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.
authors: Novartis Institute for Tropical Diseases, Singapore, Singapore.
authors: Gang
authors: G
authors: Zou
authors: Petra
authors: P
authors: Kukkaro
authors: Shee-Mei
authors: SM
authors: Lok
authors: Jowin K W
authors: JK
authors: Ng
authors: Grace K
authors: GK
authors: Tan
authors: Brendon J
authors: BJ
authors: Hanson
authors: Sylvie
authors: S
authors: Alonso
authors: Paul A
authors: PA
authors: MacAry
authors: Pei-Yong
authors: PY
authors: Shi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology*; D057134:Antibodies, Neutralizing / Q000276:immunology*; D000914:Antibodies, Viral / Q000276:immunology*; D002460:Cell Line; D004252:DNA Mutational Analysis; D003716:Dengue Virus / Q000145:classification / Q000235:genetics / Q000276:immunology*; D024882:Drug Resistance, Viral; D006801:Humans; D051379:Mice; D008826:Microbial Sensitivity Tests; D050505:Mutant Proteins / Q000235:genetics / Q000276:immunology; D020125:Mutation, Missense; D011485:Protein Binding; D014759:Viral Envelope Proteins / Q000235:genetics / Q000276:immunology*
chemical_list: D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D050505:Mutant Proteins; D014759:Viral Envelope Proteins