Resistance analysis of an antibody that selectively inhibits dengue virus serotype-1
| Autor: | Gang Zou, Shee-Mei Lok, Brendon J. Hanson, Petra Kukkaro, Pei Yong Shi, Jowin K. W. Ng, Paul A. MacAry, Sylvie Alonso, Grace K. Tan |
|---|---|
| Rok vydání: | 2012 |
| Předmět: |
medicine.drug_class
viruses DNA Mutational Analysis Mutation Missense Microbial Sensitivity Tests Dengue virus Antibodies Viral medicine.disease_cause Monoclonal antibody Epitope Cell Line Mice Viral Envelope Proteins Viral envelope Viral entry Virology Drug Resistance Viral medicine Animals Humans Antibody-dependent enhancement Neutralizing antibody Pharmacology biology Antibodies Monoclonal virus diseases Dengue Virus biochemical phenomena metabolism and nutrition Antibodies Neutralizing biology.protein Mutant Proteins Antibody Protein Binding |
| Zdroj: | Antiviral Research. 95:216-223 |
| ISSN: | 0166-3542 |
| DOI: | 10.1016/j.antiviral.2012.06.010 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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