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      Dengue virus-reactive CD8 + T cells mediate cross-protection against subsequent Zika virus challenge

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          Abstract

          Zika virus (ZIKV) and dengue virus (DENV) are antigenically related flaviviruses that share cross-reactivity in antibody and T cell responses, and co-circulate in increasing numbers of countries. Whether pre-existing DENV immunity can cross-protect or enhance ZIKV infection during sequential infection of the same host is unknown. Here, we show that DENV-immune Ifnar1 −/− or wild-type C57BL/6 mice infected with ZIKV have cross-reactive immunity to subsequent ZIKV infection and pathogenesis. Adoptive transfer and cell depletion studies demonstrate that DENV-immune CD8 + T cells predominantly mediate cross-protective responses to ZIKV. In contrast, passive transfer studies suggest that DENV-immune serum does not protect against ZIKV infection. Thus, CD8 + T cell immunity generated during primary DENV infection can confer protection against secondary ZIKV infection in mice. Further optimization of current DENV vaccines for T cell responses might confer cross-protection and prevent antibody-mediated enhancement of ZIKV infection.

          Abstract

          Dengue virus-specific antibody and CD8 + T cells that cross-react with Zika virus have been described. Here, the authors establish a functionally protective role for cross-reactive dengue virus-specific CD8 + T cells during challenge with Zika virus.

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          Most cited references 47

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          Efficacy and Long-Term Safety of a Dengue Vaccine in Regions of Endemic Disease.

          A candidate tetravalent dengue vaccine is being assessed in three clinical trials involving more than 35,000 children between the ages of 2 and 16 years in Asian-Pacific and Latin American countries. We report the results of long-term follow-up interim analyses and integrated efficacy analyses.
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            Human antibody responses after dengue virus infection are highly cross-reactive to Zika virus.

            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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              Research on dengue during World War II.

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                Author and article information

                Contributors
                sujan@lji.org
                Journal
                Nat Commun
                Nat Commun
                Nature Communications
                Nature Publishing Group UK (London )
                2041-1723
                13 November 2017
                13 November 2017
                2017
                : 8
                Affiliations
                [1 ]ISNI 0000 0004 0461 3162, GRID grid.185006.a, Division of Inflammation Biology, La Jolla Institute for Allergy & Immunology, ; La Jolla, CA 92037 USA
                [2 ]ISNI 0000 0001 0348 3990, GRID grid.268099.c, Institute of Arboviruses, School of Basic Medical Sciences, , Wenzhou Medical University, ; Wenzhou, Zhejiang 325000 China
                [3 ]ISNI 0000 0001 2355 7002, GRID grid.4367.6, Department of Medicine, Molecular Microbiology, Pathology and Immunology, The Andrew M. and Jane M. Bursky Center for Human Immunology and Immunotherapy Programs, , Washington University School of Medicine, ; St. Louis, MO 63110 USA
                [4 ]ISNI 0000 0001 2107 4242, GRID grid.266100.3, Department of Medicine, School of Medicine, , University of California, ; La Jolla, San Diego, CA 92037 USA
                Article
                1669
                10.1038/s41467-017-01669-z
                5682281
                29129917
                © The Author(s) 2017

                Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/.

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