%0 Journal Article
%T HIV-1 epitopes presented by MHC class I types associated with superior immune containment of viremia have highly constrained fitness landscapes
%A Aleksandr M. Gorin
%A Christian Hofmann
%A Franklin Y. Liu
%A Hwee L. Ng
%A Otto O. Yang
%A Ren Sun
%A Tian-Hao Zhang
%A William G. Cumberland
%A Yushen Du
%J -
%D 2017
%R 10.1371/journal.ppat.1006541
%X 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
%K HIV-1
%K Cloning
%K Viral replication
%K Amino acid substitution
%K DNA libraries
%K Genomic libraries
%K T cell receptors
%K Substitution mutation
%U https://journals.plos.org/plospathogens/article?id=10.1371/journal.ppat.1006541