Genotypic and functional impact of HIV-1 adaptation to its host population during the North American epidemic.
HLA-restricted immune escape mutations that persist following HIV transmission could gradually spread through the viral population, thereby compromising host antiviral immunity as the epidemic progresses. To assess the extent and phenotypic impact of this phenomenon in an immunogenetically diverse population, we genotypically and functionally compared linked HLA and HIV (Gag/Nef) sequences from 358 historic (1979-1989) and 382 modern (2000-2011) specimens from four key cities in the North American epidemic (New York, Boston, San Francisco, Vancouver). Inferred HIV phylogenies were star-like, with approximately two-fold greater mean pairwise distances in modern versus historic sequences. The reconstructed epidemic ancestral (founder) HIV sequence was essentially identical to the North American subtype B consensus. Consistent with gradual diversification of a "consensus-like" founder virus, the median "background" frequencies of individual HLA-associated polymorphisms in HIV (in individuals lacking the restricting HLA[s]) were ∼ 2-fold higher in modern versus historic HIV sequences, though these remained notably low overall (e.g. in Gag, medians were 3.7% in the 2000s versus 2.0% in the 1980s). HIV polymorphisms exhibiting the greatest relative spread were those restricted by protective HLAs. Despite these increases, when HIV sequences were analyzed as a whole, their total average burden of polymorphisms that were "pre-adapted" to the average host HLA profile was only ∼ 2% greater in modern versus historic eras. Furthermore, HLA-associated polymorphisms identified in historic HIV sequences were consistent with those detectable today, with none identified that could explain the few HIV codons where the inferred epidemic ancestor differed from the modern consensus. Results are therefore consistent with slow HIV adaptation to HLA, but at a rate unlikely to yield imminent negative implications for cellular immunity, at least in North America. Intriguingly, temporal changes in protein activity of patient-derived Nef (though not Gag) sequences were observed, suggesting functional implications of population-level HIV evolution on certain viral proteins.
Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
Laura A
LA
Cotton
Department of Molecular Biology and Biochemistry, Faculty of Science, Simon Fraser University, Burnaby, British Columbia, Canada.
Xiaomei T
XT
Kuang
Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
Anh Q
AQ
Le
Microsoft Research, Los Angeles, California, United States of America.
Jonathan M
JM
Carlson
Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
Benjamin
B
Chan
Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada; KwaZulu-Natal Research Institute for Tuberculosis and HIV, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, KwaZulu-Natal, South Africa.
Denis R
DR
Chopera
British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.
Chanson J
CJ
Brumme
Department of Molecular Biology and Biochemistry, Faculty of Science, Simon Fraser University, Burnaby, British Columbia, Canada.
Tristan J
TJ
Markle
Department of Molecular Biology and Biochemistry, Faculty of Science, Simon Fraser University, Burnaby, British Columbia, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.
Eric
E
Martin
Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
Aniqa
A
Shahid
Department of Molecular Biology and Biochemistry, Faculty of Science, Simon Fraser University, Burnaby, British Columbia, Canada.
Gursev
G
Anmole
Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
Philip
P
Mwimanzi
Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
Pauline
P
Nassab
Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
Kali A
KA
Penney
Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada.
Manal A
MA
Rahman
British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada; Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
M-J
MJ
Milloy
Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Martin T
MT
Schechter
Aaron Diamond AIDS Research Center, The Rockefeller University, New York, New York, United States of America.
Martin
M
Markowitz
Cancer and Inflammation Program, Laboratory of Experimental Immunology, Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, Maryland, United States of America; Ragon Institute of MGH, MIT and Harvard University, Cambridge, Massachusetts, United States of America.
Mary
M
Carrington
Ragon Institute of MGH, MIT and Harvard University, Cambridge, Massachusetts, United States of America.
Bruce D
BD
Walker
San Francisco Department of Public Health, San Francisco, California, United States of America.
Theresa
T
Wagner
San Francisco Department of Public Health, San Francisco, California, United States of America.
Susan
S
Buchbinder
San Francisco Department of Public Health, San Francisco, California, United States of America.
Jonathan
J
Fuchs
New York Blood Center, New York, New York, United States of America.
Beryl
B
Koblin
Fenway Community Health, Boston, Massachusetts, United States of America; Harvard Medical School, Boston, Massachusetts, United States of America.
Kenneth H
KH
Mayer
British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada; Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
P Richard
PR
Harrigan
Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada; Department of Molecular Biology and Biochemistry, Faculty of Science, Simon Fraser University, Burnaby, British Columbia, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.
Mark A
MA
Brockman
Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada; Faculty of Medicine, University of British Columbia, Vancouver, British Columbia, Canada.
Art F Y
AF
Poon
Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada.
Zabrina L
ZL
Brumme
D000222:Adaptation, Physiological / Q000235:genetics*; D000595:Amino Acid Sequence; D005838:Genotype; D015658:HIV Infections / Q000235:genetics*; D015497:HIV-1 / Q000235:genetics*; D006680:HLA Antigens / Q000235:genetics; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D009656:North America; D010802:Phylogeny; D011110:Polymorphism, Genetic / Q000235:genetics
D006680:HLA Antigens