期刊论文详细信息
PLoS Pathogens
HIV-1 epitopes presented by MHC class I types associated with superior immune containment of viremia have highly constrained fitness landscapes
Ren Sun1  Aleksandr M. Gorin2  Franklin Y. Liu2  Tian-Hao Zhang3  Otto O. Yang3  Yushen Du3  Christian Hofmann4  William G. Cumberland4  Hwee L. Ng5 
[1] Department of Biostatistics, Fielding School of Public Health, University of California, Los Angeles, California, United States of America;Department of Microbiology, Immunology & Molecular Genetics, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America;Department of Molecular and Medical Pharmacology, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America;Division of Infectious Diseases, David Geffen School of Medicine, University of California Los Angeles, Los Angeles, California, United States of America;Molecular Biology Institute, University of California Los Angeles, Los Angeles, California, United States of America
关键词: HIV-1;    Cloning;    Viral replication;    Amino acid substitution;    DNA libraries;    Genomic libraries;    T cell receptors;    Substitution mutation;   
DOI  :  10.1371/journal.ppat.1006541
学科分类:生物科学(综合)
来源: Public Library of Science
PDF
【 摘 要 】

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.

【 授权许可】

CC BY   

【 预 览 】
附件列表
Files Size Format View
RO201902016445622ZK.pdf 7433KB PDF download
  文献评价指标  
  下载次数:3次 浏览次数:29次