Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics
- 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 Heckerman ,
- James I. Mullins
PLoS ONE | , pp. e12463
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.