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 evolu...
| Main Authors: | , , , , , , , , , , , , , , , , |
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| Format: | Journal article |
| Language: | English |
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2010
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| _version_ | 1797074902477438976 |
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| author | Rolland, M Carlson, J Manocheewa, S Swain, J Lanxon-Cookson, E Deng, W Rousseau, C Raugi, D Learn, G Maust, B Coovadia, H Ndung'u, T Goulder, P Walker, B Brander, C Heckerman, D Mullins, J |
| author_facet | Rolland, M Carlson, J Manocheewa, S Swain, J Lanxon-Cookson, E Deng, W Rousseau, C Raugi, D Learn, G Maust, B Coovadia, H Ndung'u, T Goulder, P Walker, B Brander, C Heckerman, D Mullins, J |
| author_sort | Rolland, M |
| collection | OXFORD |
| 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. |
| first_indexed | 2024-03-06T23:42:58Z |
| format | Journal article |
| id | oxford-uuid:6ff05a03-00b5-4b29-8ee6-1e0e2ed61df2 |
| institution | University of Oxford |
| language | English |
| last_indexed | 2024-03-06T23:42:58Z |
| publishDate | 2010 |
| record_format | dspace |
| spelling | oxford-uuid:6ff05a03-00b5-4b29-8ee6-1e0e2ed61df22022-03-26T19:33:58ZAmino-acid co-variation in HIV-1 Gag subtype C: HLA-mediated selection pressure and compensatory dynamics.Journal articlehttp://purl.org/coar/resource_type/c_dcae04bcuuid:6ff05a03-00b5-4b29-8ee6-1e0e2ed61df2EnglishSymplectic Elements at Oxford2010Rolland, MCarlson, JManocheewa, SSwain, JLanxon-Cookson, EDeng, WRousseau, CRaugi, DLearn, GMaust, BCoovadia, HNdung'u, TGoulder, PWalker, BBrander, CHeckerman, DMullins, J 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. |
| spellingShingle | Rolland, M Carlson, J Manocheewa, S Swain, J Lanxon-Cookson, E Deng, W Rousseau, C Raugi, D Learn, G Maust, B Coovadia, H Ndung'u, T Goulder, P Walker, B Brander, C Heckerman, D Mullins, J 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 |
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