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Mechanistic Study of Broadly Neutralizing Human Monoclonal Antibodies against Dengue Virus That Target the Fusion Loop

Title: Mechanistic Study of Broadly Neutralizing Human Monoclonal Antibodies against Dengue Virus That Target the Fusion Loop.
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Name(s): Costin, J. M., author
Zaitseva, E., author
Kahle, K. M., author
Nicholson, C. O., author
Rowe, D. K., author
Graham, A. S., author
Bazzone, L. E., author
Hogancamp, G., author
Figueroa Sierra, M., author
Fong, R. H., author
Yang, S.-T., author
Lin, L., author
Robinson, J. E., author
Doranz, B. J., author
Chernomordik, L. V., author
Michael, S. F., author
Schieffelin, J. S., author
Isern, S., author
Scott Michael, author
Type of Resource: text
Genre: Article
Date Issued: 2013-01-01
Language(s): English
Abstract: There are no available vaccines for dengue, the most important mosquito-transmitted viral disease. Mechanistic studies with anti-dengue virus (DENV) human monoclonal antibodies (hMAbs) provide a rational approach to identify and characterize neu- tralizing epitopes on DENV structural proteins that can serve to inform vaccine strategies. Here, we report a class of hMAbs that is likely to be an important determinant in the human humoral response to DENV infection. In this study, we identified and characterized three broadly neutralizing anti-DENV hMAbs: 4.8A, D11C, and 1.6D. These antibodies were isolated from three different convalescent patients with distinct histories of DENV infection yet demonstrated remarkable similarities. All three hMAbs recognized the E glycoprotein with high affinity, neutralized all four serotypes of DENV, and mediated antibody-depen- dent enhancement of infection in Fc receptor-bearing cells at subneutralizing concentrations. The neutralization activities of these hMAbs correlated with a strong inhibition of virus-liposome and intracellular fusion, not virus-cell binding. We mapped epitopes of these antibodies to the highly conserved fusion loop region of E domain II. Mutations at fusion loop residues W101, L107, and/or G109 significantly reduced the binding of the hMAbs to E protein. The results show that hMAbs directed against the highly conserved E protein fusion loop block viral entry downstream of virus-cell binding by inhibiting E protein-mediated fusion. Characterization of hMAbs targeting this region may provide new insights into DENV vaccine and therapeutic strategies.
Identifier: 10.1128/JVI.02273-12 (doi), fgcu_ir_000061 (IID), http://jvi.asm.org/cgi/doi/10.1128/JVI.02273-12 (uri)
Persistent Link to This Record: http://purl.flvc.org/fgcu/flvc_fgcu_islandoraimporter_10.1128_JVI.02273-12_1519759192
Use and Reproduction: publisher
Owner Institution: FGCU
Is Part Of: Journal of Virology.
0022-538X