15th Conference on Retroviruses and Opportunistic Infections Boston, Massachusetts - February 3-6, 2008

Conf Retrovir Opportunistic Infect 2008 Feb 3-6;15: (abstract no. 25)

Chanson Brumme ¹, I Tao², S Szeto², Z Brumme¹, J Carlson^3,4, N Frahm¹, R Hogg^5,6, B Walker^1,7, D Heckerman³, and R Harrigan^2,8
1Partners AIDS Res Ctr, Boston, MA, US; ²BC Ctr for Excellence in HIV/AIDS, Vancouver, Canada; ³Microsoft Res, Redmond WA, US; 4Univ of Washington, Seattle, US; ⁵BC Ctr for Excellence in HIV/AIDS, Vancouver, Canada; ⁶Simon Fraser Univ, Burnaby, Canada; ⁷Howard Hughes Med Inst, Chevy Chase, MD, US; and ⁸Univ of British Columbia, Vancouver, Canada

BACKGROUND: Targeting of Gag-derived peptides by human leukocyte antigen (HLA) class I-restricted cytotoxic leukocyte (CTL) is likely a key determinant of HIV control, however the relationship between selection of Gag escape mutations and clinical markers of HIV disease remains incompletely understood.

METHODS: HLA class I-associated polymorphisms in Gag were identified in a cross-sectional analysis of 567 chronically infected, treatment-naïve individuals from British Columbia (HOMER cohort) using a phylogenetically corrected analysis featuring a multivariate adjustment for HLA linkage disequilibrium and a q-value correction for multiple tests. The relationship between clinical markers of HIV disease (plasma viral load and CD4 count) was assessed for both the overall number of HLA-associated polymorphic sites in Gag within each person (as an individual marker of total potential anti-Gag CTL pressure) and the proportion of these sites exhibiting escape.

RESULTS: A total of 114 HLA-associated substitutions were identified at 51 (of 500) Gag codons. Of these, 52 and 62 represented “escape” and “reversion” correlations (amino acids enriched in the presence or absence of specific HLA alleles, respectively). A total of 52 mapped within published CTL epitopes and another 15 mapped within or near a putative epitope as supported by in vitro CTL responses or the presence of an HLA binding motif or both. A modest yet significant inverse correlation was observed between the total number of HLA-associated Gag codons within each individual (defined by the individual’s class I allele profile) and lower HIV plasma viral load (R= –0.16, p=0.0001), suggesting that a broad ability to target Gag contributes to viral control. A modest yet significant positive correlation was observed between the proportion of these codons exhibiting HLA-associated “escape” mutations and higher plasma viral load (R=0.09, p=0.03), suggesting an incremental loss of plasma viral load control with the accumulation of CTL escape mutations. Similarly, a significant inverse correlation was observed between the proportion of “escaped” codons and lower CD4 count (R= –0.2, p=0.02), consistent with the accumulation of CTL escape mutations and concomitant decline in immune function over the natural course of untreated HIV infection.

CONCLUSIONS: We identified in vivo HLA-associated Gag escape patterns associated with measurable increases in plasma viral load, as well as lower CD4 counts. Results support the design of CTL-based vaccine strategies emphasizing Gag, which incorporate information on common escape pathways.

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2008-02-03
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