HIV-1 infection enhances innate function and <i>TLR7</i> expression in female plasmacytoid dendritic cells.

Plasmacytoid 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 compared with uninfected controls (UC) upon TLR7 activation. Because <i>TLR7</i> can escape XCI in female pDCs, we measured the contribution of <i>TLR7</i> allelic expression using SNP haplotypic markers to rigorously tag the allele of origin of <i>TLR7</i> gene at single-cell resolution. Herein, we provide evidence that the enhanced functional response of pDCs in HIV/ART women is associated with higher transcriptional activity of the <i>TLR7</i> locus from both X chromosomes, rather than differences in the frequency of <i>TLR7</i> biallelic cells. These data reinforce the interest in targeting the HIV-1 reservoir using TLR7 agonists in women.