Oral uracil raises rectal SIV susceptibility in macaques

Oral uracil treatment increased susceptibility to rectal simian immunodeficiency virus (SIV) acquisition in rhesus macaques, even though the treatment produced only limited measurable changes in the animals’ intestinal immunity, according to a study published in PLOS Pathogens.

Researchers led by Elizabeth G. Bodykevich and Alexandra M. Ortiz tested whether intestinal uracil bioavailability raises the risk of rectal HIV acquisition. The work builds on earlier findings that intestinal microbiomes of men who have sex with men differ from those of non-MSM and may increase susceptibility to rectal HIV infection, and that dysbiosis-associated disruptions to host antimicrobial immunity increase macaque susceptibility to rectal SIVmac239X acquisition. That earlier network analysis identified DUOX2, an epithelial sensor that catalyzes reactive oxygen species production upon sensing pathobiont-derived uracil, as a likely contributor to increased susceptibility.

In the new experiments, rhesus macaques received either oral uracil or uracil suppositories before low-dose intra-rectal challenge with SIVmac239X. Oral treatment reduced pro-inflammatory cytokine production from peripheral T-cells, but it did not perturb rectal immunologic transcripts or epithelial reactive oxygen species production, and it did not alter biomarkers of intestinal damage.

Uracil suppositories produced a different pattern. The suppositories led to increased concentrations of fecal uracil and indices of intestinal damage, yet caused fewer immunological perturbations relative to oral treatment.

Despite the limited evidence of intestinal damage from oral uracil, oral treatment increased susceptibility to intra-rectal SIV acquisition, whereas uracil suppositories did not. The authors say these data provide mechanistic insights into intra-rectal SIV acquisition and may lead to novel therapeutic interventions that reduce the incidence of HIV acquisition. The findings come from a macaque challenge model, so their relevance to human HIV acquisition will require further study.

Subject of Research: Effects of oral and suppository uracil treatment on rectal SIV susceptibility in rhesus macaques

Article Title: Oral uracil treatment increases susceptibility to rectal SIV infection

Article References: Bodykevich, E. G., Castello Casta, F., Flynn, J. K., Nichols, C. A., Nardone, G. A., Fennessey, C. M., Brooks, K., Ruiz, D., Simpson, J., Vinton, C. L., Keele, B. F., Brenchley, J. M., & Ortiz, A. M. (2026). Oral uracil treatment increases susceptibility to rectal SIV infection. PLOS Pathogens, 22(10), e1014716. https://doi.org/10.1371/journal.ppat.1014716

Image Credits: AI Generated

DOI: 10.1371/journal.ppat.1014716

Keywords: HIV, SIV, uracil, rhesus macaques, rectal infection, DUOX2, intestinal microbiome, dysbiosis, antimicrobial immunity, PLOS Pathogens, Oral, treatment