title: Impact of pre-adapted HIV transmission.
abstract: Human leukocyte antigen class I (HLA)-restricted CD8(+) T lymphocyte (CTL) responses are crucial to HIV-1 control. Although HIV can evade these responses, the longer-term impact of viral escape mutants remains unclear, as these variants can also reduce intrinsic viral fitness. To address this, we here developed a metric to determine the degree of HIV adaptation to an HLA profile. We demonstrate that transmission of viruses that are pre-adapted to the HLA molecules expressed in the recipient is associated with impaired immunogenicity, elevated viral load and accelerated CD4(+) T cell decline. Furthermore, the extent of pre-adaptation among circulating viruses explains much of the variation in outcomes attributed to the expression of certain HLA alleles. Thus, viral pre-adaptation exploits 'holes' in the immune response. Accounting for these holes may be key for vaccine strategies seeking to elicit functional responses from viral variants, and to HIV cure strategies that require broad CTL responses to achieve successful eradication of HIV reservoirs.
authors.affiliation: Microsoft Research, Redmond, Washington, USA.
authors.forename: Jonathan M
authors.identifier: 0000-0001-6618-3653
authors.initials: JM
authors.lastname: Carlson
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Victor Y
authors.initials: VY
authors.lastname: Du
authors.affiliation: Microsoft Research, Redmond, Washington, USA.
authors.forename: Nico
authors.initials: N
authors.lastname: Pfeifer
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Anju
authors.initials: A
authors.lastname: Bansal
authors.affiliation: Microsoft Research, Redmond, Washington, USA.
authors.forename: Vincent Y F
authors.initials: VY
authors.lastname: Tan
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Karen
authors.initials: K
authors.lastname: Power
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.
authors.forename: Chanson J
authors.initials: CJ
authors.lastname: Brumme
authors.affiliation: Microsoft Research, Redmond, Washington, USA.
authors.forename: Anat
authors.initials: A
authors.lastname: Kreimer
authors.affiliation: Microsoft Research, Redmond, Washington, USA.
authors.forename: Charles E
authors.initials: CE
authors.lastname: DeZiel
authors.affiliation: Microsoft Research, Redmond, Washington, USA.
authors.forename: Nicolo
authors.identifier: 0000-0002-4102-0169
authors.initials: N
authors.lastname: Fusi
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.
authors.forename: Malinda
authors.initials: M
authors.lastname: Schaefer
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.|Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.affiliation: International AIDS Vaccine Initiative, New York, New York, USA.|Imperial College of Science, Technology and Medicine, London, UK.
authors.forename: Jill
authors.initials: J
authors.lastname: Gilmour
authors.affiliation: International AIDS Vaccine Initiative, New York, New York, USA.|Department of Epidemiology and Biostatistics, University of California, San Francisco, San Francisco, California, USA.
authors.forename: Matt A
authors.initials: MA
authors.lastname: Price
authors.affiliation: Rwanda-Zambia HIV Research Group, Zambia-Emory HIV Research Project, Lusaka, Zambia.
authors.forename: William
authors.initials: W
authors.lastname: Kilembe
authors.affiliation: Gilead Sciences, Foster City, California, USA.
authors.forename: Richard
authors.initials: R
authors.lastname: Haubrich
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.|Department of Clinical Immunology, Royal Perth Hospital, Perth, Western Australia, Australia.
authors.forename: Mina
authors.initials: M
authors.lastname: John
authors.affiliation: Institute for Immunology and Infectious Diseases, Murdoch University, Murdoch, Western Australia, Australia.|Center for Translational Immunology and Infectious Diseases, Vanderbilt University School of Medicine, Nashville, Tennessee, USA.
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
authors.affiliation: Harvard T.H. Chan School of Public Health, Harvard University, Boston, Massachusetts, USA.
authors.forename: Roger
authors.initials: R
authors.lastname: Shapiro
authors.affiliation: Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK.|National Institute of Health Research, Oxford Biomedical Research Centre, Oxford, UK.|Institute for Emerging Infections, Oxford Martin School, University of Oxford, Oxford, UK.
authors.forename: John
authors.initials: J
authors.lastname: Frater
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.|Department of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
authors.forename: P Richard
authors.initials: PR
authors.lastname: Harrigan
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA.|HIV Pathogenesis Programme, the Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.|KwaZulu-Natal Research Institute for Tuberculosis and HIV (K-RITH), Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa.|Max Planck Institute for Infection Biology, Berlin, Germany.
authors.forename: Thumbi
authors.initials: T
authors.lastname: Ndung'u
authors.affiliation: Rwanda-Zambia HIV Research Group, Zambia-Emory HIV Research Project, Lusaka, Zambia.|Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.|Department of Global Health, Rollins School of Public Health, Emory University, Atlanta, Georgia, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Allen
authors.affiliation: Microsoft Research, Redmond, Washington, USA.
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.affiliation: Division of Vaccine Discovery, La Jolla Institute for Allergy and Immunology, La Jolla, California, USA.
authors.forename: John
authors.initials: J
authors.lastname: Sidney
authors.affiliation: Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Todd M
authors.initials: TM
authors.lastname: Allen
authors.affiliation: HIV Pathogenesis Programme, the Doris Duke Medical Research Institute, University of KwaZulu-Natal, Durban, South Africa.|Department of Paediatrics, University of Oxford, Oxford, UK.
authors.forename: Philip J R
authors.initials: PJ
authors.lastname: Goulder
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.|Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.affiliation: Emory Vaccine Center, Yerkes National Primate Research Center, Emory University, Atlanta, Georgia, USA.|Rwanda-Zambia HIV Research Group, Zambia-Emory HIV Research Project, Lusaka, Zambia.|Department of Pathology and Laboratory Medicine, Emory University, Atlanta, Georgia, USA.
authors.forename: Eric
authors.identifier: 0000-0002-4273-8631
authors.initials: E
authors.lastname: Hunter
authors.affiliation: Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Goepfert
mesh_terms: D016915:AIDS Vaccines / Q000276:immunology; D000222:Adaptation, Physiological / Q000276:immunology*; D000353:Africa, Southern; D001955:British Columbia; D018791:CD4 Lymphocyte Count; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D015331:Cohort Studies; D019143:Evolution, Molecular; D015658:HIV Infections / Q000276:immunology / Q000635:transmission*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D015395:Histocompatibility Antigens Class I / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion / Q000235:genetics / Q000276:immunology*; D007111:Immunity, Cellular / Q000276:immunology; D016014:Linear Models; D018448:Models, Immunological; D016016:Proportional Hazards Models; D011948:Receptors, Antigen, T-Cell / Q000276:immunology; D019562:Viral Load; D014779:Virus Replication / Q000235:genetics
chemical_list: D016915:AIDS Vaccines; D015395:Histocompatibility Antigens Class I; D011948:Receptors, Antigen, T-Cell