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Potent Dengue Virus Neutralization by a Therapeutic Antibody with Low Monovalent Affinity Requires Bivalent Engagement


Dengue virus (DENV) is a globally important mosquito-transmitted human pathogen for which there is no approved vaccine or antiviral therapy. In recent years, the number and severity of DENV human infections have increased due to the expanded geographic range of the virus. Neutralizing antibodies are a key component of a protective natural and vaccine-induced immune response against human DENV infections. One recently described monoclonal antibody (E106) protects mice against infection of DENV-1 when administered before or several days after virus infection. Because of these results, we investigated the mechanism of action of E106 using a combination of structural and functional approaches. E106 engaged an epitope on domain III of the viral envelope protein that is a composite of two previously described epitopes. Unexpectedly, and in contrast to the intact IgG, Fab fragments of E106 were ineffective at neutralizing virus; this was explained by their weak micromolar affinity for virus particles. Our results suggest that neutralization by E106, our most potently inhibitory and protective anti-DENV MAb, requires bivalent binding of adjacent DIII subunits on a single virion. Immunization strategies with intact virions that skew the selection of neutralizing antibodies to those with bivalently binding properties could augment the potency of antiviral humoral responses against DENV and other flaviviruses.


Vyšlo v časopise: Potent Dengue Virus Neutralization by a Therapeutic Antibody with Low Monovalent Affinity Requires Bivalent Engagement. PLoS Pathog 10(4): e32767. doi:10.1371/journal.ppat.1004072
Kategorie: Research Article
prolekare.web.journal.doi_sk: https://doi.org/10.1371/journal.ppat.1004072

Souhrn

Dengue virus (DENV) is a globally important mosquito-transmitted human pathogen for which there is no approved vaccine or antiviral therapy. In recent years, the number and severity of DENV human infections have increased due to the expanded geographic range of the virus. Neutralizing antibodies are a key component of a protective natural and vaccine-induced immune response against human DENV infections. One recently described monoclonal antibody (E106) protects mice against infection of DENV-1 when administered before or several days after virus infection. Because of these results, we investigated the mechanism of action of E106 using a combination of structural and functional approaches. E106 engaged an epitope on domain III of the viral envelope protein that is a composite of two previously described epitopes. Unexpectedly, and in contrast to the intact IgG, Fab fragments of E106 were ineffective at neutralizing virus; this was explained by their weak micromolar affinity for virus particles. Our results suggest that neutralization by E106, our most potently inhibitory and protective anti-DENV MAb, requires bivalent binding of adjacent DIII subunits on a single virion. Immunization strategies with intact virions that skew the selection of neutralizing antibodies to those with bivalently binding properties could augment the potency of antiviral humoral responses against DENV and other flaviviruses.


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Hygiena a epidemiológia Infekčné lekárstvo Laboratórium

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