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Description:
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In order to establish infection , flaviviruses induce mutations in antigenic proteins as a strategy to evade neutralizing antibodies ; a phenomenon known as antibody -mediated neutralization resistance . Most of the critical mutations associated with antibody resistance are located in the envelope protein domain 3 (ED3 ) . In West Nile virus (WNV ) , and in other flaviviruses , mutations in ED3 are found throughout its structure , including regions outside of the viral epitope and /or not accessible to antibodies . Besides the trivial effects of local perturbations due to mutations in the epitope , these observations are consistent with our hypothesis that there is long -range communication connecting distant residues linked to the viral epitope . Mutations at sites distant but coupled to the epitope would lead to an alteration of affinity to antibody ; e .g . , resistance to antibody -mediated neutralization . In support of our hypothesis , we demonstrated by multiple biophysical approaches the communications among distant sites and a network of communications of energetically coupled residues . Within this network , mutations in WNV ED3 caused perturbations only in the loop connecting strands B -C (BC loop ) by changing the magnitude of energetic coupling between these distant sites . The magnitude of perturbation conveyed by the mutations is represented by a Boltzmann distribution . This suggests that neutralization resistance is the manifestation of an equilibrium process governing the distribution between ED3 conformations that are responsible for antibody neutralization -resistance and nonresistance . Indeed we observed a linear correlation between affinity for antibody and magnitude of energetic coupling on the BC loop . To test the generality of these results , we investigated the ED3 from dengue virus type 2 (DENV2 ) , a related flavivirus . We found that only the FG loop was susceptible to mutational perturbations . Remarkably , the BC and FG loops have been shown to be the dominant epitopes in ED3 for WNV and DENV2 , respectively . Evidently these distant sites are energetically coupled to their respective viral epitope . This study reveals the strategy by which flavivirus employed to evade antibody , namely , establishment of long -range communications in viral proteins to expand the mutational repertoire to perturb the epitopes and lower the affinity for antibodies resulting in evasion of antibody -mediated neutralization . |