Flaviviruses sample an ensemble of virion conformations resulting from the conformational flexibility of their structural proteins. To investigate how sequence variation among strains impacts virus breathing, we performed studies with the monoclonal antibody (MAb) E111, which binds an inaccessible domain III envelope (E) protein epitope of @entity778 serotype 1 (DENV1). Prior studies indicated that an observed ~200-fold difference in neutralization between the DENV1 strains Western Pacific-74 (West Pac-74) and 16007 could not be explained by differences in the affinity of MAb E111 for each strain. Through neutralization studies with wild-type and variant viruses carrying genes encoding reciprocal mutations at all 13  @entity3689 differences between the E proteins of West Pac-74 and 16007, we found that E111 neutralization susceptibility mapped solely to the presence of a @entity376 or @entity369 at E domain II residue 204, located distally from the E111 epitope. This same residue correlated with neutralization differences observed for MAbs specific for epitopes distinct from E111, suggesting that this @entity3689 dictates changes in the conformational ensembles sampled by the virus. Furthermore, an observed twofold difference in the stability of infectious West Pac-74 versus 16007 in solution also mapped to E residue 204. Our results demonstrate that neutralization susceptibility can be altered in an epitope-independent manner by natural strain variation that influences the structures sampled by @entity778 . That different conformational ensembles of flaviviruses may affect the landscape available for antibody binding, as well as virus stability, has important implications for functional studies of antibody potency, a critical aspect of vaccine development. IMPORTANCE: The global burden of @entity778 ( @entity778 ) is growing, with recent estimates of ~390 million @entity1 infections each year. Antibodies play a crucial role in protection from @entity778 infection, and vaccines that elicit a robust antibody response are being actively pursued. We report here the identification of a single @entity3689 residue in the envelope protein of @entity778 serotype 1 that results in global changes to virus structure and stability when it is changed. Our results indicate that naturally occurring variation at this particular site among virus strains impacts the ensemble of structures sampled by the virus, a process referred to as virus breathing. The finding that such limited and conservative sequence changes can modulate the landscape available for antibody binding has important implications for both vaccine development and the study of @entity778 -reactive antibodies.

Genotypic Differences in Dengue Virus Neutralization Are Explained by a Single XXXX Mutation That Modulates Virus Breathing.

@entity1 :: ('9606', 'Species') :: ['human'] @entity778 :: ('MESH:D015658', 'Disease') :: ['dengue virus', 'DENV'] @entity376 :: ('CHEBI:25094', 'Chemical') :: ['lysine'] @entity3689 :: ('D000596', 'Chemical') :: ['amino acid'] @entity369 :: ('CHEBI:29016', 'Chemical') :: ['arginine']
@entity3689 :: (D000596,Chemical) :: ['Amino Acid']
