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Proc Natl Acad Sci U S A. 2014 Dec 16;111(50):E5393-400. doi: 10.1073/pnas.1413339111. Epub 2014 Dec 1.

Impact of HLA-driven HIV adaptation on virulence in populations of high HIV seroprevalence.

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  • 1Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom;
  • 2HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban 4013, South Africa;
  • 3The Institute for Emerging Infections, The Oxford Martin School, University of Oxford, Oxford OX1 3BD, United Kingdom; Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, United Kingdom;
  • 4Faculty of Health Sciences, Simon Fraser University, Vancouver, BC V5A 1S6, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC V6Z 1Y6, Canada;
  • 5ViiV Healthcare K. K., Shibuya-ku, Tokyo 151-8566, Japan;
  • 6The Institute for Emerging Infections, The Oxford Martin School, University of Oxford, Oxford OX1 3BD, United Kingdom; Nuffield Department of Medicine, University of Oxford, Oxford OX1 3SY, United Kingdom; Oxford National Institute of Health Research, Biomedical Research Centre, Oxford OX1 3SY, United Kingdom;
  • 7Botswana Harvard AIDS Institute Partnership, Gaborone BO 320, Botswana; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02215;
  • 8HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban 4013, South Africa; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA 02139;
  • 9The Institute for Emerging Infections, The Oxford Martin School, University of Oxford, Oxford OX1 3BD, United Kingdom; Department of Zoology, University of Oxford, Oxford OX1 3PS, United Kingdom; and.
  • 10Microsoft Research, eScience Group, Los Angeles, CA 90024.
  • 11Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom; HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban 4013, South Africa; philip.goulder@paediatrics.ox.ac.uk.

Abstract

It is widely believed that epidemics in new hosts diminish in virulence over time, with natural selection favoring pathogens that cause minimal disease. However, a tradeoff frequently exists between high virulence shortening host survival on the one hand but allowing faster transmission on the other. This is the case in HIV infection, where high viral loads increase transmission risk per coital act but reduce host longevity. We here investigate the impact on HIV virulence of HIV adaptation to HLA molecules that protect against disease progression, such as HLA-B*57 and HLA-B*58:01. We analyzed cohorts in Botswana and South Africa, two countries severely affected by the HIV epidemic. In Botswana, where the epidemic started earlier and adult seroprevalence has been higher, HIV adaptation to HLA including HLA-B*57/58:01 is greater compared with South Africa (P = 7 × 10(-82)), the protective effect of HLA-B*57/58:01 is absent (P = 0.0002), and population viral replicative capacity is lower (P = 0.03). These data suggest that viral evolution is occurring relatively rapidly, and that adaptation of HIV to the most protective HLA alleles may contribute to a lowering of viral replication capacity at the population level, and a consequent reduction in HIV virulence over time. The potential role in this process played by increasing antiretroviral therapy (ART) access is also explored. Models developed here suggest distinct benefits of ART, in addition to reducing HIV disease and transmission, in driving declines in HIV virulence over the course of the epidemic, thereby accelerating the effects of HLA-mediated viral adaptation.

KEYWORDS:

HIV; HLA; adaptation; antiretroviral therapy; virulence

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PMID:
25453107
PMCID:
PMC4273423
DOI:
10.1073/pnas.1413339111
[PubMed - indexed for MEDLINE]
Free PMC Article

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