Toll-like receptor 7 (TLR7) ligands than pDCs derived from men, resulting in stronger secondary activation of CD8(+) T cells. In line with these in vitro studies, treatment-naive women chronically infected with HIV-1 had considerably 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 may 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 new approach to reduce HIV-1-associated pathology.

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Figures

Figure 1
Figure 1
Sex differences in IFN-α production of pDC following TLR7/8 stimulation with HIV-1-derived ligands. (a) Representative flow plots demonstrating the IFN-α production by CD123+ pDCs derived from women (upper panel) and by CD123+ pDCs derived from men (lower panel) for unstimulated controls (left column), and following 20 h of stimulation with the HIV-1 derived TLR7/8 ligand GagRNA1166 (middle column) or the TLR9 ligand ODN2216 (right column) are shown. The percentage of IFN-α producing pDCs is shown in the upper right corner of each plot. (b) The percentage of IFN-α+ pDCs in men (shown in black, n = 20) as compared to women (shown in red, n = 23) following stimulation with the HIV-1-derived ssRNAs, GagRNA1166 and Gp160RNA2093, or the TLR9 ligand ODN2216 are shown. (c) The percentage of IFN-α+ pDCs from men (shown in black, n = 19) and women (shown in red, n = 22) following stimulation with AT-2 inactivated HIV-1 virus (AT-2) or vesicle control (Ves) is shown. (d) Representative flow plots demonstrating the TNF-α production by CD123+ pDCs are shown. The percentage of TNF-α producing pDCs is shown in the upper right corner of each plot. (e) The percentage of TNF-α+ pDCs in men (shown in black, n = 20) and women (shown in red, n = 23) following stimulation with the HIV-1-derived ssRNAs, GagRNA1166 and Gp160RNA2093, or ODN2216 are shown. All horizontal bars represent mean value for that sample group.
Figure 2
Figure 2
Impact of sex hormone levels on the IFN-α production by pDCs in response to TLR7/8 agonists. Plasma progesterone levels measured in 16 pre-menopausal women were significantly correlated to the percentage of IFN-α+ pDCs in response to stimulation with the HIV-1 derived TLR7/8 ligand GagRNA1166.
Figure 3
Figure 3
Sex differences in CD38 expression on CD8+ T cells following stimulation with HIV-1-derived TLR7/8 ligands is dependent on IFN-α (a) The percent CD38high CD8+ T cells following 20 h of stimulation with HIV-1-derived TLR7/8 ligands (Gp160RNA2093 and GagRNA1166), inactive control ssRNA (GagRNA1166A), AT-2 virus, or vesicle control for all individuals is shown. (b) Differences in the percent CD38high CD8+ T cells from men (shown in black) and from women (shown in red) following 20 h of stimulation of PBMCs with the HIV-1 derived TLR7/8 ligands, Gp160RNA2093 and GagRNA1166, inactive control ssRNA (GagRNA1166A), AT-2 virus, or vesicle control is shown. (c) The percentage of CD38highCD8+ T cells above background in response to the TLR7 ligand CL097 was set to 100%, and the remaining activation in the presence of blocking antibodies against IFN-α receptors 1 and 2 is shown in the right column (CL097 + anti-IFNAR1/2). (d) Dose dependent increase in T cell activation as represented by percent of CD38highCD8+ T cells was observed following stimulation of PBMCs from healthy donors with increasing amounts of human IFN-α ranging from 0–100 ng ml−1. All horizontal bars represent mean value for that sample group.
Figure 4
Figure 4
Sex differences in the CD4+ and CD8+ T cell activation of HIV-1-infected, treatment-naïve individuals. The association between sex and the percentage of CD38+HLA-DR+CD4+ (a) or CD38+HLA-DR+CD8+ (b) T cells adjusting for HIV-1 viral load is shown. HIV-1 RNA load measured at baseline in women (open red symbol) and men (closed blue symbol) are correlated to CD4+ and CD8+ T cell activation (correlation for women shown with red dotted line and for men with blue solid line).

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