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      Human antibody responses after dengue virus infection are highly cross-reactive to Zika virus.

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          Abstract

          Zika virus (ZIKV) is an emerging mosquito-borne flavivirus of significant public health concern. ZIKV shares a high degree of sequence and structural homology compared with other flaviviruses, including dengue virus (DENV), resulting in immunological cross-reactivity. Improving our current understanding of the extent and characteristics of this immunological cross-reactivity is important, as ZIKV is presently circulating in areas that are highly endemic for dengue. To assess the magnitude and functional quality of cross-reactive immune responses between these closely related viruses, we tested acute and convalescent sera from nine Thai patients with PCR-confirmed DENV infection against ZIKV. All of the sera tested were cross-reactive with ZIKV, both in binding and in neutralization. To deconstruct the observed serum cross-reactivity in depth, we also characterized a panel of DENV-specific plasmablast-derived monoclonal antibodies (mAbs) for activity against ZIKV. Nearly half of the 47 DENV-reactive mAbs studied bound to both whole ZIKV virion and ZIKV lysate, of which a subset also neutralized ZIKV. In addition, both sera and mAbs from the dengue-infected patients enhanced ZIKV infection of Fc gamma receptor (FcγR)-bearing cells in vitro. Taken together, these findings suggest that preexisting immunity to DENV may impact protective immune responses against ZIKV. In addition, the extensive cross-reactivity may have implications for ZIKV virulence and disease severity in DENV-experienced populations.

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          Most cited references 23

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          Structure of the dengue virus envelope protein after membrane fusion.

          Dengue virus enters a host cell when the viral envelope glycoprotein, E, binds to a receptor and responds by conformational rearrangement to the reduced pH of an endosome. The conformational change induces fusion of viral and host-cell membranes. A three-dimensional structure of the soluble E ectodomain (sE) in its trimeric, postfusion state reveals striking differences from the dimeric, prefusion form. The elongated trimer bears three 'fusion loops' at one end, to insert into the host-cell membrane. Their structure allows us to model directly how these fusion loops interact with a lipid bilayer. The protein folds back on itself, directing its carboxy terminus towards the fusion loops. We propose a fusion mechanism driven by essentially irreversible conformational changes in E and facilitated by fusion-loop insertion into the outer bilayer leaflet. Specific features of the folded-back structure suggest strategies for inhibiting flavivirus entry.
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            The human immune response to Dengue virus is dominated by highly cross-reactive antibodies endowed with neutralizing and enhancing activity.

            Antibodies protect against homologous Dengue virus (DENV) infection but can precipitate severe dengue by promoting heterotypic virus entry via Fcγ receptors (FcγR). We immortalized memory B cells from individuals after primary or secondary infection and analyzed anti-DENV monoclonal antibodies (mAbs) thus generated. MAbs to envelope (E) protein domain III (DIII) were either serotype specific or cross-reactive and potently neutralized DENV infection. DI/DII- or viral membrane protein prM-reactive mAbs neutralized poorly and showed broad cross-reactivity with the four DENV serotypes. All mAbs enhanced infection at subneutralizing concentrations. Three mAbs targeting distinct epitopes on the four DENV serotypes and engineered to prevent FcγR binding did not enhance infection and neutralized DENV in vitro and in vivo as postexposure therapy in a mouse model of lethal DENV infection. Our findings reveal an unexpected degree of cross-reactivity in human antibodies against DENV and illustrate the potential for an antibody-based therapy to control severe dengue. Copyright © 2010 Elsevier Inc. All rights reserved.
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              A new class of highly potent, broadly neutralizing antibodies isolated from viremic patients infected with dengue virus.

              Dengue is a rapidly emerging, mosquito-borne viral infection, with an estimated 400 million infections occurring annually. To gain insight into dengue immunity, we characterized 145 human monoclonal antibodies (mAbs) and identified a previously unknown epitope, the envelope dimer epitope (EDE), that bridges two envelope protein subunits that make up the 90 repeating dimers on the mature virion. The mAbs to EDE were broadly reactive across the dengue serocomplex and fully neutralized virus produced in either insect cells or primary human cells, with 50% neutralization in the low picomolar range. Our results provide a path to a subunit vaccine against dengue virus and have implications for the design and monitoring of future vaccine trials in which the induction of antibody to the EDE should be prioritized.
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                Author and article information

                Journal
                Proc. Natl. Acad. Sci. U.S.A.
                Proceedings of the National Academy of Sciences of the United States of America
                1091-6490
                0027-8424
                Jul 12 2016
                : 113
                : 28
                Affiliations
                [1 ] Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; Division of Infectious Disease, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322;
                [2 ] Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322;
                [3 ] Department of Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand;
                [4 ] Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; Department of Microbiology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand;
                [5 ] The Hope Clinic of the Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; Department of Medicine, Division of Infectious Diseases, Emory University School of Medicine, Atlanta, GA 30322;
                [6 ] Department of Pediatrics, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand;
                [7 ] Section of Rheumatology, The Knapp Center for Lupus and Immunology Research, Department of Medicine, University of Chicago, Chicago, IL 60637.
                [8 ] Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; Department of Microbiology and Immunology, Emory University School of Medicine, Atlanta, GA 30322; jwramme@emory.edu rahmed@emory.edu.
                [9 ] Emory Vaccine Center, Emory University School of Medicine, Atlanta, GA 30322; Division of Infectious Disease, Department of Pediatrics, Emory University School of Medicine, Atlanta, GA 30322; jwramme@emory.edu rahmed@emory.edu.
                Article
                1607931113
                10.1073/pnas.1607931113
                4948328
                27354515

                cross-reactivity, antibodies, Zika virus, B-cell responses

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