{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"institution":[{"name":"medRxiv"}],"indexed":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T13:42:18Z","timestamp":1786196538239,"version":"build-2736575974"},"posted":{"date-parts":[[2026,8,6]]},"group-title":"HIV\/AIDS","reference-count":30,"publisher":"openRxiv","license":[{"start":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T00:00:00Z","timestamp":1785974400000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"The Intramural Research Program of the National Institute of Health","award":["R01AI155080-01A1"],"award-info":[{"award-number":["R01AI155080-01A1"]}]},{"name":"The Intramural Research Program of the National Institute of Health","award":["R01AI143333-01"],"award-info":[{"award-number":["R01AI143333-01"]}]},{"name":"Gates Foundation","award":["OPP1175094"],"award-info":[{"award-number":["OPP1175094"]}]},{"name":"Gates Foundation","award":["OPP1084362"],"award-info":[{"award-number":["OPP1084362"]}]},{"name":"HIV Prevention Trials Network Laboratory Center","award":["UM1-AI068613"],"award-info":[{"award-number":["UM1-AI068613"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"accepted":{"date-parts":[[2026,8,6]]},"abstract":"<jats:title>Summary<\/jats:title>\n                <jats:sec>\n                  <jats:title>Background<\/jats:title>\n                  <jats:p>As HIV incidence declines in African settings with high treatment coverage, it remains unclear how transmission is structured within populations and whether new infections arise from external introductions or local transmission. We characterized the molecular epidemiology of ongoing transmission in a mature multi-subtype epidemic in Uganda.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Methods<\/jats:title>\n                  <jats:p>We analyzed HIV genome sequences and survey data from the Rakai Community Cohort Study collected between 1994 and 2019. We identified phylogenetic clusters at 5\u00b73% and 2\u00b75% genetic distance thresholds and inferred long-horizon transmission chains with phylogeographic models. Newly diagnosed infections identified between 2016 and 2019 were mapped onto subtype- specific phylogenies to assess their origins and transmission context. A Bayesian negative binomial branching process model estimated undersampled chain sizes and case reproduction numbers.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Findings<\/jats:title>\n                  <jats:p>Among 4215 participants living with HIV between December 2016 and May 2019, 474 were newly diagnosed, of whom 269 had at least one pure-subtype sequence available. We identified 649 phylogenetic clusters at 5\u00b73% genetic distance and 673 phylogeographic chains including \u22652 individuals. Most clusters and chains were small (median sizes 2 [IQR 2\u20133] and 3 [2\u20134], respectively), with new diagnoses rarely clustered together. Only 46\/269 (17\u00b71%) new diagnoses had phylogeographic external origins, while the remaining 82\u00b79% were partially or fully linked to local chains. Mixed-subtypes\/recombinant chains were larger and had higher case reproduction numbers (A1\/D: 0.84 [95% CrI: 0.79-0.93]; mixed: 0.84 [0.73-0.97]) than single- subtype chains (A1: 0.56 [0.51-0.60]; D: 0.63 [0.59-0.66]; C: 0.55 [0.41-0.71]), yet all estimates were less than one.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Interpretation<\/jats:title>\n                  <jats:p>HIV transmission was fragmented across numerous, slowly propagating lineages, maintained by local clusters with occasional introduction. Continued transmission across many chains suggests that further reductions in HIV incidence will require maintaining high levels of population-wide treatment and prevention coverage.<\/jats:p>\n                <\/jats:sec>\n                <jats:sec>\n                  <jats:title>Funding<\/jats:title>\n                  <jats:p>The National Institute of Allergy and Infectious Diseases, the Gates Foundation, and the HIV Prevention Trials Network Laboratory Center<\/jats:p>\n                <\/jats:sec>","DOI":"10.64898\/2026.08.04.26359711","type":"posted-content","created":{"date-parts":[[2026,8,6]],"date-time":"2026-08-06T21:45:11Z","timestamp":1786052711000},"source":"Crossref","is-referenced-by-count":0,"title":["Molecular Epidemiology of HIV in an African Epidemic with Declining HIV incidence but High Prevalence: A Longitudinal, Population-based Study in Uganda"],"prefix":"10.64898","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-5509-0969","authenticated-orcid":false,"given":"Seungwon","family":"Kim","sequence":"first","affiliation":[{"name":"Department of Epidemiology, Gillings School of Global Public Health, University of North Carolina, NC, USA"},{"name":"Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2328-8671","authenticated-orcid":false,"given":"Alexandra","family":"Blenkinsop","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Imperial College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9689-4066","authenticated-orcid":false,"given":"Michael A.","family":"Martin","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2760-5443","authenticated-orcid":false,"given":"Batsirai M.","family":"Mabvakure","sequence":"additional","affiliation":[{"name":"Lombardi Comprehensive Cancer Center, Georgetown University, Washington, DC, USA"},{"name":"Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1245-4774","authenticated-orcid":false,"given":"Robert","family":"Ssekubugu","sequence":"additional","affiliation":[{"name":"Rakai Health Sciences Program, Kalisizo, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-6429-4760","authenticated-orcid":false,"given":"Oliver","family":"Laeyendecker","sequence":"additional","affiliation":[{"name":"Rakai Health Sciences Program, Kalisizo, Uganda"},{"name":"Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"name":"National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas C.","family":"Quinn","sequence":"additional","affiliation":[{"name":"Rakai Health Sciences Program, Kalisizo, Uganda"},{"name":"Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"name":"National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6977-3405","authenticated-orcid":false,"given":"Edward N.","family":"Kankaka","sequence":"additional","affiliation":[{"name":"Rakai Health Sciences Program, Kalisizo, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-6193-2790","authenticated-orcid":false,"given":"Gertrude","family":"Nakigozi","sequence":"additional","affiliation":[{"name":"Rakai Health Sciences Program, Kalisizo, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0008-9142-6870","authenticated-orcid":false,"given":"Godfrey","family":"Kigozi","sequence":"additional","affiliation":[{"name":"Rakai Health Sciences Program, Kalisizo, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4337-3707","authenticated-orcid":false,"given":"Andrew","family":"Rambaut","sequence":"additional","affiliation":[{"name":"Institute of Evolutionary Biology, University of Edinburgh, Edinburgh, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-3662-4192","authenticated-orcid":false,"given":"Lucie","family":"Abeler-D\u00f6rner","sequence":"additional","affiliation":[{"name":"Pandemic Sciences Institute, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2399-9657","authenticated-orcid":false,"given":"Christophe","family":"Fraser","sequence":"additional","affiliation":[{"name":"Pandemic Sciences Institute, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Bonsall","sequence":"additional","affiliation":[{"name":"Centre for Human Genetics, Nuffield Department of Medicine, University of Oxford, Oxford, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5403-2759","authenticated-orcid":false,"given":"Steven J.","family":"Reynolds","sequence":"additional","affiliation":[{"name":"Rakai Health Sciences Program, Kalisizo, Uganda"},{"name":"Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"name":"National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7985-4567","authenticated-orcid":false,"given":"Larry W.","family":"Chang","sequence":"additional","affiliation":[{"name":"Department of Medicine, Johns Hopkins School of Medicine, Baltimore, MD, USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8667-4118","authenticated-orcid":false,"given":"Oliver","family":"Ratmann","sequence":"additional","affiliation":[{"name":"Department of Mathematics, Imperial College London, London, UK"},{"name":"Imperial-X, Imperial College London, London, UK"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5962-151X","authenticated-orcid":false,"given":"Ronald M","family":"Galiwango","sequence":"additional","affiliation":[{"name":"Rakai Health Sciences Program, Kalisizo, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4451-3436","authenticated-orcid":false,"given":"M. Kate","family":"Grabowski","sequence":"additional","affiliation":[{"name":"Department of Pathology, Johns Hopkins School of Medicine, Baltimore, MD, USA"},{"name":"Department of Epidemiology, Johns Hopkins Bloomberg School of Public Health, Baltimore, MD, USA"},{"name":"Rakai Health Sciences Program, Kalisizo, Uganda"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"name":"the Rakai Health Sciences Program PANGEA-HIV consortium","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"54368","reference":[{"key":"2026080805450809000_2026.08.04.26359711v1.1","doi-asserted-by":"crossref","unstructured":"UNAIDS. UNAIDS GLOBAL AIDS UPDATE 2025: aids, crisis and the power to transform. S.l.: UNITED NATIONS, 2025.","DOI":"10.18356\/9789211544350"},{"key":"2026080805450809000_2026.08.04.26359711v1.2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1702150"},{"key":"2026080805450809000_2026.08.04.26359711v1.3","doi-asserted-by":"publisher","DOI":"10.1002\/JIA2.25818"},{"key":"2026080805450809000_2026.08.04.26359711v1.4","doi-asserted-by":"publisher","DOI":"10.1016\/S1473-3099(18)30647-9"},{"key":"2026080805450809000_2026.08.04.26359711v1.5","doi-asserted-by":"crossref","first-page":"1174","DOI":"10.3390\/v13061174","article-title":"The Role of Phylogenetics in Discerning HIV-1 Mixing among Vulnerable Populations and Geographic Regions in Sub- Saharan Africa: A Systematic Review","volume":"13","year":"2021","journal-title":"Viruses"},{"key":"2026080805450809000_2026.08.04.26359711v1.6","doi-asserted-by":"crossref","unstructured":"Kim S , Kigozi G , Martin MA , et al. Intra- and inter-subtype HIV diversity between 1994 and 2018 in southern Uganda: a longitudinal population-based study. Virus Evol 2024; : veae065.","DOI":"10.1093\/ve\/veae065"},{"key":"2026080805450809000_2026.08.04.26359711v1.7","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001610"},{"key":"2026080805450809000_2026.08.04.26359711v1.8","doi-asserted-by":"crossref","unstructured":"Monod M , Brizzi A , Galiwango RM , et al. Longitudinal population-level HIV epidemiologic and genomic surveillance highlights growing gender disparity of HIV transmission in Uganda. Nat Microbiol 2023; 9: 35\u201354.","DOI":"10.1038\/s41564-023-01530-8"},{"key":"2026080805450809000_2026.08.04.26359711v1.9","doi-asserted-by":"publisher","DOI":"10.1089\/aid.2020.0062"},{"key":"2026080805450809000_2026.08.04.26359711v1.10","doi-asserted-by":"crossref","unstructured":"Wawer MJ , Gray RH , Sewankambo NK , et al. A randomized, community trial of intensive sexually transmitted disease control for AIDS prevention, Rakai, Uganda: AIDS 1998; 12: 1211\u201325.","DOI":"10.1097\/00002030-199810000-00014"},{"key":"2026080805450809000_2026.08.04.26359711v1.11","doi-asserted-by":"publisher","DOI":"10.1089\/aid.1995.11.1413"},{"key":"2026080805450809000_2026.08.04.26359711v1.12","doi-asserted-by":"crossref","unstructured":"Ragonnet-Cronin M , Hodcroft E , Hu\u00e9 S , et al. Automated analysis of phylogenetic clusters. BMC Bioinformatics 2013; 14: 317.","DOI":"10.1186\/1471-2105-14-317"},{"key":"2026080805450809000_2026.08.04.26359711v1.13","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-019-09139-4"},{"key":"2026080805450809000_2026.08.04.26359711v1.14","doi-asserted-by":"publisher","DOI":"10.1089\/AID.2016.0205"},{"key":"2026080805450809000_2026.08.04.26359711v1.15","doi-asserted-by":"publisher","DOI":"10.1093\/ve\/vew031"},{"key":"2026080805450809000_2026.08.04.26359711v1.16","doi-asserted-by":"crossref","first-page":"182","DOI":"10.1007\/s11904-018-0384-1","article-title":"Genetic Cluster Analysis for HIV Prevention","volume":"15","year":"2018","journal-title":"Curr HIV\/AIDS Rep"},{"key":"2026080805450809000_2026.08.04.26359711v1.17","doi-asserted-by":"publisher","DOI":"10.1093\/ve\/vey016"},{"key":"2026080805450809000_2026.08.04.26359711v1.18","doi-asserted-by":"publisher","DOI":"10.1093\/molbev\/msx304"},{"key":"2026080805450809000_2026.08.04.26359711v1.19","doi-asserted-by":"crossref","first-page":"e76487","DOI":"10.7554\/eLife.76487","article-title":"Estimating the potential to prevent locally acquired HIV infections in a UNAIDS Fast-Track City, Amsterdam","volume":"11","year":"2022","journal-title":"eLife"},{"key":"2026080805450809000_2026.08.04.26359711v1.20","doi-asserted-by":"crossref","unstructured":"Peters PJ , Pontones P , Hoover KW , et al. HIV Infection Linked to Injection Use of Oxymorphone in Indiana, 2014\u20132015. N Engl J Med 2016; 375: 229\u201339.","DOI":"10.1056\/NEJMoa1515195"},{"key":"2026080805450809000_2026.08.04.26359711v1.21","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pmed.1001568"},{"key":"2026080805450809000_2026.08.04.26359711v1.22","doi-asserted-by":"crossref","first-page":"e1001898","DOI":"10.1371\/journal.pmed.1001898","article-title":"Dispersion of the HIV-1 Epidemic in Men Who Have Sex with Men in the Netherlands: A Combined Mathematical Model and Phylogenetic Analysis","volume":"12","year":"2015","journal-title":"PLOS Med"},{"key":"2026080805450809000_2026.08.04.26359711v1.23","doi-asserted-by":"publisher","DOI":"10.1093\/infdis\/jiaa276"},{"key":"2026080805450809000_2026.08.04.26359711v1.24","doi-asserted-by":"crossref","first-page":"e0002891","DOI":"10.1371\/journal.pgph.0002891","article-title":"HIV epidemiologic trends among occupational groups in Rakai, Uganda: A population-based longitudinal study, 1999\u20132016","volume":"4","year":"2024","journal-title":"PLOS Glob Public Health"},{"key":"2026080805450809000_2026.08.04.26359711v1.25","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-020-14636-y"},{"key":"2026080805450809000_2026.08.04.26359711v1.26","doi-asserted-by":"publisher","DOI":"10.64898\/2026.04.29.26350859"},{"key":"2026080805450809000_2026.08.04.26359711v1.27","doi-asserted-by":"crossref","first-page":"e181","DOI":"10.1016\/S2352-3018(18)30009-2","article-title":"Migration and risk of HIV acquisition in Rakai, Uganda: a population-based cohort study","volume":"5","year":"2018","journal-title":"Lancet HIV"},{"key":"2026080805450809000_2026.08.04.26359711v1.28","doi-asserted-by":"crossref","first-page":"150","DOI":"10.1097\/QAI.0000000000003553","article-title":"HIV and Viremia Prevalence in Nonmigrating Members of Migrant Households in Southern Uganda: A Cross-Sectional Population-Based Study","volume":"98","year":"2025","journal-title":"JAIDS J Acquir Immune Defic Syndr"},{"key":"2026080805450809000_2026.08.04.26359711v1.29","doi-asserted-by":"publisher","DOI":"10.1007\/s10461-018-2367-z"},{"key":"2026080805450809000_2026.08.04.26359711v1.30","doi-asserted-by":"crossref","first-page":"212","DOI":"10.1186\/s12859-025-06189-y","article-title":"HIV-phyloTSI: subtype-independent estimation of time since HIV-1 infection for cross-sectional measures of population incidence using deep sequence data","volume":"26","year":"2025","journal-title":"BMC Bioinformatics"}],"container-title":[],"original-title":[],"link":[{"URL":"https:\/\/syndication.highwire.org\/content\/doi\/10.64898\/2026.08.04.26359711","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,8,8]],"date-time":"2026-08-08T12:45:15Z","timestamp":1786193115000},"score":1,"resource":{"primary":{"URL":"http:\/\/medrxiv.org\/lookup\/doi\/10.64898\/2026.08.04.26359711"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,8,6]]},"references-count":30,"URL":"https:\/\/doi.org\/10.64898\/2026.08.04.26359711","relation":{},"subject":[],"published":{"date-parts":[[2026,8,6]]},"subtype":"preprint"}}