The Contribution of Cervicovaginal Microbiota and Hormonal Contraceptives to Genital Inflammation and HIV Acquisition Risk

Abstract

The HIV epidemic persists in many parts of the world, with the majority of new infections occurring through the female genital tract (FGT). The permissiveness of the genital mucosa to HIV is modulated by the integrity of the epithelial barrier, the presence of pro-inflammatory cytokines, and the frequency of CCR5+CD4+ T cell targets. Here we focus on two biological perturbations: endogenous alterations in cervicovaginal bacteria and exogenous injectable progestin-only contraceptives (IPCs). We examine their effects on the genital mucosal environment and their link to HIV susceptibility in a cohort of young South African women.

We first sought to determine how genital microbiota modulate host inflammatory responses. The existing paradigm is that vaginal monocolonization by Lactobacillus is normal, and encroachment by other bacteria is pathologic. By characterizing cervicovaginal bacterial communities in 94 South African women using 16S rRNA and shotgun sequencing, we found that the majority of participants had low Lactobacillus abundance and high ecological diversity. One diverse Prevotella-containing community type strongly correlated with increased concentrations of multiple genital pro-inflammatory cytokines in vivo. We found that these cytokines were produced by epithelial cells and antigen presenting cells via different bacterial sensing mechanisms. Our results identify specific bacterial species that alter the inflammatory state of the FGT and may more broadly impact reproductive health in women.

We also investigated the immunological effects of IPCs, the most common form of birth control in sub-Saharan Africa. Although highly effective as a contraceptive, IPCs are controversially associated with increased HIV susceptibility by an unclear mechanism. We found that IPC users had a 5.5-fold higher risk of acquiring HIV than women not using family planning (p=0.0031, 95% CI: 1.733 – 16.80). Phenotypic cellular analysis revealed that IPC users also had a significantly higher frequency of activated HIV target cells in the cervix. Since the availability of target cells in the genital mucosa enables early viral replication, recruitment or retention of these cells by IPCs may explain the observed increased HIV acquisition rates. Furthermore, IPC use was not associated with differences in genital cytokine levels, indicating that cervicovaginal bacteria and exogenous progesterone increase HIV susceptibility by unique pathways.