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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...

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Autores principales: 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.
Formato: Texto
Lenguaje:English
Publicado: Public Library of Science 2010
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.
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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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