Identification of HLA Class I-Associated Amino Acid Polymorphisms in the HIV-1C Proteome

Abstract

Human immunodeficiency virus type 1 (HIV-1) evasion of host cytotoxic T lymphocyte (CTL) targeting is linked to the expression of variant amino acid residues, or escape mutations, in positions that alter the normal processing, presentation, or recognition of targeted epitopes. The combined genetic variability of HIV and the class I human leukocyte antigen (HLA) loci makes it difficult to characterize CTL escape mutations on a population level. However, a role in CTL escape may be inferred by identifying HIV amino acid polymorphisms that are specifically associated with particular HLA class I alleles. We describe here the results of a comprehensive analysis of HIV-1 subtype C (HIV-1C) to identify HLA class I-associated amino acid polymorphisms. We identified 94 HLA-associated amino acid polymorphisms distributed across the 15 major viral proteins analyzed. HLA-B alleles were involved in more associations (50%) than alleles from either the HLA-A (27%) or HLA-C (24%) loci. HLA-associated polymorphisms were identified in 18 of 26 previously described HIV-1C CTL immunoreactive regions including 7 of the 8 classified as immunodominant. Comparison to known HIV-1 CTL epitopes revealed that 19 of the HLA-associated polymorphisms were located in CTL epitopes restricted by the associated HLA allele. These results suggest that HIV-1C retains the potential for CTL escape across the entire proteome including regions that are broadly targeted on a population scale. The impact of CTL escape on natural and vaccine-induced CTL immunity warrants the continued characterization of the role of such HLA-associated polymorphisms in this process.