HIV-1 infection enhances innate function and TLR7 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 anti-retroviral therapy (ART) on pDC functional responses remains poorly understood. Here, we show that pDCs from HIV/ART women exhibit exacerbated production of IFN-alpha and TNF-alpha compared with 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 enhanced functional response of pDCs in HIV/ART women is associated with higher transcriptional activity of the TLR7 locus from both X chromosomes, rather than differences in the frequency of TLR7 biallelic cells. These data reinforce the interest in targeting the HIV-1 reservoir using TLR7 agonists in women.

Automated summary

This study found that pDCs from HIV/ART women exhibited exacerbated production of IFN-alpha and TNF-alpha compared with uninfected controls upon TLR7 activation. The enhanced functional response was associated with higher transcriptional activity of the TLR7 locus from both X chromosomes, rather than differences in the frequency of TLR7 biallelic cells.