1. Neutralization epitope responsible for the hepatitis B virus subtype-specific protection in chimpanzees
- Author
-
Pei Zhang, Richard M. Venable, Harvey J. Alter, Mei-ying W. Yu, and J. Wai-Kou Shih
- Subjects
Models, Molecular ,Hepatitis B virus ,Pan troglodytes ,Protein Conformation ,medicine.drug_class ,Molecular Sequence Data ,Biology ,Crystallography, X-Ray ,Monoclonal antibody ,medicine.disease_cause ,Virus ,Epitope ,Epitopes ,Antigen ,Antibody Specificity ,medicine ,Animals ,Amino Acid Sequence ,Neutralizing antibody ,Multidisciplinary ,Linear epitope ,Antibodies, Monoclonal ,Biological Sciences ,Hepatitis B ,Virology ,Molecular biology ,biology.protein ,Antibody ,Peptides ,Sequence Alignment - Abstract
Neutralizing monoclonal antibody (BX-182) directed against theddeterminant of hepatitis B virus (HBV) surface antigen protected chimpanzees from infection by HBV subtypeadwbut not by subtypeayw, as demonstrated by intravenously inoculating a mixture of the antibody with the respective subtype of the virus. To elucidate the mechanism underlying the subtype-specific protection, a combinatorial approach of screening random peptide phage libraries, bioinformatics, and structure analysis was used in this study to identify the neutralization epitope responsible for the observed protection. The epitope was mapped at the N terminus of the pre-S1 region of the hepatitis B surface antigen between residues 17 and 21, of which the residues Val-18/Pro-19 were critical for antibody binding. Alignment of amino acid sequences derived from diverse genetic variants of HBV revealed that the epitope was present inadsubtypes and in their corresponding genotypes A, B, C, F, and H. By contrast, this epitope was not found in a majority ofaysubtypes or in genotypes D, E, and G, where the antigenic residues Val-18/Pro-19 within the epitope were replaced by Thr/Ser, Thr/Thr, or Ala/Ser, respectively, resulting in a drastic conformational change of the epitope. These data indicate that, by binding discriminately to the subtype “d” epitope in the pre-S1 region, neutralizing antibody BX-182 protects chimpanzees from HBV infection in a subtype-specific manner, suggesting a potential escape mechanism for HBV genetic variants.
- Published
- 2006