Oral uracil treatment increases susceptibility to rectal SIV infection

The intestinal microbiomes of men who have sex with men (MSM) are distinct as compared to non-MSM and may increase susceptibility to rectal HIV infection. We recently demonstrated that dysbiosis-associated disruptions to host antimicrobial immunity increase macaque susceptibility to rectal SIVmac239X acquisition. The described susceptibility-associated network identified Dual Oxidase 2 (DUOX2) - an epithelial sensor that catalyzes reactive oxygen species (ROS) production upon sensing pathobiont-derived uracil - as a likely contributor to increased SIV susceptibility. We hypothesized that intestinal, uracil bioavailability increases susceptibility to rectal HIV acquisition. Here, we treated rhesus macaques with oral uracil or uracil suppositories, prior to low-dose intra-rectal challenge with SIVmac239X. Oral treatment reduced pro-inflammatory cytokine production from peripheral T-cells but did not perturb rectal immunologic transcripts or epithelial ROS production and did not alter biomarkers of intestinal damage. Although treatment with uracil suppositories led to increased concentrations of fecal uracil and indices of intestinal damage, there were fewer immunological perturbations relative to oral treatment. Despite limited evidence of intestinal damage, oral uracil treatment increased susceptibility to intra-rectal SIV acquisition whereas uracil suppositories did not. These data provide mechanistic insights into intra-rectal SIV acquisition and may lead to novel therapeutic interventions that reduce incidence of HIV acquisition.