HLA-associated immune escape pathways in HIV-1 subtype B Gag, Pol and Nef proteins.
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.
Brumme
Zabrina L
ZL
Ragon Institute of MGH, MIT and Harvard, Charlestown, MA, USA. zbrumme@partners.org
John
Mina
M
Carlson
Jonathan M
JM
Brumme
Chanson J
CJ
Chan
Dennison
D
Brockman
Mark A
MA
Swenson
Luke C
LC
Tao
Iris
I
Szeto
Sharon
S
Rosato
Pamela
P
Sela
Jennifer
J
Kadie
Carl M
CM
Frahm
Nicole
N
Brander
Christian
C
Haas
David W
DW
Riddler
Sharon A
SA
Haubrich
Richard
R
Walker
Bruce D
BD
Harrigan
P Richard
PR
Heckerman
David
D
Mallal
Simon
S
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
D015683:Gene Products, gag; D015693:Gene Products, nef; D015684:Gene Products, pol; D006680:HLA Antigens
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