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

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

Fecha de publicación online: 19/08/2009

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.
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-naı¨ve 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.

Autores: Brumme, Z.L., M. John, J.M. Carlson, C.J. Brumme, D. Chan, M.A. Brockman, L.C. Swenson, I. Tao, S. Szeto, P. Rosato, J. Sela, C.M. Kadie, N. Frahm, C. Brander, D.W. Haas, S.A. Riddler, R. Haubrich, B.D. Walker, P.R. Harrigan, D. Heckerman, and S. Mallal.
  • Código Doi: PLoS One 4:e6687.

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