Show simple item record

dc.contributor.authorBrumme, Zabrina L
dc.contributor.authorBrumme, Chanson J
dc.contributor.authorHeckerman, David
dc.contributor.authorKorber, Bette T
dc.contributor.authorDaniels, Marcus
dc.contributor.authorKadie, Carl
dc.contributor.authorBhattacharya, Tanmoy
dc.contributor.authorChui, Celia
dc.contributor.authorSzinger, James
dc.contributor.authorMo, Theresa
dc.contributor.authorHogg, Robert S
dc.contributor.authorMontaner, Julio S. G
dc.contributor.authorFrahm, Nicole
dc.contributor.authorHarrigan, P. Richard
dc.contributor.authorCarlson, Jonathan Courtland
dc.contributor.authorBrander, Christian
dc.contributor.authorWalker, Bruce David
dc.date.accessioned2012-01-03T03:24:58Z
dc.date.issued2007
dc.identifier.citationBrumme, Zabrina L, Chanson J Brumme, David Heckerman, Bette T Korber, Marcus Daniels, Jonathan Carlson, Carl Kadie, and et al. 2007. Evidence of differential HLA class I-mediated viral evolution in functional and accessory/regulatory genes of HIV-1. PLoS Pathogens 3(7): e94.en_US
dc.identifier.issn1553-7366en_US
dc.identifier.urihttp://nrs.harvard.edu/urn-3:HUL.InstRepos:5978745
dc.description.abstractDespite 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.en_US
dc.language.isoen_USen_US
dc.publisherPublic Library of Scienceen_US
dc.relation.isversionofdoi://10.1371/journal.ppat.0030094en_US
dc.relation.hasversionhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC1904471/pdf/en_US
dash.licenseLAA
dc.subjectvirologyen_US
dc.subjectimmunologyen_US
dc.subjectvirusesen_US
dc.titleEvidence of Differential HLA Class I-Mediated Viral Evolution in Functional and Accessory/Regulatory Genes of HIV-1en_US
dc.typeJournal Articleen_US
dc.description.versionVersion of Recorden_US
dc.relation.journalPLoS Pathogensen_US
dash.depositing.authorBrander, Christian
dc.date.available2012-01-03T03:24:58Z
dash.affiliation.otherHMS^Medicine-Massachusetts General Hospitalen_US
dash.affiliation.otherHMS^Medicine-Massachusetts General Hospitalen_US
dash.affiliation.otherSPH^Immunology and Infectious Diseasesen_US
dc.identifier.doi10.1371/journal.ppat.0030094*
dash.authorsorderedfalse
dash.contributor.affiliatedCarlson, Jonathan
dash.contributor.affiliatedBrander, Christian
dash.contributor.affiliatedWalker, Bruce
dc.identifier.orcid0000-0001-6122-9245


Files in this item

Thumbnail

This item appears in the following Collection(s)

Show simple item record