Relationship between HLA class I-driven evolution in Gag, Pol and Nef and clinical markers of HIV disease: A multi-center collaborative study
Brumme, Z.L., John, M., Brumme, C.J., Carlson, J.M., Haubrich, R., Riddler, S., Swenson, L., Tao, I., Szeto, S., Chan, D., Kadie, C., Frahm, N., Brander, C., Walker, B., Heckerman, D., Harrigan, P.R. and Mallal, S. (2008) Relationship between HLA class I-driven evolution in Gag, Pol and Nef and clinical markers of HIV disease: A multi-center collaborative study. In: AIDS Vaccine 2008, 13 - 16 October, Cape Town, South Africa.
Background: The relationship between immune escape and HIV disease is incompletely understood. Here we examine the relationship between CTL selection pressure and plasma viral load (pVL) by defining HLA class I-associated polymorphisms in Gag, Pol and Nef in a large cohort of untreated HIV-1 subtype B-infected persons.
Methods: HLA-associated polymorphisms were identified in >1200 chronically-infected, treatment-naïve individuals from Canada (HOMER cohort), the USA (ACTG5142/5128 protocols), and Western Australia (WAHC), using phylogenetically-corrected analysis methods incorporating a multivariate adjustment for HLA linkage disequilibrium and a q-value correction for multiple tests. In individuals for whom clinical data were available (N~550), correlations between pVL and HLA-associated polymorphisms were assessed using Spearman’s rank test.
Results: >1000 unique HLA-associated polymorphisms were identified, but the number of codons involved varied by protein: 22%, 16% and 48% of Gag, Pol and Nef codons harbored an HLA-associated polymorphism. Roughly 60% of polymorphisms mapped in or near known or predicted CTL epitopes; a further 20% likely represent compensatory mutations. A modest inverse correlation was observed between the total number of HLA-associated sites in Gag (but not Pol/Nef) and pVL (R=-0.13;p=0.002), suggesting that Gag CTL targeting contributes more substantially to viremia control than targeting other proteins. A positive correlation was observed between the proportion of escaped Gag (but not Pol/Nef) sites and pVL (R=0.11;p=0.01), suggesting that the consequences of escape in Gag may be greater than other proteins.
Conclusion: Results support strong CTL-mediated selection on HIV, the effects of which vary by protein. The list of >1000 HLA-associated polymorphisms represents the most comprehensive to date for HIV-subtype-B. The associations between pVL and CTL selection pressure/escape in Gag suggest that in vivo CTL targeting of Gag may be important clinically. These data have implications for HIV vaccines.
|Publication Type:||Conference Item|
|Murdoch Affiliation:||Centre for Clinical Immunology and Biomedical Statistics|
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