title: Impact of HLA-driven HIV adaptation on virulence in populations of high HIV seroprevalence.
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.
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom;
authors.forename: Rebecca
authors.initials: R
authors.lastname: Payne
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom;
authors.forename: Maximilian
authors.initials: M
authors.lastname: Muenchhoff
authors.affiliation: HIV Pathogenesis Programme, The Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban 4013, South Africa;
authors.forename: Jaclyn
authors.initials: J
authors.lastname: Mann
authors.affiliation: The 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;
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Roberts
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom;
authors.forename: Philippa
authors.initials: P
authors.lastname: Matthews
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom;
authors.forename: Emily
authors.initials: E
authors.lastname: Adland
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom;
authors.forename: Allison
authors.initials: A
authors.lastname: Hempenstall
authors.affiliation: The 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;
authors.forename: Kuan-Hsiang
authors.initials: KH
authors.lastname: Huang
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Vancouver, BC V5A 1S6, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC V6Z 1Y6, Canada;
authors.forename: Mark
authors.initials: M
authors.lastname: Brockman
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Vancouver, BC V5A 1S6, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC V6Z 1Y6, Canada;
authors.forename: Zabrina
authors.initials: Z
authors.lastname: Brumme
authors.affiliation: Department of Paediatrics, University of Oxford, Oxford OX1 3SY, United Kingdom;
authors.forename: Marc
authors.initials: M
authors.lastname: Sinclair
authors.affiliation: ViiV Healthcare K. K., Shibuya-ku, Tokyo 151-8566, Japan;
authors.forename: Toshiyuki
authors.initials: T
authors.lastname: Miura
authors.affiliation: The 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;
authors.forename: John
authors.initials: J
authors.lastname: Frater
authors.affiliation: Botswana Harvard AIDS Institute Partnership, Gaborone BO 320, Botswana; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02215;
authors.forename: Myron
authors.initials: M
authors.lastname: Essex
authors.affiliation: Botswana Harvard AIDS Institute Partnership, Gaborone BO 320, Botswana; Department of Immunology and Infectious Diseases, Harvard School of Public Health, Boston, MA 02215;
authors.forename: Roger
authors.initials: R
authors.lastname: Shapiro
authors.affiliation: HIV 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;
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: HIV 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;
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.affiliation: The 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.
authors.forename: Angela R
authors.initials: AR
authors.lastname: McLean
authors.affiliation: Microsoft Research, eScience Group, Los Angeles, CA 90024.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.affiliation: Department 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.
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
mesh_terms: D000220:Adaptation, Biological / Q000235:genetics*; D000328:Adult; D001483:Base Sequence; D001902:Botswana / Q000453:epidemiology; D015331:Cohort Studies; D019143:Evolution, Molecular; D006678:HIV / Q000235:genetics* / Q000472:pathogenicity*; D015658:HIV Infections / Q000453:epidemiology* / Q000635:transmission; D015235:HLA-B Antigens / Q000235:genetics* / Q000276:immunology; D006801:Humans; D008969:Molecular Sequence Data; D017422:Sequence Analysis, DNA; D016036:Seroepidemiologic Studies; D013019:South Africa / Q000453:epidemiology; D014774:Virulence
chemical_list: D015235:HLA-B Antigens
keywords: HIV; HLA; adaptation; antiretroviral therapy; virulence