Computational and Population-Based HLA Permissiveness to HIV Drug Resistance-Associated Mutations

The presentation of HIV peptides by the human leukocyte antigen (HLA) complex to CD8+ cytotoxic T-cells (CTLs) is critical to limit viral pathogenesis. HIV can mutate to evade HLA-restricted CTL responses and resist antiretroviral drugs, raising questions about how it balances these evolutionary pressures. Here, we used a computational approach to assess how drug resistance-associated mutations (RAMs) affect the binding of HIV-1 subtype B or C peptides to the most prevalent HLA alleles in US, European, and South African populations. We predict RAMs that may be favored in certain populations and report the under-representation of Y181C in people expressing HLA-B*57:01. This finding agreed with our computational predictions when Y181C was at the major anchor site P2, suggesting the potential relevance of our approach. Overall, our findings lay out a conceptual framework to study the implications of HLA alleles on the emergence of HIV RAMs at the individual and population levels.