Widespread impact of HLA restriction on immune control and escape pathways of HIV-1
Microsoft Research, eScience Group, Los Angeles, CA, United States; Microsoft Research, eScience Group, Redmond, WA, United States; Ragon Institute of Massachusetts General Hospital, Massachusetts Institute of Technology and Harvard University, Boston, MA, United States; Howard Hughes Medical Institute, Chevy Chase, MD, United States; HIV Pathogenesis Programme, Doris Duke Medical Research Institute, Nelson R. Mandela School of Medicine, University of KwaZulu-Natal, Durban, South Africa; Division of Infectious Diseases, Beth Israel Deaconess Medical Center, Boston, MA, United States; Nuffield Department of Clinical Medicine, Oxford University, Oxford, United Kingdom; Faculty of Health Sciences, Simon Fraser University, Burnaby, BC, Canada; British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC, Canada; Department of Paediatrics, University of Oxford, Oxford, United Kingdom
The promiscuous presentation of epitopes by similar HLA class I alleles holds promise for a universal T-cell-based HIV-1 vaccine. However, in some instances, cytotoxic T lymphocytes (CTL) restricted by HLA alleles with similar or identical binding motifs are known to target epitopes at different frequencies, with different functional avidities and with different apparent clinical outcomes. Such differences may be illuminated by the association of similar HLA alleles with distinctive escape pathways. Using a novel computational method featuring phylogenetically corrected odds ratios, we systematically analyzed differential patterns of immune escape across all optimally defined epitopes in Gag, Pol, and Nef in 2,126 HIV-1 clade C-infected adults. Overall, we identified 301 polymorphisms in 90 epitopes associated with HLA alleles belonging to shared supertypes. We detected differential escape in 37 of 38 epitopes restricted by more than one allele, which included 278 instances of differential escape at the polymorphism level. The majority (66 to 97%) of these resulted from the selection of unique HLA-specific polymorphisms rather than differential epitope targeting rates, as confirmed by gamma interferon (IFN-γ) enzyme-linked immunosorbent spot assay (ELISPOT) data. Discordant associations between HLA alleles and viral load were frequently observed between allele pairs that selected for differential escape. Furthermore, the total number of associated polymorphisms strongly correlated with average viral load. These studies confirm that differential escape is a widespread phenomenon and may be the norm when two alleles present the same epitope. Given the clinical correlates of immune escape, such heterogeneity suggests that certain epitopes will lead to discordant outcomes if applied universally in a vaccine. © 2012, American Society for Microbiology.
epitope; Gag protein; gamma interferon; HLA antigen; Nef protein; Pol protein; allele; antigen specificity; article; cladistics; cohort analysis; DNA polymorphism; enzyme linked immunospot assay; HLA system; human; human cell; Human immunodeficiency virus 1; Human immunodeficiency virus 1 infection; immune escape; immunological parameters; immunoregulation; major clinical study; nonhuman; priority journal; virus load; virus typing; Alleles; Epitopes; Gene Expression; HIV Infections; HIV-1; HLA Antigens; Humans; Immune Evasion; Mutation; Polymorphism, Genetic; Viral Load; Human immunodeficiency virus 1