Evidence of Differential HLA Class I-Mediated Viral Evolution in Functional and Accessory/Regulatory Genes of HIV-1

PLoS Pathogens

David Heckerman¹  P. Richard Harrigan¹  Christian Brander¹  Marcus Daniels¹  Nicole Frahm²  Chanson J Brumme³  Theresa Mo⁴  Carl Kadie⁴  Celia Chui⁴  Robert S Hogg⁵  James Szinger⁵  Jonathan Carlson⁵  Zabrina L Brumme⁶  Bette T Korber⁶  Julio S. G Montaner⁷  Tanmoy Bhattacharya⁷  Bruce D Walker⁷ 

[1] British Columbia Centre for Excellence in HIV/AIDS, Vancouver, British Columbia, Canada;Department of Computer Science and Engineering, University of Washington, Seattle, Washington, United States of America;Howard Hughes Medical Institute, Chevy Chase, Maryland, United States of America;Los Alamos National Laboratory, Los Alamos, New Mexico, United States of America;Microsoft Research, Redmond, Washington, United States of America;Partners AIDS Research Center, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, United States of America;Santa Fe Institute, Santa Fe, New Mexico, United States of America

关键词: HIV;    Alleles;    Sequence motif analysis;    HIV-1;    Epitope mapping;    Protein sequencing;    Microbial mutation;    Proteases;   

DOI  :  10.1371/journal.ppat.0030094

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Despite the formidable mutational capacity and sequence diversity of HIV-1, evidence suggests that viral evolution in response to specific selective pressures follows generally predictable mutational pathways. Population-based analyses of clinically derived HIV sequences may be used to identify immune escape mutations in viral genes; however, prior attempts to identify such mutations have been complicated by the inability to discriminate active immune selection from virus founder effects. Furthermore, the association between mutations arising under in vivo immune selection and disease progression for highly variable pathogens such as HIV-1 remains incompletely understood. We applied a viral lineage-corrected analytical method to investigate HLA class I-associated sequence imprinting in HIV protease, reverse transcriptase (RT), Vpr, and Nef in a large cohort of chronically infected, antiretrovirally naïve individuals. A total of 478 unique HLA-associated polymorphisms were observed and organized into a series of “escape maps,” which identify known and putative cytotoxic T lymphocyte (CTL) epitopes under selection pressure in vivo. Our data indicate that pathways to immune escape are predictable based on host HLA class I profile, and that epitope anchor residues are not the preferred sites of CTL escape. Results reveal differential contributions of immune imprinting to viral gene diversity, with Nef exhibiting far greater evidence for HLA class I-mediated selection compared to other genes. Moreover, these data reveal a significant, dose-dependent inverse correlation between HLA-associated polymorphisms and HIV disease stage as estimated by CD4+ T cell count. Identification of specific sites and patterns of HLA-associated polymorphisms across HIV protease, RT, Vpr, and Nef illuminates regions of the genes encoding these products under active immune selection pressure in vivo. The high density of HLA-associated polymorphisms in Nef compared to other genes investigated indicates differential HLA class I-driven evolution in different viral genes. The relationship between HLA class I-associated polymorphisms and lower CD4+ cell count suggests that immune escape correlates with disease status, supporting an essential role of maintenance of effective CTL responses in immune control of HIV-1. The design of preventative and therapeutic CTL-based vaccine approaches could incorporate information on predictable escape pathways.

【 授权许可】

CC BY