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

Jinsheng Wen,Sujan Shresta,Matthew J Gorman,Jose Angel Regla-Nava,Kenneth Kim,Michael S Diamond,Annie Elong Ngono

doi:10.1038/s41467-017-01669-z

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.

Highlights

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
A study focusing on cross-reactive T cell responses in Ifnar1−/− HLA-transgenic mice has shown that prior DENV immunity alters immunodominance patterns of CD8+ T cell responses to subsequent ZIKV infection[38], while another has demonstrated that passive transfer of DENV-immune plasma into naive Stat2−/− mice can enhance ZIKV infection and disease severity[12]
The following question needs to be answered urgently: What is the role of prior DENV immunity during sequential ZIKV infection of the same host? Epidemiologic studies in humans will take years to perform, and the precise contributions of cellular vs. humoral immunity cannot be dissected in humans

Summary

Introduction

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. Further optimization of current DENV vaccines for T cell responses might confer cross-protection and prevent antibody-mediated enhancement of ZIKV infection. The non-mutually exclusive hypotheses of antibody-dependent enhancement (ADE) and T cell original antigenic sin[21] have been proposed to explain why infection with a first virus can increase disease severity upon future infection with a second antigenically related virus. Initial studies supported a role for pathogenic, serotype cross-reactive T cells in promoting original antigenic sin in DENV infection[27,28,29,30,31], more recent data indicate a protective role for T cells is HLA-linked. Recent studies have revealed that the magnitude and breadth of DENV-specific CD8+ T cell responses are associated with HLA alleles that correlate with clinical dengue disease[36,37]

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