Intestinal microbial communities and Holdemanella biformis isolated from HIV+/− men who have sex with men increase frequencies of lamina propria CCR5+ CD4+ T cells. H Biformis HIV

Men who have sex with men (MSM), regardless of HIV infection status, have an intestinal microbiome that is compositionally distinct from men who have sex with women (MSW) and women. We recently showed HIV-negative MSM have elevated levels of intestinal CD4+ T cells expressing CCR5, a critical co-receptor for HIV. Whether elevated expression of CCR5 is driven by the altered gut microbiome composition in MSM has not been explored. Here we used in vitro stimulation of gut Lamina Propria Mononuclear Cells (LPMCs) with whole intact microbial cells isolated from stool to demonstrate that fecal bacterial communities (FBCs) from HIV-positive/negative MSM induced higher frequencies of CCR5+ CD4+ T cells compared to FBCs from HIV-negative MSW. To identify potential microbial drivers, we related the frequency of CCR5+ CD4+ T cells to the abundance of individual microbial taxa in rectal biopsy of HIV-positive/negative MSM and controls, and Holdemanella biformis was strongly associated with increased frequency of CCR5+ CD4+ T cells (p = 0.004). In vitro stimulation of gut LPMCs with wild type and 2 H. biformis strains, cultured from either a HIV-positive or a HIV-negative MSM stool, elevated the frequency of CCR5+ CD4+ T cells in association with the ratio of TNF-α/IL-10 in the culture, but with strain level variation. Genomic comparisons of the 3 H. biformis isolates revealed unique cell wall and capsular components, which may be responsible for their differences in immunogenicity. These findings describe a novel mechanism potentially linking intestinal dysbiosis in MSM to HIV transmission and mucosal pathogenesis.