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

Zou, Gang and Kukkaro, Petra and Lok, Shee Mei and Ng, Jowin and Tan, Grace and Alonso, Sylvie and Macary, Paul and Shi, Pei-Yong (2012) Resistance analysis of an antibody that selectively inhibits dengue virus serotype-1. Antiviral Reseaech, 95 (3). pp. 216-223. ISSN 0166-3542

Abstract

The four serotypes of dengue virus (DENV) is the causative agent of the most prevalent mosquito-borne viral disease in human. No clinically approved antiviral therapy is currently available. Therapeutic antibody is a viable approach for potential treatment of DENV infection. We recently generated a human monoclonal antibody (HM14c10) that selectively neutralizes DENV serotype 1 (DENV-1) isolates, but not serotypes 2 to 4 isolates. This antibody potently inhibits DENV-1 both in vitro and in vivo through blockage of virus attachment to cells. Here we report that, besides inhibiting virus attachment, this antibody could also suppress a post-attachment step during infection. To analyze emergence of viral resistance, we selected escape mutants by culturing wild-type DENV-1 in the presence of HM14c10 antibody. Sequencing of resistance viruses revealed a single T51K substitution in the domain I/II hinge region of viral envelope protein. Amino acid T51 is located within the epitope of HM14c10 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 showed that the T51K mutation completely abolished the antibody binding to the virion of DENV-1. Collectively, the results demonstrate that a single amino change in DENV envelope protein can confer resistance to a potent antibody through abolishing the antibody-virus interaction.

Item Type: Article
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Keywords: Dengue virus, neutralizing antibody, escape mutant, virus entry, flavivirus envelope protein
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Date Deposited: 13 Oct 2015 13:14
Last Modified: 13 Oct 2015 13:14
URI: https://oak.novartis.com/id/eprint/7782

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