title: HLA-associated immune escape pathways in HIV-1 subtype B Gag, Pol and Nef proteins.
abstract: 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.
  
  
  RESULTS
  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< or =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 approximately 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< or =0.05, illustrating the dense and complex networks of linked escape and secondary/compensatory mutations.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Ragon Institute of MGH, MIT and Harvard, Charlestown, MA, USA. zbrumme@partners.org
authors.forename: Zabrina L
authors.initials: ZL
authors.lastname: Brumme
authors.forename: Mina
authors.initials: M
authors.lastname: John
authors.forename: Jonathan M
authors.initials: JM
authors.lastname: Carlson
authors.forename: Chanson J
authors.initials: CJ
authors.lastname: Brumme
authors.forename: Dennison
authors.initials: D
authors.lastname: Chan
authors.forename: Mark A
authors.initials: MA
authors.lastname: Brockman
authors.forename: Luke C
authors.initials: LC
authors.lastname: Swenson
authors.forename: Iris
authors.initials: I
authors.lastname: Tao
authors.forename: Sharon
authors.initials: S
authors.lastname: Szeto
authors.forename: Pamela
authors.initials: P
authors.lastname: Rosato
authors.forename: Jennifer
authors.initials: J
authors.lastname: Sela
authors.forename: Carl M
authors.initials: CM
authors.lastname: Kadie
authors.forename: Nicole
authors.initials: N
authors.lastname: Frahm
authors.forename: Christian
authors.initials: C
authors.lastname: Brander
authors.forename: David W
authors.initials: DW
authors.lastname: Haas
authors.forename: Sharon A
authors.initials: SA
authors.lastname: Riddler
authors.forename: Richard
authors.initials: R
authors.lastname: Haubrich
authors.forename: Bruce D
authors.initials: BD
authors.lastname: Walker
authors.forename: P Richard
authors.initials: PR
authors.lastname: Harrigan
authors.forename: David
authors.initials: D
authors.lastname: Heckerman
authors.forename: Simon
authors.initials: S
authors.lastname: Mallal
mesh_terms: D000595:Amino Acid Sequence; D015331:Cohort Studies; D015683:Gene Products, gag / Q000737:chemistry / Q000276:immunology*; D015693:Gene Products, nef / Q000276:immunology*; D015684:Gene Products, pol / Q000276:immunology*; D005838:Genotype; D015658:HIV Infections / Q000276:immunology*; D015497:HIV-1 / Q000235:genetics / Q000276:immunology*; D006680:HLA Antigens / Q000276:immunology*; D006801:Humans; D057131:Immune Evasion; D008969:Molecular Sequence Data
chemical_list: D015683:Gene Products, gag; D015693:Gene Products, nef; D015684:Gene Products, pol; D006680:HLA Antigens
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