Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics
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Rolland-2010-Amino-Acid Co-Variat.pdf
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Author(s)
Brander, Christian
Walker, Bruce D.
Goulder, Philip J. R.
Rolland, Morgane
Carlson, Jonathan M.
Manocheewa, Siriphan
Rousseau, Christine M.
Raugi, Dana N.
Learn, Gerald H.
Maust, Brandon S.
Date Issued
September 2010
Journal
PLoS ONE
Publisher
Public Library of Science
Citation
Rolland, Morgane et al. “Amino-Acid Co-Variation in HIV-1 Gag Subtype C: HLA-Mediated Selection Pressure and Compensatory Dynamics.” PLoS ONE 5.9 (2010): e12463.
Version
Final published version
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.
MIT Department
Ragon Institute of MGH, MIT and Harvard
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DOI of Published Version
https://doi.org/10.1371/journal.pone.0012463
