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

doi:10.1016/j.antiviral.2012.06.010

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 journal › Article › peer-review

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 language	English (US)
Pages (from-to)	216-223
Number of pages	8
Journal	Antiviral research
Volume	95
Issue number	3
DOIs	https://doi.org/10.1016/j.antiviral.2012.06.010
State	Published - Sep 2012
Externally published	Yes

Keywords

Dengue virus
Escape mutant
Flavivirus envelope protein
Neutralizing antibody
Virus entry

ASJC Scopus subject areas

Pharmacology
Virology

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10.1016/j.antiviral.2012.06.010

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title = "Resistance analysis of an antibody that selectively inhibits dengue virus serotype-1",

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.",

keywords = "Dengue virus, Escape mutant, Flavivirus envelope protein, Neutralizing antibody, Virus entry",

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

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AU - Zou, Gang

AU - Kukkaro, Petra

AU - Lok, Shee Mei

AU - Ng, Jowin K.W.

AU - Tan, Grace K.

AU - Hanson, Brendon J.

AU - Alonso, Sylvie

AU - MacAry, Paul A.

AU - Shi, Pei Yong

PY - 2012/9

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N2 - 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.

AB - 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.

KW - Dengue virus

KW - Escape mutant

KW - Flavivirus envelope protein

KW - Neutralizing antibody

KW - Virus entry

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

Abstract

Keywords

ASJC Scopus subject areas

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