PLoS ONE (Aug 2009)

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

  • Zabrina L Brumme,
  • Mina John,
  • Jonathan M Carlson,
  • Chanson J Brumme,
  • Dennison Chan,
  • Mark A Brockman,
  • Luke C Swenson,
  • Iris Tao,
  • Sharon Szeto,
  • Pamela Rosato,
  • Jennifer Sela,
  • Carl M Kadie,
  • Nicole Frahm,
  • Christian Brander,
  • David W Haas,
  • Sharon A Riddler,
  • Richard Haubrich,
  • Bruce D Walker,
  • P Richard Harrigan,
  • David Heckerman,
  • Simon Mallal

DOI
https://doi.org/10.1371/journal.pone.0006687
Journal volume & issue
Vol. 4, no. 8
p. e6687

Abstract

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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< 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/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.