The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1

Bimmi Shrestha, James D. Brien, Soila Sukupolvi-Petty, S. Kyle Austin, Melissa A. Edeling, Taekyung Kim, Katie M. O'Brien, Christopher A. Nelson, Syd Johnson, Daved H. Fremont, Michael S. Diamond

Research output: Contribution to journalArticle

165 Scopus citations

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.

Original languageEnglish
Pages (from-to)1-18
Number of pages18
JournalPLoS pathogens
Volume6
Issue number4
StatePublished - Apr 1 2010

Fingerprint Dive into the research topics of 'The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1'. Together they form a unique fingerprint.

  • Cite this

    Shrestha, B., Brien, J. D., Sukupolvi-Petty, S., Austin, S. K., Edeling, M. A., Kim, T., O'Brien, K. M., Nelson, C. A., Johnson, S., Fremont, D. H., & Diamond, M. S. (2010). The development of therapeutic antibodies that neutralize homologous and heterologous genotypes of dengue virus type 1. PLoS pathogens, 6(4), 1-18.