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

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 SA, Haubrich R, Walker BD, Harrigan PR, Heckerman D, Mallal S - PLoS ONE (2009)

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Ragon Institute of MGH, MIT and Harvard, Charlestown, MA, USA. zbrumme@partners.org

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-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.

Show MeSH
Protease Immune Escape Map.
© Copyright Policy
Related In: Results  -  Collection


getmorefigures.php?uid=PMC2723923&req=5

pone-0006687-g002: Protease Immune Escape Map.

Mentions: All HLA-associated polymorphisms at q≤0.05 were organized into gene-wide “immune escape maps” (Figures 1, 2, 3, 4, 5) indicating their location, HLA restriction, specific amino acids, and their direction of association (“adapted” vs. “non-adapted”) with respect to the current HIV subtype B consensus sequence (http://www.hiv.lanl.gov). Published, optimally-described CTL epitopes [49] containing HLA-associated polymorphisms are also shown. In addition, the maps discriminate between HLA-associated polymorphisms directly attributable to selection pressure by the allele (meaning that they survive correction for HIV covariation), from those that may be better explained indirectly (meaning that their occurrence may be better explained by the presence of an HLA-associated covarying residue, rather than the allele itself). The full list of direct (covariation-corrected) plus indirect (covariation uncorrected) HLA-associated polymorphisms within each viral protein at q≤0.2 is provided in Table S1.


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

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 SA, Haubrich R, Walker BD, Harrigan PR, Heckerman D, Mallal S - PLoS ONE (2009)

Protease Immune Escape Map.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2723923&req=5

pone-0006687-g002: Protease Immune Escape Map.
Mentions: All HLA-associated polymorphisms at q≤0.05 were organized into gene-wide “immune escape maps” (Figures 1, 2, 3, 4, 5) indicating their location, HLA restriction, specific amino acids, and their direction of association (“adapted” vs. “non-adapted”) with respect to the current HIV subtype B consensus sequence (http://www.hiv.lanl.gov). Published, optimally-described CTL epitopes [49] containing HLA-associated polymorphisms are also shown. In addition, the maps discriminate between HLA-associated polymorphisms directly attributable to selection pressure by the allele (meaning that they survive correction for HIV covariation), from those that may be better explained indirectly (meaning that their occurrence may be better explained by the presence of an HLA-associated covarying residue, rather than the allele itself). The full list of direct (covariation-corrected) plus indirect (covariation uncorrected) HLA-associated polymorphisms within each viral protein at q≤0.2 is provided in Table S1.

Bottom Line: 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.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.

View Article: PubMed Central - PubMed

Affiliation: Ragon Institute of MGH, MIT and Harvard, Charlestown, MA, USA. zbrumme@partners.org

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-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.

Show MeSH