Abstract
Plasmacytoid dendritic cells (pDCs) produce type I interferon (IFN-I) during HIV-1 infection in response to TLR7 stimulation. However, IFN-I-signaling has been shown to play opposite effects in HIV-1 and SIV infection. TLR7-driven type I interferon production in pDCs is higher in women than in men due to the cell-intrinsic actions of estrogen and X-chromosome complement. Indeed, TLR7 is encoded on the X-chromosome, and the TLR7 gene escapes the X-chromosome inactivation in immune cells of women which express significantly higher levels of TLR7 protein than male cells. Following HIV infection, women have a lower viremia during acute infection and exhibit stronger antiviral responses than men, which has been attributed to the increased capacity of female pDCs to produce IFN-α upon TLR7-stimulation. However, a deleterious functional impact of an excessive TLR7 response on acute viremia in women has been recently revealed by the analysis of the frequent rs179008 c.32A>T SNP of TLR7. This SNP was identified as a sex-specific protein abundance quantitative trait locus (pQTL) causing a difference in the TLR7 protein dosage and effector function in females only. T allele expression was associated with a lower TLR7 protein synthesis, blunted production of IFN-α by pDCs upon TLR7 stimulation, and an unexpectedly lower viral load during primary HIV-1 infection in women. In the present review, the author will revisit the role of TLR7-driven pDC innate function in the context of HIV-1 infection to discuss at what stage of primary HIV-1 infection the TLR7 rs179008 T allele is likely to be protective in women.
Highlights
Sex differences in the acquisition and pathogenesis of human immunodeficiency virus 1 (HIV-1) disease between men and women have long been reported in epidemiological studies, reviewed in [1, 2]
In chronic HIV infection, women have a higher level of CD8+ T cells activation after adjustment for viral loads, that correlates with an enhanced functional response of plasmacytoid dendritic cells (pDCs), suggesting that the sex-bias in the Toll-like receptor 7 (TLR7)-driven production of type interferon (IFN-I) by pDCs could contribute to the inflammatory mechanism responsible for the more rapid disease progression seen in women [8]
In women carrying the rs179008 T allele, not totally inhibited, such early mechanisms initiated by pDCs-derived IFN-I would be less operating resulting in a significant inhibition of viral spreading and expansion at the early stage of infection (Figure 2)
Summary
Sex differences in the acquisition and pathogenesis of HIV-1 disease between men and women have long been reported in epidemiological studies, reviewed in [1, 2]. Based on the recent study [26], the author will propose that the higher propensity of female pDCs to produce IFN-I in response to TLR7 stimulation is unlikely to contribute to the sex differences in an acute HIV-1 infection.
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