Journal
JOURNAL OF VIROLOGY
Volume 87, Issue 1, Pages 52-66Publisher
AMER SOC MICROBIOLOGY
DOI: 10.1128/JVI.02273-12
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Funding
- Defense Threat Reduction Agency [HDTRA1-08-1-0003, HDTRA1-09-1-0004, HDTRA1-10-1-0009]
- National Science Foundation [CBET-0923030]
- Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH)
- National Institute of Allergy and Infectious Diseases (NIAID) NIH Intramural Biodefense Research grant
- Intramural AIDS Targeted Antiviral Program
- NIAID [HHSN272200900055C]
- NIH Centers of Biomedical Research Excellence award [P20RR021970-06]
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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 neutralizing 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-dependent 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.
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