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

作者：Rolland Morgane^*; Carlson Jonathan M; Manocheewa Siriphan; Swain J Victor; Lanxon Cookson Erinn; Deng Wenjie; Rousseau Christine M; Raugi Dana N; Learn Gerald H; Maust Brandon S; Coovadia Hoosen; Ndung'u Thumbi; Goulder Philip J R; Walker Bruce D; Brander Christian; Heckerman David E; Mullins James I

来源：PLos One, 2010, 5(9): e12463.

DOI：10.1371/journal.pone.0012463

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.

• 出版日期2010-9-1
• 单位Microsoft