dc.contributor.author | Rolland, Morgane | |
dc.contributor.author | Manocheewa, Siriphan | |
dc.contributor.author | Lanxon-Cookson, Erinn | |
dc.contributor.author | Deng, Wenjie | |
dc.contributor.author | Rousseau, Christine M. | |
dc.contributor.author | Raugi, Dana N. | |
dc.contributor.author | Learn, Gerald H. | |
dc.contributor.author | Maust, Brandon S. | |
dc.contributor.author | Coovadia, Hoosen | |
dc.contributor.author | Ndung'u, Thumbi | |
dc.contributor.author | Heckerman, David E. | |
dc.contributor.author | Mullins, James I. | |
dc.contributor.author | Carlson, Jonathan Courtland | |
dc.contributor.author | Swain, Jabaris | |
dc.contributor.author | Goulder, Philip J. | |
dc.contributor.author | Walker, Bruce David | |
dc.contributor.author | Brander, Christian | |
dc.date.accessioned | 2011-05-10T02:00:25Z | |
dc.date.issued | 2010 | |
dc.identifier.citation | Rolland, Morgane, Jonathan M. Carlson, Siriphan Manocheewa, J. Victor Swain, Erinn Lanxon-Cookson, Wenjie Deng, Christine M. Rousseau, et al. 2010. Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics. PLoS ONE 5(9): e12463. | en_US |
dc.identifier.issn | 1932-6203 | en_US |
dc.identifier.uri | http://nrs.harvard.edu/urn-3:HUL.InstRepos:4885975 | |
dc.description.abstract | Background: Despite high potential for HIV-1 genetic variation, the emergence of some mutations is constrained by fitness costs, and may be associated with compensatory amino acid (AA) co-variation. To characterize the interplay between Cytotoxic T Lymphocyte (CTL)-mediated pressure and HIV-1 evolutionary pathways, we investigated AA co-variation in Gag sequences obtained from 449 South African individuals chronically infected with HIV-1 subtype C. Methodology/Principal Findings: Individuals with CTL responses biased toward Gag presented lower viral loads than individuals with under-represented Gag-specific CTL responses. Using methods that account for founder effects and HLA linkage disequilibrium, we identified 35 AA sites under Human Leukocyte Antigen (HLA)-restricted CTL selection pressure and 534 AA-to-AA interactions. Analysis of two-dimensional distances between co-varying residues revealed local stabilization mechanisms since 40% of associations involved neighboring residues. Key features of our co-variation analysis included sites with a high number of co-varying partners, such as HLA-associated sites, which had on average 55% more connections than other co-varying sites. Conclusions/Significance: Clusters of co-varying AA around HLA-associated sites (especially at typically conserved sites) suggested that cooperative interactions act to preserve the local structural stability and protein function when CTL escape mutations occur. These results expose HLA-imprinted HIV-1 polymorphisms and their interlinked mutational paths in Gag that are likely due to opposite selective pressures from host CTL-mediated responses and viral fitness constraints. | en_US |
dc.language.iso | en_US | en_US |
dc.publisher | Public Library of Science | en_US |
dc.relation.isversionof | doi:10.1371/journal.pone.0012463 | en_US |
dc.relation.hasversion | http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931691/pdf/ | en_US |
dash.license | LAA | |
dc.subject | evolutionary biology | en_US |
dc.subject | bioinformatics | en_US |
dc.subject | virology | en_US |
dc.subject | host antiviral responses | en_US |
dc.subject | immune evasion | en_US |
dc.subject | immunodeficiency viruses | en_US |
dc.subject | virus evolution and symbiosis | en_US |
dc.title | Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics | en_US |
dc.type | Journal Article | en_US |
dc.description.version | Version of Record | en_US |
dc.relation.journal | PLoS ONE | en_US |
dash.depositing.author | Walker, Bruce David | |
dc.date.available | 2011-05-10T02:00:25Z | |
dash.affiliation.other | HMS^Medicine-Massachusetts General Hospital | en_US |
dash.affiliation.other | HMS^Medicine-Massachusetts General Hospital | en_US |
dash.affiliation.other | SPH^Immunology and Infectious Diseases | en_US |
dash.affiliation.other | HMS^Medicine-Massachusetts General Hospital | en_US |
dc.identifier.doi | 10.1371/journal.pone.0012463 | * |
dash.authorsordered | false | |
dash.contributor.affiliated | Swain, Jabaris | |
dash.contributor.affiliated | Carlson, Jonathan | |
dash.contributor.affiliated | Brander, Christian | |
dash.contributor.affiliated | Goulder, Philip J. | |
dash.contributor.affiliated | Walker, Bruce | |
dc.identifier.orcid | 0000-0001-6122-9245 | |