Resistance analysis of an antibody that selectively inhibits dengue virus serotype-1

Gang Zou, Petra Kukkaro, Shee Mei Lok, Jowin K.W. Ng, Grace K. Tan, Brendon J. Hanson, Sylvie Alonso, Paul A. MacAry, Pei Yong Shi

Research output: Contribution to journalArticle

11 Scopus citations

Abstract

The four serotypes of dengue virus (DENV) are the causative agents of the most prevalent mosquito-borne viral disease in human. No clinically approved antiviral therapy is currently available. Therapeutic antibodies represent a viable approach for potential treatment of DENV infection. We recently isolated a human monoclonal antibody (HM14c10) that selectively neutralizes DENV serotype 1 (DENV-1), but not serotypes 2, 3, and 4. Here we report the resistance profile of DENV-1 against HM14c10 in cell culture. Escape mutant viruses readily emerged by culturing wild-type DENV-1 in the presence of the HM14c10 antibody. Sequencing of resistant viruses revealed a single T51K substitution in the domain I/II hinge region of the viral envelope protein. Residue T51 is located within the HM14c10 epitope and is highly conserved among various DENV-1 isolates. Recombinant DENV-1 containing the T51K mutation could not be neutralized by HM14c10 in vitro or in vivo. Biochemical assay revealed that the T51K mutation completely abolished the antibody binding to the DENV-1 virion. Collectively, the results demonstrate that a single amino acid change in DENV envelope protein can confer resistance to a potent antibody through abolishing the antibody-virus interaction.

Original languageEnglish (US)
Pages (from-to)216-223
Number of pages8
JournalAntiviral research
Volume95
Issue number3
DOIs
StatePublished - Sep 1 2012
Externally publishedYes

Keywords

  • Dengue virus
  • Escape mutant
  • Flavivirus envelope protein
  • Neutralizing antibody
  • Virus entry

ASJC Scopus subject areas

  • Pharmacology
  • Virology

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  • Cite this

    Zou, G., Kukkaro, P., Lok, S. M., Ng, J. K. W., Tan, G. K., Hanson, B. J., Alonso, S., MacAry, P. A., & Shi, P. Y. (2012). Resistance analysis of an antibody that selectively inhibits dengue virus serotype-1. Antiviral research, 95(3), 216-223. https://doi.org/10.1016/j.antiviral.2012.06.010