title: Population-Level Immune-Mediated Adaptation in HIV-1 Polymerase during the North American Epidemic.
abstract: Human leukocyte antigen (HLA) class I-associated polymorphisms in HIV-1 that persist upon transmission to HLA-mismatched hosts may spread in the population as the epidemic progresses. Transmission of HIV-1 sequences containing such adaptations may undermine cellular immune responses to the incoming virus in future hosts. Building upon previous work, we investigated the extent of HLA-associated polymorphism accumulation in HIV-1 polymerase (Pol) through comparative analysis of linked HIV-1/HLA class I genotypes sampled during historic (1979 to 1989; n = 338) and modern (2001 to 2011; n = 278) eras from across North America (Vancouver, BC, Canada; Boston, MA; New York, NY; and San Francisco, CA). Phylogenies inferred from historic and modern HIV-1 Pol sequences were star-like in shape, with an inferred most recent common ancestor (epidemic founder virus) sequence nearly identical to the modern North American subtype B consensus sequence. Nevertheless, modern HIV-1 Pol sequences exhibited roughly 2-fold-higher patristic (tip-to-tip) genetic distances than historic sequences, with HLA pressures likely driving ongoing diversification. Moreover, the frequencies of published HLA-associated polymorphisms in individuals lacking the selecting HLA class I allele was on average ∼2.5-fold higher in the modern than in the historic era, supporting their spread in circulation, though some remained stable in frequency during this time. Notably, polymorphisms restricted by protective HLA alleles appear to be spreading to a greater relative extent than others, though these increases are generally of modest absolute magnitude. However, despite evidence of polymorphism spread, North American hosts generally remain at relatively low risk of acquiring an HIV-1 polymerase sequence substantially preadapted to their HLA profiles, even in the present era.
  
  
  OBJECTIVE
  HLA class I-restricted cytotoxic T-lymphocyte (CTL) escape mutations in HIV-1 that persist upon transmission may accumulate in circulation over time, potentially undermining host antiviral immunity to the transmitted viral strain. We studied >600 experimentally collected HIV-1 polymerase sequences linked to host HLA information dating back to 1979, along with phylogenetically reconstructed HIV-1 sequences dating back to the virus' introduction into North America. Overall, our results support the gradual spread of many-though not all-HIV-1 polymerase immune escape mutations in circulation over time. This is consistent with recent observations from other global regions, though the extent of polymorphism accumulation in North America appears to be lower than in populations with high seroprevalence, older epidemics, and/or limited HLA diversity. Importantly, the risk of acquiring an HIV-1 polymerase sequence at transmission that is substantially preadapted to one's HLA profile remains relatively low in North America, even in the present era.
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Natalie N
authors.initials: NN
authors.lastname: Kinloch
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Daniel R
authors.initials: DR
authors.lastname: MacMillan
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Anh Q
authors.initials: AQ
authors.lastname: Le
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada.
authors.forename: Laura A
authors.initials: LA
authors.lastname: Cotton
authors.affiliation: Massachusetts General Hospital, Boston, Massachusetts, USA Harvard Medical School, Cambridge, Massachusetts, USA.
authors.forename: David R
authors.initials: DR
authors.lastname: Bangsberg
authors.affiliation: San Francisco Department of Public Health, San Francisco, California, USA University of California, San Francisco, San Francisco, California, USA.
authors.forename: Susan
authors.initials: S
authors.lastname: Buchbinder
authors.affiliation: Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, USA Ragon Institute of Massachusetts General Hospital, MIT, and Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Mary
authors.initials: M
authors.lastname: Carrington
authors.affiliation: San Francisco Department of Public Health, San Francisco, California, USA University of California, San Francisco, San Francisco, California, USA.
authors.forename: Jonathan
authors.initials: J
authors.lastname: Fuchs
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: P Richard
authors.initials: PR
authors.lastname: Harrigan
authors.affiliation: New York Blood Center, New York, New York, USA.
authors.forename: Beryl
authors.initials: B
authors.lastname: Koblin
authors.affiliation: University of California, San Francisco, San Francisco, California, USA.
authors.forename: Margot
authors.initials: M
authors.lastname: Kushel
authors.affiliation: Aaron Diamond AIDS Research Center, New York, New York, USA.
authors.forename: Martin
authors.initials: M
authors.lastname: Markowitz
authors.affiliation: Harvard Medical School, Cambridge, Massachusetts, USA Fenway Community Health, Boston, Massachusetts, USA.
authors.forename: Kenneth
authors.initials: K
authors.lastname: Mayer
authors.affiliation: British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: M J
authors.initials: MJ
authors.lastname: Milloy
authors.affiliation: Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Martin T
authors.initials: MT
authors.lastname: Schechter
authors.affiliation: San Francisco Department of Public Health, San Francisco, California, USA.
authors.forename: Theresa
authors.initials: T
authors.lastname: Wagner
authors.affiliation: Ragon Institute of Massachusetts General Hospital, MIT, and Harvard University, Cambridge, Massachusetts, USA.
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.affiliation: Microsoft Research, Seattle, Washington, USA.
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada.
authors.forename: Art F Y
authors.initials: AF
authors.lastname: Poon
authors.affiliation: Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada zbrumme@sfu.ca.
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
mesh_terms: D000220:Adaptation, Biological; D015331:Cohort Studies; D058872:Epidemics; D014644:Genetic Variation; D005838:Genotype; D015658:HIV Infections / Q000453:epidemiology* / Q000821:virology*; D015497:HIV-1 / Q000201:enzymology* / Q000235:genetics / Q000276:immunology; D015395:Histocompatibility Antigens Class I / Q000235:genetics*; D006801:Humans; D008297:Male; D009656:North America / Q000453:epidemiology; D010802:Phylogeny; D054302:pol Gene Products, Human Immunodeficiency Virus / Q000235:genetics*
chemical_list: D015395:Histocompatibility Antigens Class I; D054302:pol Gene Products, Human Immunodeficiency Virus