Abstract
We previously developed a panel of neutralizing monoclonal antibodies against Dengue virus (DENV)-1, of which few exhibited inhibitory activity against all DENV-1 genotypes. This finding is consistent with reports observing variable neutralization of different DENV strains and genotypes using serum from individuals that experienced natural infection or immunization. Herein, we describe the crystal structures of DENV1-E111 bound to a novel CC′ loop epitope on domain III (DIII) of the E protein from two different DENV-1 genotypes. Docking of our structure onto the available cryo-electron microscopy models of DENV virions revealed that the DENV1-E111 epitope was inaccessible, suggesting that this antibody recognizes an uncharacterized virus conformation. While the affinity of binding between DENV1-E111 and DIII varied by genotype, we observed limited correlation with inhibitory activity. Instead, our results support the conclusion that potent neutralization depends on genotype-dependent exposure of the CC′ loop epitope. These findings establish new structural complexity of the DENV virion, which may be relevant for the choice of DENV strain for induction or analysis of neutralizing antibodies in the context of vaccine development.
Highlights
Dengue viruses (DENV) are mosquito-borne viruses of the Flavivirus genus, which include other significant human pathogens such as West Nile (WNV), Japanese encephalitis, and yellow fever viruses
Within each Dengue virus (DENV) serotype, viruses are subdivided into genotypes based upon the protein sequence variation
We used structural and molecular approaches to determine that DENV1-E111 binds to an epitope in domain III of the envelope protein
Summary
Dengue viruses (DENV) are mosquito-borne viruses of the Flavivirus genus, which include other significant human pathogens such as West Nile (WNV), Japanese encephalitis, and yellow fever viruses. Infection with DENV can cause symptoms in humans ranging from a mild febrile illness (Dengue Fever, DF) to a more severe hemorrhagic fever (DHF) and life-threatening dengue shock syndrome (DSS). It is estimated that DENV infects ,50 to 100 million people per year resulting in ,250,000 to 500,000 cases of DHF/DSS [1]. The four serotypes of DENV (DENV-1, DENV-2, DENV-3, and DENV-4) comprise a genetically related yet antigenically distinct serocomplex, varying from one another by 25 to 40% at the amino acid level. Each DENV serotype is further divided into genotypes, which can vary up to 3% [2,3]. There are no specific antiviral therapies or vaccines approved for use in humans, and treatment of severe disease remains supportive in a tertiary care setting
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