HLA-associated mutations occur less frequently in HIV elite controllers than in chronically infected individuals

Background: HIV elite controllers (EC) are a rare group of persons who spontaneously control plasma viral load (pVL) to less than 50 RNA copies/ml without antiretroviral treatment. Mechanisms responsible for viral control remain unknown, but cytotoxic T lymphocytes (CTL) are believed to play a crucial role. CTL pressure can select for HLA-associated escape mutations, but a comprehensive analysis of the frequency of CTL escape mutations in EC has not been done. Methods: A previously described list of HLA-associated polymorphisms in HIV subtype B, which represent likely CTL escape mutations, was used to compare the frequency of these polymorphisms in plasma viral sequences from EC and untreated chronic individuals. HLA-associated mutations in 54 Gag, 41 RT and 39 Nef sequences from EC were compared with 567 Gag, 531 RT, and 686 Nef sequences from chronic individuals. Statistical analyses were conducted using the Mann-Whitney U test. Results: HLA alleles enriched among EC were associated with more HLA-associated polymorphisms in Gag (p ¼ 0.001), particularly in the p24 protein. Despite having undetectable pVL, HLAassociated polymorphisms were commonly observed in plasma virus from EC, but the proportion of HLA-associated codons exhibiting escape was significantly lower in EC than in chronic patients for Gag (0.375 vs 0.500; p < 0.001), RT (0.308 vs 0.400; p < 0.001) and Nef (0.421 vs 0.533; p < 0.001). Significant differences in the frequency of HLA-associated polymorphisms were seen for A*03, A*30, B*15, B*27, Cw*06 and Cw*07 in Gag, and for B*57, Cw*07 and Cw*12 in Nef. Conclusion: These results indicate that HLA-associated polymorphisms are common in plasma viral sequences from EC, but are significantly less frequent during controlled than chronic infection. Larger studies of EC viruses will be necessary to examine the role of particular HLA-associated mutations in control of HIV viremia