Amino-acid co-variation in HIV-1 Gag subtype C: HLA-mediated selection pressure and compensatory dynamics.

Autor: 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
Jazyk: angličtina
Rok vydání: 2010
Předmět:
Zdroj: PLoS ONE, Vol 5, Iss 9 (2010)
Druh dokumentu: article
ISSN: 1932-6203
DOI: 10.1371/journal.pone.0012463
Popis: 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.
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