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Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[2026,5,12]]},"abstract":"<jats:p>\n                    MHC polymorphism is explained by natural selection driven by the MHC-dependent impact of certain infections, inflammatory conditions, autoimmune diseases, and cancers. However, examples of human disease driving this process are rare. We evaluated the impact of HIV-1 in altering HLA-I frequencies in KwaZulu-Natal, South Africa, and the influence of antiretroviral therapy (ART) on this process. In a historical mother-child cohort in the pre-ART era (1998\u20132005), HIV-1 survival and vertical transmission were both strongly HLA-B dependent: \u201cdisease-susceptible\u201d HLA-B alleles (HLA-B*18\/B*45:01\/B*58:02) increased adult AIDS progression and vertical transmission (OR 1.6,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    = 0.01), whereas \u201cprotective\u201d HLA-B alleles (HLA-B*57\/B*58:01\/B*81:01) slowed AIDS progression, and decreased vertical transmission (OR 0.57,\n                    <jats:italic toggle=\"yes\">P<\/jats:italic>\n                    = 0.002). By contrast, in contemporary antenatal KwaZulu-Natal cohorts in the ART era (2015\u20132025) the impact of HLA-B on HIV-1 disease outcome and vertical transmission is dramatically reduced. Using these and reported data, we constructed a model to estimate the impact of HIV-1 on HLA-B frequencies in KwaZulu-Natal, both in the prevailing setting of ART and in a hypothetical counterfactual scenario where ART was never rolled out. Over the 45-y period 1990\u20132035, in the absence of ART, the proportion of the population possessing any \u201cprotective\u201d HLA-B allele was projected to increase from 23 to 42% (allele frequencies increasing from 0.12 to 0.24), and the proportion of the population possessing any \u201cdisease-susceptible\u201d HLA-B allele was projected to decrease from 28 to 18% (allele frequencies declining from 0.15 to 0.092). The introduction of ART radically slows HLA-B frequency change. These data therefore demonstrate the potential for natural selection from an infectious disease to alter human population genetics within decades, and for the successful roll-out of therapy to halt this process.\n                  <\/jats:p>","DOI":"10.1073\/pnas.2502683123","type":"journal-article","created":{"date-parts":[[2026,4,27]],"date-time":"2026-04-27T19:06:03Z","timestamp":1777316763000},"update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":0,"title":["Antiretroviral therapy blocks natural selection on protective and disease-susceptible HLA-B alleles in HIV-1 infection"],"prefix":"10.1073","volume":"123","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3708-694X","authenticated-orcid":false,"given":"Nicholas G.","family":"Herbert","sequence":"first","affiliation":[{"name":"Peter Medawar Building for Pathogen Research, Department of Paediatrics, University of Oxford","place":["Oxford, United 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