Natural Strain Variation and Antibody Neutralization of Dengue Serotype 3 Viruses

PLoS Pathogens

Aravinda M. de Silva¹  Eric F. Donaldson¹  Mary Ann Accavitti-Loper²  Wahala M. P. B. Wahala³  Ralph S. Baric³  Ruklanthi de Alwis³ 

[1] Department of Epidemiology, Gillings School of Global Health, University of North Carolina, Chapel Hill, North Carolina, United States of America;Department of Medicine, University of Alabama at Birmingham, Birmingham, Alabama, United States of America;Department of Microbiology and Immunology, University of North Carolina School of Medicine, Chapel Hill, North Carolina, United States of America

关键词: Antibodies;    Enzyme-linked immunoassays;    Dengue fever;    Dengue virus;    Flaviviruses;    Sequence alignment;    Vaccines;    Recombinant proteins;   

DOI  :  10.1371/journal.ppat.1000821

学科分类：生物科学（综合）

来源: Public Library of Science

【 摘 要 】

Dengue viruses (DENVs) are emerging, mosquito-borne flaviviruses which cause dengue fever and dengue hemorrhagic fever. The DENV complex consists of 4 serotypes designated DENV1-DENV4. Following natural infection with DENV, individuals develop serotype specific, neutralizing antibody responses. Monoclonal antibodies (MAbs) have been used to map neutralizing epitopes on dengue and other flaviviruses. Most serotype-specific, neutralizing MAbs bind to the lateral ridge of domain III of E protein (EDIII). It has been widely assumed that the EDIII lateral ridge epitope is conserved within each DENV serotype and a good target for vaccines. Using phylogenetic methods, we compared the amino acid sequence of 175 E proteins representing the different genotypes of DENV3 and identified a panel of surface exposed amino acids, including residues in EDIII, that are highly variant across the four DENV3 genotypes. The variable amino acids include six residues at the lateral ridge of EDIII. We used a panel of DENV3 mouse MAbs to assess the functional significance of naturally occurring amino acid variation. From the panel of antibodies, we identified three neutralizing MAbs that bound to EDIII of DENV3. Recombinant proteins and naturally occurring variant viruses were used to map the binding sites of the three MAbs. The three MAbs bound to overlapping but distinct epitopes on EDIII. Our empirical studies clearly demonstrate that the antibody binding and neutralization capacity of two MAbs was strongly influenced by naturally occurring mutations in DENV3. Our data demonstrate that the lateral ridge “type specific” epitope is not conserved between strains of DENV3. This variability should be considered when designing and evaluating DENV vaccines, especially those targeting EDIII.

【 授权许可】

CC BY