Breaking down barriers Prevotella timonensis and mucosal immunity in HIV-1 susceptibility

HIV-1 remains a major global health problem with the highest burden of new infections among adolescent girls and young women living in sub-Saharan Africa. While the immune system plays a crucial role in defending against HIV-1, several factors increase the risk of HIV-1 acquisition, such as dysbiosis of the vaginal microbiome. Bacterial vaginosis (BV) is characterized by disruption of the vaginal microbiome and overgrowth of anaerobic bacteria, consistently associated with increased susceptibility to sexual HIV-1 transmission. This research aimed to unravel how BV-associated bacteria, particularly Prevotella timonensis, shape mucosal immunity and HIV-1 uptake and transmission by immune cells and identify underlying mechanisms. We examined how the vaginal microbiota influences HIV-1 susceptibility at the mucosal interface, focusing on P. timonensis, a bacterium strongly associated with vaginal dysbiosis. Using primary human immune cells, we showed P. timonensis directly enhanced HIV-1 uptake by dendritic cells and CD4⁺ T cells, facilitating viral dissemination. Furthermore, we showed P. timonensis also altered immune cell behaviour by promoting dendritic cell–T cell clustering and shaping local immune responses, indicating a broader role in mucosal immune dysregulation. Mechanistically, we identified a highly potent membrane-bound enzyme expressed by P. timonensis as a key driver of the observed effects. Collectively, these findings provide new insights into how BV-associated bacteria modulate immune cells and promote HIV-1 dissemination and highlight specific bacterial enzymes as potential targets for future prevention strategies.