Antibody‐dependent enhancement (ADE) of dengue virus: Identification of the key amino acid that is vital in DENV vaccine research. (17th January 2021)

• Record Type: Journal Article
• Authors: Cui, Guohui; Si, Lulu; Wang, Ying; Zhou, Junmei; Yan, Huijun; Jiang, Lifang
• Is Part Of: Journal of gene medicine. Volume 23:Number 2(2021)
• Page Start: n/a
• Page End: n/a
• Publication Date: 2021-01-17
• Subjects: ADE -- dengue virus -- epitope -- prM antibodies -- vaccine; Genetic transformation -- Periodicals; Gene Transfer -- Periodicals; Gene Therapy -- Periodicals; 616.042
• DOI: 10.1002/jgm.3297
• Languages: English
• ISSNs: 1099-498X

Abstract

Abstract: Background: The antibody‐dependent enhancement (ADE) of dengue virus (DENV) has critically restricted vaccine development. Prior research suggested pr4 as the probable ADE epitope of DENV. Methods: Chimeric DENV was constructed by replacing the DENV pr4 gene with the corresponding Japanese encephalitis virus (JEV) gene to determine whether it can reduce ADE activities. An alanine scanning method and bioinformatics analysis were utilized to identify the amino acid of pr4 that was crucial as an ADE epitope. Results: Chimeric virus reduced ADE and virulence. The amino acids at the following locations on the mutant peptides showed significantly reduced binding ability to prM antibody: pr4.5 (position 5 – leucine), pr4.6 (position 6 – leucine), pr4.7 (position 7 – phenyalanine) and pr4.16 (position 16 – cysteine). The four amino acids had formed a pocket‐like structure, which could increase the possibility of binding to an antibody. Conclusions: ADE activities could be reduced by replacing the DENV pr4 gene with the corresponding JEV gene. Leucine at position 5, leucine at position 6, phenyalanine at position 7 and cysteine at position 16 were the key amino acid sites in the ADE response of DENV. The occurrence of ADE can potentially be reduced by the replacement of key amino acids, hence highlighting its possible contribution to dengue vaccine design, paving a way for future vaccine research. Abstract : The pr4 gene was replaced with the JEV pr4 gene. The chimeric virus reduced virulence and the anti‐sera could reduce the ADE of DENV infection significantly. An alanine scanning method was used to confirm which amino acid of pr4 was the key ADE epitope. We found that the binding ability of pr4.5, pr4.6, pr4.7 and pr4.16 in the mutant peptides to prM antibody was significantly reduced, indicating that amino acids at positions 5 (leucine), 6 (leucine), 7 (phenylalanine) and 16 (cysteine) played an important role in the binding process of pr4 epitope and prM antibody. The tertiary structure of pr peptide was analyzed by Swiss‐Model homology modeling. We found that the leucine, phenylalanine and cysteine of pr4 could form a pocket‐like structure in space, which could increase the possibility of combining the antibody. The key amino acid site mutant peptide has a reduced ADE effect on DENV2.