Dengue-Zika: Correlates of Cross-Protection in Non-Human Primates

摘要 寨卡病毒(ZIKV)是一种重新出现的蚊媒黄病毒，最近在美洲引起了疫情。这个 在其他亲缘关系密切的黄病毒特有的热带/亚热带地区建立ZIKV传播循环 如登革热病毒(DENV)引起了人们的关注，主要是由于它们的交叉免疫学相互作用及其影响 这是因为出现了严重的临床表现。几个小组已经证明了DENV免疫血清 在免疫缺陷小鼠模型中，来自人类的病毒可以在体外和体内增强ZIKV感染。这一现象已知 抗体依赖增强(ADE)与严重的登革热临床表现有关。人们对此知之甚少 先前对寨卡病毒的免疫对随后的DENV感染的影响。刻画相关性是非常必要的。 在存在先前DENV或ZIKV的情况下控制异源继发性DENV或ZIKV感染的保护作用 ZIKV在一种类似于人类免疫系统的具有免疫能力的动物模型中的免疫 人类灵长类动物。我们小组的初步数据显示，细胞免疫反应在心脏疾病中可能具有保护作用 在异源继发感染寨卡病毒或登革热期间，登革热免疫或寨卡病毒免疫受试者。整体而言 这项工作背后的假设是，交叉启动的细胞免疫反应可能是控制DENV和 ZIKV感染，并提供针对彼此的异种保护。为了检验这一假设，我们提出了一系列 通过在初选或初选前的不同时间点耗尽CD4或CD8或CD20细胞进行的直接实验 二次感染登革热或寨卡病毒。这种类型的实验以前从未在NHP中进行过。为了这些 我们将使用在加勒比海灵长类研究中心饲养和饲养的恒河猴进行实验，事实证明 在美国所有种群或进口动物中，更纯粹的印第安人起源的猕猴种群，没有显著的 近亲交配的水平。在黄病毒领域的任何研究中，我们将第一次使用关于这种病毒的MHC分型的大量数据 鉴定在T细胞免疫应答中起作用的特异性CD4和/或CD8 T细胞表位的人群 登革热和寨卡病毒。了解ZIKV和DENV之间的保护相关性对于预测结果至关重要 对于二次感染，诊断方法的设计和相关性更强，支持设计的高效 ZIKV和DENV疫苗分别在以前DENV或ZIKV免疫的情况下接种。毫无疑问，NHP提供了 我们拥有一种非常接近人类系统的独特免疫学工具，为我们所面临的问题提供答案 在这份申请表上。

Abstract Zika virus (ZIKV) is a re-emerging mosquito-borne Flavivirus that recently caused an outbreak in the Americas. The establishment of ZIKV transmission cycle in tropical/sub-tropical regions that are endemic to other close-related flaviviruses such as Dengue virus (DENV) has raised concerns, mainly by their cross-immunological interactions and the implications of this for development of severe clinical manifestations. Several groups have demonstrated that DENV-immune serum from humans can enhance ZIKV infection in vitro and in vivo in an immunodeficient mice model. This phenomenon known as Antibody Dependent-Enhancement (ADE) has been linked to severe dengue clinical manifestations. Little is known about the effect of a previous immunity to ZIKV on a subsequent DENV infection. It is highly necessary to characterize correlates of protection in the control of a heterologous secondary DENV or ZIKV infection in the presence of previous DENV or ZIKV immunity in an immunological competent animal model that resemble the human immune system like the Non- Human Primates. Our group have preliminary data showing a potential protective role of the cellular immune response in dengue- immune or ZIKV-immune subjects during a heterologous secondary infection with ZIKV or dengue. The overall hypothesis behind this work is that the cross-primed cellular immune response may be critical controlling the DENV and ZIKV infection and provides heterologous protection against each other. To test this hypothesis, we propose a series of straightforward experiments by depleting the CD4+ or CD8+ or CD20+ cells at different time points before a primary or a secondary infection with dengue or ZIKV. This type of experiment has not been performed before in NHP. For these experiments we will use rhesus macaques bred and housed at the Caribbean Primate Research Center that has proven to be the purer Indian-origin macaque population of all populations in the USA or imported animals, without having a significant level of inbreeding. For first time in any study in the flavivirus field, we will use a large data on the MHC typing of this population to characterize specific CD4 and/or CD8 T cells epitopes playing a role in the T cells immune response against dengue and ZIKV. Understanding correlates of protection between ZIKV and DENV is essential to anticipate the outcome of the secondary infection, the design of diagnostics methods and more relevant, to support the design of highly effective ZIKV and DENV vaccines in the scenario of previous DENV or ZIKV immunity, respectively. Undoubtedly, NHP provide us with a unique immunological tool very close to the human system to provide the answers to the questions we are outlying on this application.