Abstract
Antibody protection against flaviviruses is associated with the development of neutralizing antibodies against the viral envelope (E) protein. Prior studies with West Nile virus (WNV) identified therapeutic mouse and human monoclonal antibodies (MAbs) that recognized epitopes on domain III (DIII) of the E protein. To identify an analogous panel of neutralizing antibodies against DENV type-1 (DENV-1), we immunized mice with a genotype 2 strain of DENV-1 virus and generated 79 new MAbs, 16 of which strongly inhibited infection by the homologous virus and localized to DIII. Surprisingly, only two MAbs, DENV1-E105 and DENV1-E106, retained strong binding and neutralizing activity against all five DENV-1 genotypes. In an immunocompromised mouse model of infection, DENV1-E105 and DENV1-E106 exhibited therapeutic activity even when administered as a single dose four days after inoculation with a heterologous genotype 4 strain of DENV-1. Using epitope mapping and X-ray crystallographic analyses, we localized the neutralizing determinants for the strongly inhibitory MAbs to distinct regions on DIII. Interestingly, sequence variation in DIII alone failed to explain disparities in neutralizing potential of MAbs among different genotypes. Overall, our experiments define a complex structural epitope on DIII of DENV-1 that can be recognized by protective antibodies with therapeutic potential.
Highlights
Dengue virus (DENV) is a member of the Flaviviridae family and is related to the viruses that cause yellow fever, and the Japanese, St
To begin to address this, we evaluated whether individual monoclonal antibodies (MAbs) differentially recognized domain III (DIII) from 16007 or West Pac-74 strains when expressed on yeast; the DIII of these two strain differ by only two amino acids at positions 339 and 345 in the C strand and CC9 loop (Fig 3B)
One primary goal of this study was to generate a collection of strongly neutralizing MAbs that would recognize virtually all DENV type-1 (DENV-1) strains and protect against infection as post-exposure therapy
Summary
Dengue virus (DENV) is a member of the Flaviviridae family and is related to the viruses that cause yellow fever, and the Japanese, St. DENV infection after mosquito inoculation causes a spectrum of clinical disease ranging from a self-limited febrile illness (DF) to a life threatening hemorrhagic and capillary leak syndrome (Dengue Hemorrhagic Fever (DHF)/Dengue Shock Syndrome (DSS)). There is significant diversity among DENV strains, including four distinct serotypes (DENV-1, DENV-2, DENV-3, and DENV-4) that differ at the amino acid level in the viral envelope proteins by 25 to 40 percent. There is additional complexity within a given DENV serotype, as genotypes vary further by up to ,6% and 3% at the nucleotide and amino acid levels, respectively [2,3]. DENV causes an estimated 25 to 100 million infections and 250,000 cases of DHF/DSS per year worldwide, with 2.5 billion people at risk [4,5]
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