Mechanistic study of broadly neutralizing human monoclonal antibodies against dengue virus that target the fusion loop.
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.
Department of Biological Sciences, Florida Gulf Coast University, Fort Myers, Florida, USA.
Joshua M
JM
Costin
Elena
E
Zaitseva
Kristen M
KM
Kahle
Cindo O
CO
Nicholson
Dawne K
DK
Rowe
Amanda S
AS
Graham
Lindsey E
LE
Bazzone
Greg
G
Hogancamp
Marielys
M
Figueroa Sierra
Rachel H
RH
Fong
Sung-Tae
ST
Yang
Li
L
Lin
James E
JE
Robinson
Benjamin J
BJ
Doranz
Leonid V
LV
Chernomordik
Scott F
SF
Michael
John S
JS
Schieffelin
Sharon
S
Isern
D019943:Amino Acid Substitution; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology* / Q000302:isolation & purification; D057134:Antibodies, Neutralizing / Q000276:immunology* / Q000302:isolation & purification; D000914:Antibodies, Viral / Q000276:immunology* / Q000302:isolation & purification; D019067:Antibody-Dependent Enhancement; D002460:Cell Line; D003716:Dengue Virus / Q000276:immunology*; D018604:Epitope Mapping; D018985:Epitopes, B-Lymphocyte / Q000235:genetics / Q000276:immunology; D006801:Humans; D008253:Macaca mulatta; D050505:Mutant Proteins / Q000276:immunology; D009500:Neutralization Tests; D014759:Viral Envelope Proteins / Q000276:immunology*
D000911:Antibodies, Monoclonal; D057134:Antibodies, Neutralizing; D000914:Antibodies, Viral; D018985:Epitopes, B-Lymphocyte; D050505:Mutant Proteins; D014759:Viral Envelope Proteins