Amino-acid co-variation in HIV-1 Gag subtype C: HLA-mediated selection pressure and compensatory dynamics.
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 pathw...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Public Library of Science (PLoS)
2010-09-01
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| Series: | PLoS ONE |
| Online Access: | http://europepmc.org/articles/PMC2931691?pdf=render |
| _version_ | 1819021937733533696 |
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| author | Morgane Rolland Jonathan M Carlson Siriphan Manocheewa J Victor Swain Erinn Lanxon-Cookson Wenjie Deng Christine M Rousseau Dana N Raugi Gerald H Learn Brandon S Maust Hoosen Coovadia Thumbi Ndung'u Philip J R Goulder Bruce D Walker Christian Brander David E Heckerman James I Mullins |
| author_facet | Morgane Rolland Jonathan M Carlson Siriphan Manocheewa J Victor Swain Erinn Lanxon-Cookson Wenjie Deng Christine M Rousseau Dana N Raugi Gerald H Learn Brandon S Maust Hoosen Coovadia Thumbi Ndung'u Philip J R Goulder Bruce D Walker Christian Brander David E Heckerman James I Mullins |
| author_sort | Morgane Rolland |
| collection | DOAJ |
| description | 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.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.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. |
| first_indexed | 2024-12-21T04:15:02Z |
| format | Article |
| id | doaj.art-f4df0c7bf2524d97bd249e82a543bae6 |
| institution | Directory Open Access Journal |
| issn | 1932-6203 |
| language | English |
| last_indexed | 2024-12-21T04:15:02Z |
| publishDate | 2010-09-01 |
| publisher | Public Library of Science (PLoS) |
| record_format | Article |
| series | PLoS ONE |
| spelling | doaj.art-f4df0c7bf2524d97bd249e82a543bae62022-12-21T19:16:21ZengPublic Library of Science (PLoS)PLoS ONE1932-62032010-09-015910.1371/journal.pone.0012463Amino-acid co-variation in HIV-1 Gag subtype C: HLA-mediated selection pressure and compensatory dynamics.Morgane RollandJonathan M CarlsonSiriphan ManocheewaJ Victor SwainErinn Lanxon-CooksonWenjie DengChristine M RousseauDana N RaugiGerald H LearnBrandon S MaustHoosen CoovadiaThumbi Ndung'uPhilip J R GoulderBruce D WalkerChristian BranderDavid E HeckermanJames I MullinsDespite 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.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.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.http://europepmc.org/articles/PMC2931691?pdf=render |
| spellingShingle | Morgane Rolland Jonathan M Carlson Siriphan Manocheewa J Victor Swain Erinn Lanxon-Cookson Wenjie Deng Christine M Rousseau Dana N Raugi Gerald H Learn Brandon S Maust Hoosen Coovadia Thumbi Ndung'u Philip J R Goulder Bruce D Walker Christian Brander David E Heckerman James I Mullins Amino-acid co-variation in HIV-1 Gag subtype C: HLA-mediated selection pressure and compensatory dynamics. PLoS ONE |
| 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 |
| url | http://europepmc.org/articles/PMC2931691?pdf=render |
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