Journal article
Antiretroviral therapy blocks natural selection on protective and disease-susceptible HLA-B alleles in HIV-1 infection
- Abstract:
- 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 (1998–2005), HIV-1 survival and vertical transmission were both strongly HLA-B dependent: “disease-susceptible” HLA-B alleles (HLA-B*18/B*45:01/B*58:02) increased adult AIDS progression and vertical transmission (OR 1.6, P = 0.01), whereas “protective” HLA-B alleles (HLA-B*57/B*58:01/B*81:01) slowed AIDS progression, and decreased vertical transmission (OR 0.57, P = 0.002). By contrast, in contemporary antenatal KwaZulu-Natal cohorts in the ART era (2015–2025) 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 1990–2035, in the absence of ART, the proportion of the population possessing any “protective” 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 “disease-susceptible” 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.
- Publication status:
- Published
- Peer review status:
- Peer reviewed
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(Preview, Accepted manuscript, pdf, 1.0MB, Terms of use)
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- Publisher copy:
- 10.1073/pnas.2502683123
Authors
+ Wellcome Trust
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- Funder identifier:
- https://ror.org/029chgv08
- Grant:
- WT104748MA
+ National Institutes of Health
More from this funder
- Funder identifier:
- https://ror.org/01cwqze88
- Grant:
- U01AI168655
- AI133673
+ Frederick National Laboratory for Cancer Research
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- Funder identifier:
- https://ror.org/03v6m3209
- Grant:
- 75N91019D00024
- Publisher:
- National Academy of Sciences
- Journal:
- Proceedings of the National Academy of Sciences More from this journal
- Volume:
- 123
- Issue:
- 19
- Article number:
- e2502683123
- Publication date:
- 2026-04-27
- Acceptance date:
- 2026-03-18
- DOI:
- EISSN:
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1091-6490
- ISSN:
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0027-8424
- Language:
-
English
- Keywords:
- Pubs id:
-
2412143
- Local pid:
-
pubs:2412143
- Deposit date:
-
2026-04-28
- ARK identifier:
Terms of use
- Copyright holder:
- Herbert et al.
- Copyright date:
- 2026
- Rights statement:
- ©2026 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).
- Notes:
- The author accepted manuscript (AAM) of this paper has been made available under the University of Oxford's Open Access Publications Policy, and a CC BY public copyright licence has been applied.
- Licence:
- CC Attribution (CC BY)
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