PMID- 26559841 OWN - NLM STAT- MEDLINE DCOM- 20160523 LR - 20181113 IS - 1098-5514 (Electronic) IS - 0022-538X (Print) IS - 0022-538X (Linking) VI - 90 IP - 3 DP - 2016 Feb 1 TI - Population-Level Immune-Mediated Adaptation in HIV-1 Polymerase during the North American Epidemic. PG - 1244-58 LID - 10.1128/JVI.02353-15 [doi] AB - 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 approximately 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. IMPORTANCE: 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. CI - Copyright (c) 2016, American Society for Microbiology. All Rights Reserved. FAU - Kinloch, Natalie N AU - Kinloch NN AD - Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada. FAU - MacMillan, Daniel R AU - MacMillan DR AD - Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada. FAU - Le, Anh Q AU - Le AQ AD - Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada. FAU - Cotton, Laura A AU - Cotton LA AD - Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada. FAU - Bangsberg, David R AU - Bangsberg DR AD - Massachusetts General Hospital, Boston, Massachusetts, USA Harvard Medical School, Cambridge, Massachusetts, USA. FAU - Buchbinder, Susan AU - Buchbinder S AD - San Francisco Department of Public Health, San Francisco, California, USA University of California, San Francisco, San Francisco, California, USA. FAU - Carrington, Mary AU - Carrington M AD - 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. FAU - Fuchs, Jonathan AU - Fuchs J AD - San Francisco Department of Public Health, San Francisco, California, USA University of California, San Francisco, San Francisco, California, USA. FAU - Harrigan, P Richard AU - Harrigan PR AD - British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. FAU - Koblin, Beryl AU - Koblin B AD - New York Blood Center, New York, New York, USA. FAU - Kushel, Margot AU - Kushel M AD - University of California, San Francisco, San Francisco, California, USA. FAU - Markowitz, Martin AU - Markowitz M AD - Aaron Diamond AIDS Research Center, New York, New York, USA. FAU - Mayer, Kenneth AU - Mayer K AD - Harvard Medical School, Cambridge, Massachusetts, USA Fenway Community Health, Boston, Massachusetts, USA. FAU - Milloy, M J AU - Milloy MJ AD - British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. FAU - Schechter, Martin T AU - Schechter MT AD - Faculty of Medicine, University of British Columbia, Vancouver, BC, Canada. FAU - Wagner, Theresa AU - Wagner T AD - San Francisco Department of Public Health, San Francisco, California, USA. FAU - Walker, Bruce D AU - Walker BD AD - Ragon Institute of Massachusetts General Hospital, MIT, and Harvard University, Cambridge, Massachusetts, USA. FAU - Carlson, Jonathan M AU - Carlson JM AD - Microsoft Research, Seattle, Washington, USA. FAU - Poon, Art F Y AU - Poon AF AD - 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. FAU - Brumme, Zabrina L AU - Brumme ZL AD - Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada zbrumme@sfu.ca. LA - eng GR - Intramural NIH HHS/United States GR - UM1 AI069496/AI/NIAID NIH HHS/United States GR - HHSN261200800001E/PHS HHS/United States GR - MOP-93536/Canadian Institutes of Health Research/Canada GR - HHSN261200800001C/RC/CCR NIH HHS/United States GR - HHSN261200800001E/CA/NCI NIH HHS/United States GR - HOP-115700/Canadian Institutes of Health Research/Canada PT - Journal Article PT - Observational Study PT - Research Support, N.I.H., Extramural PT - Research Support, N.I.H., Intramural PT - Research Support, Non-U.S. Gov't DEP - 20151111 PL - United States TA - J Virol JT - Journal of virology JID - 0113724 RN - 0 (Histocompatibility Antigens Class I) RN - 0 (pol Gene Products, Human Immunodeficiency Virus) SB - IM MH - *Adaptation, Biological MH - Cohort Studies MH - Epidemics MH - *Genetic Variation MH - Genotype MH - HIV Infections/*epidemiology/*virology MH - HIV-1/*enzymology/genetics/immunology MH - Histocompatibility Antigens Class I/*genetics MH - Humans MH - Male MH - North America/epidemiology MH - Phylogeny MH - pol Gene Products, Human Immunodeficiency Virus/*genetics PMC - PMC4719594 EDAT- 2015/11/13 06:00 MHDA- 2016/05/24 06:00 PMCR- 2016/07/15 CRDT- 2015/11/13 06:00 PHST- 2015/09/14 00:00 [received] PHST- 2015/11/06 00:00 [accepted] PHST- 2015/11/13 06:00 [entrez] PHST- 2015/11/13 06:00 [pubmed] PHST- 2016/05/24 06:00 [medline] PHST- 2016/07/15 00:00 [pmc-release] AID - JVI.02353-15 [pii] AID - 02353-15 [pii] AID - 10.1128/JVI.02353-15 [doi] PST - epublish SO - J Virol. 2015 Nov 11;90(3):1244-58. doi: 10.1128/JVI.02353-15. Print 2016 Feb 1.