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，最近在美洲爆发。的 在其他密切相关黄病毒流行的热带/亚热带地区建立ZIKV传播循环 如登革病毒（DENV）引起了人们的关注，主要是通过它们的交叉免疫相互作用和影响， 严重临床表现的发展。一些研究小组已经证明，DENV免疫血清 来自人的ZIKV可以增强免疫缺陷小鼠模型中的体外和体内ZIKV感染。这种现象众所周知 因为抗体依赖性增强（ADE）与严重的登革热临床表现有关。知之甚少 先前对ZIKV的免疫对随后的DENV感染的影响。因此，非常有必要对相关物进行表征 在先前DENV或ZIKV感染的存在下， 在类似于人免疫系统的免疫活性动物模型中的ZIKV免疫，如非人免疫系统。 人类灵长类我们小组的初步数据显示，细胞免疫反应在 本发明涉及在ZIKV或登革热的异源二次感染期间对登革热免疫或ZIKV免疫的受试者进行治疗的方法。整体 这项工作背后的假设是，交叉致敏的细胞免疫应答可能是控制DENV的关键， ZIKV感染并提供针对彼此的异源保护。为了验证这一假设，我们提出了一系列 通过在原代或免疫前的不同时间点耗尽CD 4+或CD 8+或CD 20+细胞， 登革热或ZIKV的继发感染。这种类型的实验在NHP之前没有进行过。为这些 实验中，我们将使用在加勒比灵长类动物研究中心饲养和圈养的恒河猴， 在美国或进口动物的所有种群中，印度猕猴种群的纯度更高， 近亲繁殖的水平。在黄病毒领域的任何研究中，我们将首次使用关于这种病毒的MHC分型的大量数据。 群体以表征在针对人T细胞的T细胞免疫应答中起作用的特异性CD 4和/或CD 8 T细胞表位。 登革热和ZIKV。了解ZIKV和DENV之间的保护相关性对于预测结果至关重要 对继发感染，设计的诊断方法更有针对性，支持设计高效 分别在先前DENV或ZIKV免疫的情况下的ZIKV和DENV疫苗。毫无疑问，NHP提供 我们有一个独特的免疫工具非常接近人类系统，以提供答案的问题，我们是外围 在这个应用程序上。

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.