Supertype Motifs by HLA Class I Molecules with Common HIV - 1 : Highly Divergent Selection Imposed

Currently, 1.1 million individuals in the United States are living with HIV-1 infection. Although this is a relatively small proportion of the global pandemic, the remarkable mix of ancestries in the United States, drawn together over the past two centuries of continuous population migrations, provides an important and unique perspective on adaptive interactions between HIV-1 and human genetic diversity. HIV-1 is a rapidly adaptable organism and mutates within or near immune epitopes that are determined by the HLA class I genotype of the infected host. We characterized HLA-associated polymorphisms across the full HIV-1 proteome in a large, ethnically diverse national United States cohort of HIV-1–infected individuals. We found a striking divergence in the immunoselection patterns associated with HLA variants that have very similar or identical peptide-binding specificities but are differentially distributed among racial/ethnic groups. Although their similarity in peptide binding functionally clusters these HLA variants into supertypes, their differences at sites within the peptide-binding groove contribute to race-specific selection effects on circulating HIV-1 viruses. This suggests that the interactions between the HLA/HIV peptide complex and the TCR vary significantly within HLA supertype groups, which, in turn, influences HIV-1 evolution. W hole-genome association studies have shown that the most significant genetic determinants of HIV disease outcome are within the MHC and, more specifically, the highly variable HLA class I loci (1, 2). This builds upon many studies showing associations between HLA class I genotypes and HIV disease progression (3). The HLA class I allele repertoire of an individual determines which peptide epitopes derived from a pathogen may be presented to Ag-specific CD8 T cells. The bulk of genetic variation among .2000 known HLA class I subtypes worldwide is within exons 2 and 3, coding for the peptide-binding region of the mature HLA protein (4). Polymorphism in this region provides for the broadest defense against a variety of different pathogens and variability within a pathogen species. There was allelic divergence at MHC class I loci during primate evolution, and the combination of early human colonization history and diverse selection pressures of prevalent microbes in different regions of the world led to the global diversity of HLA alleles today (5, 6). Although the complex interactions between founder effects, pathogen driven selection, and population admixtures are continuous, the timescale of human evolution is such that the HLA allele distribution of modern human populations still reflects, in large part, the early ancestry of the individuals …