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Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics
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 evolut...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Texto |
Lenguaje: | English |
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Public Library of Science
2010
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931691/ https://www.ncbi.nlm.nih.gov/pubmed/20824187 http://dx.doi.org/10.1371/journal.pone.0012463 |
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author | Rolland, Morgane Carlson, Jonathan M. Manocheewa, Siriphan Swain, J. Victor Lanxon-Cookson, Erinn Deng, Wenjie Rousseau, Christine M. Raugi, Dana N. Learn, Gerald H. Maust, Brandon S. Coovadia, Hoosen Ndung'u, Thumbi Goulder, Philip J. R. Walker, Bruce D. Brander, Christian Heckerman, David E. Mullins, James I. |
author_facet | Rolland, Morgane Carlson, Jonathan M. Manocheewa, Siriphan Swain, J. Victor Lanxon-Cookson, Erinn Deng, Wenjie Rousseau, Christine M. Raugi, Dana N. Learn, Gerald H. Maust, Brandon S. Coovadia, Hoosen Ndung'u, Thumbi Goulder, Philip J. R. Walker, Bruce D. Brander, Christian Heckerman, David E. Mullins, James I. |
author_sort | Rolland, Morgane |
collection | PubMed |
description | 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. |
format | Text |
id | pubmed-2931691 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2010 |
publisher | Public Library of Science |
record_format | MEDLINE/PubMed |
spelling | pubmed-29316912010-09-03 Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics Rolland, Morgane Carlson, Jonathan M. Manocheewa, Siriphan Swain, J. Victor Lanxon-Cookson, Erinn Deng, Wenjie Rousseau, Christine M. Raugi, Dana N. Learn, Gerald H. Maust, Brandon S. Coovadia, Hoosen Ndung'u, Thumbi Goulder, Philip J. R. Walker, Bruce D. Brander, Christian Heckerman, David E. Mullins, James I. PLoS One Research Article 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. Public Library of Science 2010-09-01 /pmc/articles/PMC2931691/ /pubmed/20824187 http://dx.doi.org/10.1371/journal.pone.0012463 Text en Rolland et al. http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited. |
spellingShingle | Research Article Rolland, Morgane Carlson, Jonathan M. Manocheewa, Siriphan Swain, J. Victor Lanxon-Cookson, Erinn Deng, Wenjie Rousseau, Christine M. Raugi, Dana N. Learn, Gerald H. Maust, Brandon S. Coovadia, Hoosen Ndung'u, Thumbi Goulder, Philip J. R. Walker, Bruce D. Brander, Christian Heckerman, David E. Mullins, James I. Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics |
title | Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics |
title_full | Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics |
title_fullStr | Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics |
title_full_unstemmed | Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics |
title_short | Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics |
title_sort | amino-acid co-variation in hiv-1 gag subtype c: hla-mediated selection pressure and compensatory dynamics |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931691/ https://www.ncbi.nlm.nih.gov/pubmed/20824187 http://dx.doi.org/10.1371/journal.pone.0012463 |
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