Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics

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Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics

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Title: Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics
Author: Rolland, Morgane; Manocheewa, Siriphan; Lanxon-Cookson, Erinn; Deng, Wenjie; Rousseau, Christine M.; Raugi, Dana N.; Learn, Gerald H.; Maust, Brandon S.; Coovadia, Hoosen; Ndung'u, Thumbi; Heckerman, David E.; Mullins, James I.; Carlson, Jonathan Courtland; Swain, Jabaris; Goulder, Philip J.; Walker, Bruce David; Brander, Christian

Note: Order does not necessarily reflect citation order of authors.

Citation: Rolland, Morgane, Jonathan M. Carlson, Siriphan Manocheewa, J. Victor Swain, Erinn Lanxon-Cookson, Wenjie Deng, Christine M. Rousseau, et al. 2010. Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics. PLoS ONE 5(9): e12463.
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Abstract: 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.
Published Version: doi:10.1371/journal.pone.0012463
Other Sources: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2931691/pdf/
Terms of Use: This article is made available under the terms and conditions applicable to Other Posted Material, as set forth at http://nrs.harvard.edu/urn-3:HUL.InstRepos:dash.current.terms-of-use#LAA
Citable link to this page: http://nrs.harvard.edu/urn-3:HUL.InstRepos:4885975

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