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HLA-associated immune escape pathways in HIV-1 subtype B Gag, Pol and Nef proteins

Brumme, ZL and John, M and Carlson, JM and Brumme, CJ and Chan, D and Brockman, MA and Swenson, LC and Tao, I and Szeto, S and Rosato, P and Sela, J and Kadie, CM and Frahm, N and Brander, C and Haas, DW and Riddler, SA and Haubrich, R and Walker, BD and Harrigan, PR and Heckerman, D and Mallal, S (2009) HLA-associated immune escape pathways in HIV-1 subtype B Gag, Pol and Nef proteins. PLoS ONE, 4 (8).

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Background: Despite the extensive genetic diversity of HIV-1, viral evolution in response to immune selective pressures follows broadly predictable mutational patterns. Sites and pathways of Human Leukocyte-Antigen (HLA)-associated polymorphisms in HIV-1 have been identified through the analysis of population-level data, but the full extent of immune escape pathways remains incompletely characterized. Here, in the largest analysis of HIV-1 subtype B sequences undertaken to date, we identify HLA-associated polymorphisms in the three HIV-1 proteins most commonly considered in cellular-based vaccine strategies. Results are organized into protein-wide escape maps illustrating the sites and pathways of HLA-driven viral evolution. Methodology/Principal Findings: HLA-associated polymorphisms were identified in HIV-1 Gag, Pol and Nef in a multicenter cohort of >1500 chronically subtype-B infected, treatment-naïve individuals from established cohorts in Canada, the USA and Western Australia. At q≤0.05, 282 codons commonly mutating under HLA-associated immune pressures were identified in these three proteins. The greatest density of associations was observed in Nef (where close to 40% of codons exhibited a significant HLA association), followed by Gag then Pol (where ∼15-20% of codons exhibited HLA associations), confirming the extensive impact of immune selection on HIV evolution and diversity. Analysis of HIV codon covariation patterns identified over 2000 codon-codon interactions at q≤0.05, illustrating the dense and complex networks of linked escape and secondary/compensatory mutations. Conclusions/Significance: The immune escape maps and associated data are intended to serve as a user-friendly guide to the locations of common escape mutations and covarying codons in HIV-1 subtype B, and as a resource facilitating the systematic identification and classification of immune escape mutations. These resources should facilitate research in HIV epitope discovery and host-pathogen co-evolution, and are relevant to the continued search for an effective CTL-based AIDS vaccine. © 2009 Brumme et al.


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Item Type: Article
Status: Published
CreatorsEmailPitt UsernameORCID
Brumme, ZL
John, M
Carlson, JM
Brumme, CJ
Chan, D
Brockman, MA
Swenson, LC
Tao, I
Szeto, S
Rosato, P
Sela, J
Kadie, CM
Frahm, N
Brander, C
Haas, DW
Riddler, SAriddler@pitt.eduRIDDLER
Haubrich, R
Walker, BD
Harrigan, PR
Heckerman, D
Mallal, S
ContributionContributors NameEmailPitt UsernameORCID
Date: 18 August 2009
Date Type: Publication
Journal or Publication Title: PLoS ONE
Volume: 4
Number: 8
DOI or Unique Handle: 10.1371/journal.pone.0006687
Refereed: Yes
MeSH Headings: Amino Acid Sequence; Cohort Studies; Gene Products, gag--chemistry; Gene Products, gag--immunology; Gene Products, nef--immunology; Gene Products, pol--immunology; Genotype; HIV Infections--immunology; HIV-1--genetics; HIV-1--immunology; HLA Antigens--immunology; Humans; Immune Evasion; Molecular Sequence Data
Other ID: NLM PMC2723923
PubMed Central ID: PMC2723923
PubMed ID: 19690614
Date Deposited: 03 Aug 2012 16:08
Last Modified: 05 Feb 2019 03:55


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