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

Abstract

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...

TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands

“…Our data adds to previous reports on the influence of sex on production of IFNα by pDCs, demonstrating that also surface maturation markers are upregulated more in female pDCs (Berghöfer et al, 2006;Meier et al, 2009;Seillet et al, 2012Seillet et al, , 2013. The effect of sex on upregulation of especially CD40 but also CD86 was respectively mostly or partially explained by the rs179008 variant allele.…”

“…For HBV, the prevalence of the variant allele among chronic patients has not yet been explored. pDC function is also affected by sex: male pDCs, as compared to female pDCs, produce less IFNα upon TLR7 but not TLR9 ligation (Berghöfer et al, 2006;Meier et al, 2009). This difference is believed to derive from expression differences of X-chromosomal genes downstream of TLR7, combined with hormonal effects (Seillet et al, 2012(Seillet et al, , 2013Griesbeck et al, 2015).…”

Inhibitory effects of chloroquine on the activation of plasmacytoid dendritic cells in SIVmac239-infected Chinese rhesus macaques

“…20 Therefore, type I IFN levels are likely to play a role in the pathogenesis of AIDS during HIV or SIV infection. 23 Meier et al 24 reported the difference in the rate of AIDS progression between male and female HIV-positive patients correlated with level of IFN-a, as the PBMCs derived from female patients produced higher levels of IFN-a in response to TLR7 ligands than those derived from male patients. It was also reported that circulating pDCs in HIVinfected individuals showed an increase in IFN-a expression.…”

Immune Activation in the Pathogenesis of Treated Chronic HIV Disease: A Workshop Summary

“…Work from Dr. Marcus Altfeld's laboratory has shown a gender difference in the profile of interferon production, with HIV-mediated interferon induction much higher in women compared to men. 51 Women also have higher immune activation than men, which increases through reproductive aging. 52 Many of the clinical aspects associated with aging appear to be accelerated in ART-treated HIV-infected adults.…”