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

Journal Article · Fri Jul 06 00:00:00 EDT 2007 · PLoS Pathogens

DOI:https://doi.org/10.1371/journal.ppat.0030094· OSTI ID:1627888

Brumme, Zabrina L. ^[1]; Brumme, Chanson J. ^[2]; Heckerman, David ^[3]; Korber, Bette T. ^[4]; Daniels, Marcus ^[5]; Carlson, Jonathan ^[6]; Kadie, Carl ^[3]; Bhattacharya, Tanmoy ^[7]; Chui, Celia ^[8]; Szinger, James ^[5]; Mo, Theresa ^[8]; Hogg, Robert S. ^[9]; Montaner, Julio S. G. ^[10]; Frahm, Nicole ^[11]; Brander, Christian ^[11]; Walker, Bruce D. ^[12]; Harrigan, P. Richard ^[10]

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1. Harvard Medical School, Boston, MA (United States); Howard Hughes Medical Inst., Chevy Chase, MD (United States); British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC (Canada); DOE/OSTI
2. Harvard Medical School, Boston, MA (United States); British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC (Canada)
3. Microsoft Research, Redmond, WA (United States)
4. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States); Santa Fe Institute (SFI), Santa Fe, NM (United States)
5. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
6. Microsoft Research, Redmond, WA (United States); University of Washington, Seattle, WA (United States)
7. Los Alamos National Laboratory (LANL), Los Alamos, NM (United States); University of Washington, Seattle, WA (United States)
8. British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC (Canada)
9. British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC (Canada); Simon Fraser University, Burnaby, BC (Canada)
10. British Columbia Centre for Excellence in HIV/AIDS, Vancouver, BC (Canada); University of British Columbia, Vancouver, BC (Canada)
11. Harvard Medical School, Boston, MA (United States)
12. Harvard Medical School, Boston, MA (United States); Howard Hughes Medical Institute, Chevy Chase, MD (United States)

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.

• Research Organization: Los Alamos National Laboratory (LANL), Los Alamos, NM (United States)
• Sponsoring Organization: National Institutes of Health (NIH); USDOE Office of Science (SC), Biological and Environmental Research (BER)
• Grant/Contract Number: AC52-06NA25396
• OSTI ID: 1627888
• Journal Information: PLoS Pathogens, Journal Name: PLoS Pathogens Journal Issue: 7 Vol. 3; ISSN 1553-7374
• Publisher: Public Library of Science
• Country of Publication: United States
• Language: English

Related Subjects

59 BASIC BIOLOGICAL SCIENCES
HIV
HIV-1
alleles
epitope mapping
microbial mutation
mutation
proteases
protein sequencing