HIV-1 infection induces functional reprogramming of female plasmacytoid dendritic cells associated with enhanced TLR7 expression

Abstract

AbstractPlasmacytoid dendritic cells (pDCs) express TLR7, a ssRNA-sensor encoded on the X chromosome, which escapes X chromosome inactivation (XCI) in females. pDCs are specialized in the production of type 1 interferons (IFN-I) through TLR7 activation which mediates both immune cell activation and also reactivation of latent HIV-1. The effect of HIV-1 infection in women under antiretroviral therapy (ART) on pDC functional responses remains poorly understood. Here, we show that pDCs from HIV/ART women exhibit exacerbated production of IFN-α and TNF-α as compared to uninfected controls (UC) upon TLR7-activation. Because TLR7 can escape XCI in female pDCs, we measured the contribution of TLR7 allelic expression using SNP haplotypic markers to rigorously tag the allele of origin of TLR7 gene at single cell resolution. Herein, we provide evidence that the functional reprogramming of pDCs in HIV/ART women is associated with enhanced transcriptional activity of the TLR7 locus from both X chromosomes, rather than differences in the frequency of TLR7 bi-allelic cells. These data reinforce the interest in targeting the HIV-1 reservoir using TLR7 agonists in women.