{ "abstract": "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. Author summary: The intestinal microbiome is increasingly recognized as an important contributor to susceptibility to HIV infection, but the mechanisms underlying this relationship remain poorly understood. We previously identified changes in antimicrobial immune pathways associated with increased rectal SIV acquisition, including pathways responsive to the metabolite uracil. Here, we tested whether increased intestinal uracil availability alters susceptibility to rectal SIV infection in rhesus macaques. Despite limited evidence of rectal inflammation or epithelial damage, oral uracil treatment increased the number of viruses establishing infection, indicating increased susceptibility. Oral treatment also altered peripheral and small intestinal immune responses and perturbed the fecal microbiome. In contrast, uracil delivered directly to the large intestine by suppository increased markers of intestinal epithelial damage but did not increase SIV acquisition. These findings demonstrate that uracil can alter susceptibility to rectal SIV infection, but that increased susceptibility does not require overt damage to the rectal epithelial barrier. Our results highlight the potential for microbiome-associated metabolites to influence HIV transmission through mechanisms beyond local intestinal inflammation.", "abstract_shown": true, "affiliations": [ "Barrier Immunity Section, Laboratory of Viral Diseases, Division of Intramural Research, National Institute of Allergy and Infectious Diseases (NIAID), National Institutes of Health (NIH), Bethesda, Maryland, United States of America.", "Proteins and Chemistry Section, Research Technologies Branch, NIAID, NIH, Bethesda, Maryland, United States of America.", "AIDS and Cancer Virus Program, Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America." ], "article_type": "Research Article", "arxiv": null, "author_total": 13, "authors": [ { "affs": [ 0 ], "name": "Elizabeth G Bodykevich" }, { "affs": [ 0 ], "name": "Fabiola Castello Casta" }, { "affs": [ 0 ], "name": "Jacob K Flynn" }, { "affs": [ 0 ], "name": "Charlotte A Nichols" }, { "affs": [ 1 ], "name": "Glenn A Nardone" }, { "affs": [ 2 ], "name": "Christine M Fennessey" }, { "affs": [ 0 ], "name": "Kelsie Brooks" }, { "affs": [ 0 ], "name": "Delmy Ruiz" }, { "affs": [ 0 ], "name": "Jennifer Simpson" }, { "affs": [ 0 ], "name": "Carol L Vinton" }, { "affs": [ 2 ], "name": "Brandon F Keele", "orcid": "0000-0002-2381-1151" }, { "affs": [ 0 ], "name": "Jason M Brenchley" }, { "affs": [ 0 ], "name": "Alexandra M Ortiz", "orcid": "0000-0001-5835-9380" } ], "bibtex": "https://research.draconitic.com/paper/2gmy3p8j65f6z.bib", "cited_by": 0, "doi": "10.1371/journal.ppat.1014716", "fulltext_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014716", "id": "2gmy3p8j65f6z", "issns": [ "1553-7374", "1553-7366" ], "landing_url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014716", "language": "eng", "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "2406|HIV Research and Treatment" ], [ "plos", "/Biology and life sciences/Anatomy/Digestive system/Gastrointestinal tract" ], [ "plos", "/Biology and life sciences/Anatomy/Digestive system/Gastrointestinal tract/Jejunum" ], [ "plos", "/Biology and life sciences/Anatomy/Digestive system/Gastrointestinal tract/Rectum" ], [ "plos", "/Biology and life sciences/Biochemistry/Nucleotides/Nucleobases/Uracils" ], [ "plos", "/Biology and life sciences/Genetics/Genomics/Microbial genomics/Microbiome" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Immunodeficiency viruses/HIV" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Immunodeficiency viruses/SIV" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Retroviruses/Lentivirus/HIV" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbial pathogens/Viral pathogens/Retroviruses/Lentivirus/SIV" ], [ "plos", "/Biology and life sciences/Microbiology/Medical microbiology/Microbiome" ], [ "plos", "/Biology and life sciences/Microbiology/Microbial genomics/Microbiome" ], [ "plos", "/Biology and life sciences/Organisms/Eukaryota/Animals/Vertebrates/Amniotes/Mammals/Primates/Monkeys/Old World monkeys/Macaque" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Immunodeficiency viruses/HIV" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Immunodeficiency viruses/SIV" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/RNA viruses/Retroviruses/Lentivirus/HIV" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/RNA viruses/Retroviruses/Lentivirus/SIV" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Immunodeficiency viruses/HIV" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Immunodeficiency viruses/SIV" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Retroviruses/Lentivirus/HIV" ], [ "plos", "/Biology and life sciences/Organisms/Viruses/Viral pathogens/Retroviruses/Lentivirus/SIV" ], [ "plos", "/Biology and life sciences/Zoology/Animals/Vertebrates/Amniotes/Mammals/Primates/Monkeys/Old World monkeys/Macaque" ], [ "plos", "/Medicine and health sciences/Anatomy/Digestive system/Gastrointestinal tract" ], [ "plos", "/Medicine and health sciences/Anatomy/Digestive system/Gastrointestinal tract/Jejunum" ], [ "plos", "/Medicine and health sciences/Anatomy/Digestive system/Gastrointestinal tract/Rectum" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Immunodeficiency viruses/HIV" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Immunodeficiency viruses/SIV" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Retroviruses/Lentivirus/HIV" ], [ "plos", "/Medicine and health sciences/Pathology and laboratory medicine/Pathogens/Microbial pathogens/Viral pathogens/Retroviruses/Lentivirus/SIV" ] ], "openalex": "W7223231002", "pdf_url": "https://journals.plos.org/plospathogens/article/file?id=10.1371/journal.ppat.1014716&type=printable", "pmcid": "PMC13690236", "pmid": "42911942", "published": "2026-10-22", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/2gmy3p8j65f6z.ris", "sources": [ { "first_seen": "2026-10-30T12:17:23Z", "native_id": "10.1371/journal.ppat.1014716", "source": "plos", "url": "https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1014716" }, { "first_seen": "2026-10-30T12:20:10Z", "native_id": "MED:42911942", "source": "europepmc", "url": "https://europepmc.org/article/MED/42911942" } ], "subjects": [ { "field": "biology", "origin": "plos:microbiology", "subfield": "microbiology" }, { "field": "medicine", "origin": "plos:anatomy", "subfield": "physiology" } ], "title": "Oral uracil treatment increases susceptibility to rectal SIV infection", "title_text": "Oral uracil treatment increases susceptibility to rectal SIV infection", "type": "peer-reviewed", "updated_at": "2026-10-30T12:20:10Z", "url": "https://research.draconitic.com/paper/2gmy3p8j65f6z", "venue": "PLOS Pathogens", "versions": [] }