Platform: Computational Methods
2/26/2012 12:30:00 PM
ANALYSIS OF COLLECTIVE COEVOLUTION IN HIV PROTEINS SUGGESTS STRATEGIES FOR RATIONAL VACCINE DESIGN
, Vincent Dahirel
, Bruce D. Walker
, Arup K. Chakraborty
Massachusetts Institute of Technology, Cambridge, MA, USA,
Universite Pierre et Marie Curie, Paris, France,
Ragon Institute of MGH, MIT and Harvard, Cambridge, MA, USA.
The rapid evolution of HIV in sequence space evades adaptive immune responses (T cells and neutralizing antibodies) and has posed significant challenges in the design of protective vaccines. We hypothesized that characterizing collective correlations between different amino acid mutations within HIV proteins would reveal proteomic regions that evolve independently from other such regions, but exhibit highly collective mutational correlations. Using a method from physics(1, 2) , we analyzed publicly available sequences of HIV’s structural protein Gag to discover independently coevolving groups of residues (termed ‘sectors’) where, mutations within a sector are highly coupled. One sector displayed far more collective constraints than others, suggesting a potentially vulnerable vaccine target. Protein structures revealed that a large fraction of residues within this sector were located at critical oligomeric interfaces of the viral capsid, where multiple mutations would not be tolerated. Cellular immune responses within natural controllers of HIV were found to preferentially target these residues. Circulating viral strains sequenced from HIV controllers displayed very few multiple mutations in this sector compared to another sector of similar size.The absence of an immunogen that faithfully mimics the native structure of the heterotrimeric HIV receptor has precluded experimental attempts to raise broadly neutralizing antibodies. Using related methods, we are also confronting this challenge. Our results suggest a new concept in design of vaccines against rapidly mutating viruses.
1.Plerou et al., Phys. Rev. E 65, 066126 (2002)
2. Halabi et al., Cell, 138, 774-786 (2009)
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