Vaginal microbiota and mucosal HIV-1 transmission

This thesis aimed to unravel the unique immune mechanisms in vaginal mucosa. We developed and validated a primary human vaginal tissue model that allowed us to study the most relevant immune cells during dysbiosis of the vaginal microbiome and HIV-1 transmission in people assigned female at birth.
Key findings include that Prevotella timonensis, a bacterium associated with dysbiosis of the vaginal microbiome, induced strong pro-inflammatory immune responses in dendric cells, typically associated with adverse pregnancy outcomes. We furthermore show that vaginal Langerhans cells (LCs) can restrict HIV-1 infection through langerin-autophagy-mediated mechanisms, but lose this protective function after immune activation in response to bacterial ligands. Notably, autophagy-enhancing drugs showed potential in suppressing mucosal HIV-1 infection in prophylactic and therapeutic settings. Moreover, vaginal LCs selectively transmit R5-tropic HIV-1 to CD4+ T cells, explaining the predominance of R5 variants in early infections.
Further studies revealed that Prevotella timonensis exposure increased HIV-1 sequestration in vaginal LCs and CD4+ T cells, leading to productive infection in CD4+ T cells and creating viral reservoirs in LCs. These reservoirs were drug resistant, remained infectious and facilitated HIV-1 dissemination. Additionally, vaginal LC-T cell clustering mediated by langerin promotes HIV-1 transmission, suggesting conflicting roles for langerin in HIV-1 infections.
Overall, this research provides critical insights into the interplay between mucosal immunity, vaginal microbiota and HIV-1.