HIV-1 epitopes presented by MHC class I types associated with superior immune containment of viremia have highly constrained fitness landscapes

• Published in: PLoS pathogens 2017-08, Vol.13 (8), p.e1006541
• Main Authors: Gorin, Aleksandr M, Du, Yushen, Liu, Franklin Y, Zhang, Tian-Hao, Ng, Hwee L, Hofmann, Christian, Cumberland, William G, Sun, Ren, Yang, Otto O
• Format: Article
• Language: English
• Subjects: Acquired immune deficiency syndrome; AIDS; Antigen Presentation - immunology; Antigenic determinants; Biology and Life Sciences; CD8 antigen; Containment; Cytotoxicity; Diagnosis; Epitopes; Epitopes, T-Lymphocyte - immunology; Fitness; Health aspects; High-Throughput Nucleotide Sequencing; Histocompatibility Antigens Class I - immunology; HIV; HIV infections; HIV Infections - immunology; HIV-1 - immunology; Human immunodeficiency virus; Humans; Immune Evasion - immunology; Immunodominant Epitopes - immunology; Landscape; Lymphocytes; Lymphocytes T; Major histocompatibility complex; Medicine and Health Sciences; Mutagenesis, Site-Directed; Mutation; Pattern recognition; Physical Sciences; Receptors; Reproductive fitness; Research and Analysis Methods; Saturation; Saturation mutagenesis; T cell receptors; T-Lymphocytes, Cytotoxic - immunology; Viability; Viremia; Viremia - immunology
• ISSN: 1553-7374; 1553-7366; 1553-7374
• DOI: 10.1371/journal.ppat.1006541

Certain Major Histocompatibility-I (MHC-I) types are associated with superior immune containment of HIV-1 infection by CD8+ cytotoxic T lymphocytes (CTLs), but the mechanisms mediating this containment are difficult to elucidate in vivo. Here we provide controlled assessments of fitness landscapes and CTL-imposed constraints for immunodominant epitopes presented by two protective (B*57 and B*27) and one non-protective (A*02) MHC-I types. Libraries of HIV-1 with saturation mutagenesis of CTL epitopes are propagated with and without CTL selective pressure to define the fitness landscapes for epitope mutation and escape from CTLs via deep sequencing. Immunodominant B*57- and B*27- present epitopes are highly limited in options for fit mutations, with most viable variants recognizable by CTLs, whereas an immunodominant A*02 epitope-presented is highly permissive for mutation, with many options for CTL evasion without loss of viability. Generally, options for evasion overlap considerably between CTL clones despite highly distinct T cell receptors. Finally, patterns of variant recognition suggest population-wide CTL selection for the A*02-presented epitope. Overall, these findings indicate that these protective MHC-I types yield CTL targeting of highly constrained epitopes, and underscore the importance of blocking public escape pathways for CTL-based interventions against HIV-1.