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

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

Journal article

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

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.

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APA Style

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. (2010). Amino-acid co-variation in HIV-1 Gag subtype C: HLA-mediated selection pressure and compensatory dynamics. PloS One, 5(9), e12489.

MLA Style

Rolland, M., et al. “Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics.” PloS One, vol. 5, no. 9, 2010, p. e12489.

Chicago Style

Rolland, M, J Carlson, S Manocheewa, J Swain, E Lanxon-Cookson, W Deng, C 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): e12489.
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