5th International AIDS Society Conference on HIV Pathogenesis and Treatment Cape Town - July 19 - 22, 2009

IMPACT OF HLA CLASS I-ASSOCIATED IMMUNE PRESSURE ON IN VITRO REPLICATION CAPACITY OF HIV VARIANTS ENCODING CLINICALLY-DERIVED GAG-PROTEASE

IAS Conf HIV Pathog Treat 2009 Jul 19-22;5th: Abstract No. MOPDA102

M.A. Brockman ^1,2, Z.L. Brumme^1,2,3, C.J. Brumme¹, J. Sela¹, P. Rosato¹, T. Miura⁴, J.M. Carlson⁵, A. Schneidewind⁶, C. McCullough², J. Spring², R. McGovern², D. Chan², C. Woods², W. Dong², T. Mo², D. Heckerman⁵, B.D. Walker¹, P. R. Harrigan², T.M. Allen^1
1Ragon Institute of MGH, MIT and Harvard, Charlestown, United States, ²BC Centre for Excellence in HIV/ AIDS, Vancouver, Canada, ³Simon Fraser University, Faculty of Health Sciences, Burnaby, Canada, ⁴University of Tokyo, Institute of Medical Sciences, Tokyo, Japan, ⁵Microsoft Research, Redmond, United States, ⁶University Hospital Regensburg, Regensburg, Germany

BACKGROUND: The clinical significance of HLA class I-driven immune escape in HIV is incompletely understood. Disease progression may be influenced by mutations that compromise viral replication, particularly in Gag epitopes restricted by HLA-B alleles. We assessed the impact of HLA on viral replication capacity (RC) in a cross-sectional, population-based panel of viruses encoding clinically-derived Gag-Protease sequences.

METHODS: Plasma HIV Gag-Protease amplicons were generated from 628 antiretroviral naïve individuals for whom plasma viral load (pVL), CD4, HLA, and HIV sequences were known (BC HOMER cohort). NL4-3 variants containing patient-derived Gag-Protease were constructed by recombination and re-sequenced. RC was determined as the slope of viral spread in replicate assays using a GFP-reporter T-cell line. HLA-associated polymorphisms were defined in a cross-sectional analysis of a multicenter cohort of >1,200 individuals.

RESULTS: Mean±SD RC of the recombinant viruses was 102±14% (NL4-3=100%). Modest yet statistically significant associations were observed between RC and pVL (R=0.12, p=0.002) and CD4 count (R=-0.19, p<0.0001). When RC values were stratified based on HLA alleles expressed, HLA-B exhibited the broadest range (mean RC 82% for B*53 to 112% for B*50), whereas ranges for HLA-A and C alleles were narrower. Alleles significantly associated with lower or higher RC were also identified, including A*26 (p=0.008) and B*35 (p=0.044), respectively. No correlation was observed between RC and the total number of HLA-associated polymorphisms, however, RC of viruses from B*57+ individuals encoding the T242N escape mutation in TW10-Gag (N=37) correlated positively with the number of known T242N-associated compensatory mutations (R=0.39, p=0.02).

CONCLUSIONS: This study is the most comprehensive analysis of HLA-associated immune pressure on HIV replication to date and suggests a relevant role for Gag-Protease sequence variation on pathogenesis. Results support a dominant influence of HLA-B on RC and highlight a complex relationship between immune escape and compensatory mutations.

2009-07-22
MOPDA102
Poster Discussion MOPDA1 - HLA Pathogen Interactions

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