Evaluating risks of ZIKV co-infection in SIV-infected macaques

项目总结 超过3600万人携带艾滋病毒，黄病毒流行地区有很大的地理重叠 感染。尽管发生了大规模的黄病毒暴发，但对 黄病毒感染可能对艾滋病毒携带者(PLWH)产生影响。目前尚不清楚HIV合并感染会产生什么影响 对黄病毒感染的临床后果的影响，目前对人类的研究受到低患者的限制 在对黄病毒病的解释中，艾滋病毒疾病的数量和不一致的纳入。非- 寨卡病毒(ZIKV)感染的人类(NHP)模型概括了人类疾病的几个方面，是理想的 评估人类黄病毒感染对艾滋病毒携带者的影响。然而，没有确凿的艾滋病毒- ZIKV混合感染动物模型存在。在这项建议中，我们将研究艾滋病毒与 了解PLWH的风险、原因和临床转归。在NHPS之前，我们展示了 CD16单核细胞是ZIKV体内的主要血液靶点，在人类中也发现了类似的结果。 单核细胞频率在HIV感染期间增加，尽管ART降低了HIV感染的总频率 人外周血中，CD16单核细胞持续升高。我们将调查艾滋病毒感染促进 对黄病毒感染的易感性通过降低抗病毒先天和获得性免疫反应，增加 炎症和不断扩大的细胞感染靶点，包括单核细胞。艾滋病病毒侵袭中部 神经系统(CNS)由CD16单核细胞介导，因此单核细胞也可以起到传播ZIKV的作用。 中枢神经系统和促进神经疾病。因此，HIV感染可促进ZIKV的发病和 通过扩大细胞靶点池和诱导炎症进行神经侵袭。此外，我们假设 增强型ZIKV致病机制发生在PLWH中，我们将使用SIV的NHP模型进行实验测试 感染。具体地说，在目标1中，我们将评估SIV感染动物的细胞是否支持更大的ZIKV 复制。在目标2中，我们将确定ZIKV在感染SIV的猕猴中的致病作用是否增强。我们 将确定SIV感染是否促进ZIKV对中枢神经系统的入侵，并确定先天和 与增强感染相对应的适应性免疫反应。这些研究将提供重要的见解 探讨HIV人群中ZIKV致病能力增强的潜在风险，并确定PLWH是否具有 寨卡病毒相关疾病的风险更大。这款K01的目标是支持发展我的 自己的独立研究计划侧重于了解PLWH中病毒混合感染的影响。按顺序 为了实现这一目标，我将使用艾滋病毒和ZIKV人类感染的NHP模型来扩展我之前的培训， 将利用华盛顿大学和华盛顿国家灵长类动物研究中心的资源 他将与我的导师黛博拉·富勒博士和迈克尔·盖尔博士密切合作。

PROJECT SUMMARY Over 36 million people are living with HIV and there is large geographic overlap for areas endemic with flavivirus infection. Despite the occurrence of large flavivirus outbreaks, there is a severe lack of knowledge regarding the impact flavivirus infections may have on people living with HIV (PLWH). It is unclear what effect HIV co-infection has on the clinical consequences of flavivirus infection and current studies in humans are limited by low patient numbers and inconsistent incorporation of HIV disease status into interpretations of flavivirus disease. Non- human (NHP) models of Zika virus (ZIKV) infection recapitulate several aspects of human disease and are ideal for evaluating the impact of human flavivirus infection in people living with HIV. However, no established HIV- ZIKV co-infection animal model exists. In this proposal, we will study the natural history of HIV co-infection with flaviviruses to understand the risks, causes, and clinical outcomes in PLWH. Previously in NHPs, we showed that CD16+ monocytes are the major in vivo blood targets of ZIKV and similar results have been found in humans. Monocyte frequencies increase during HIV infection and although ART reduces total frequencies in HIV infected persons, CD16+ monocytes remain elevated. We will investigate the hypothesis that HIV infection promotes susceptibility to flavivirus infection by decreasing anti-viral innate and adaptive immune responses, increasing inflammation, and expanding cellular targets of infection, including monocytes. HIV invasion of the central nervous system (CNS) is mediated by CD16+ monocytes, therefore monocytes could also act to spread ZIKV to the CNS and promote neurological disease. Thus, HIV infection could promote ZIKV pathogenesis and neuroinvasion by expanding the cellular target pool and inducing inflammation. Additionally, we hypothesize that enhanced ZIKV pathogenesis occurs in PLWH, and we will experimentally test this using an NHP model of SIV infection. Specifically, in Aim 1 we will evaluate whether cells from SIV infected animals support greater ZIKV replication. In Aim 2 we will determine whether ZIKV pathogenesis is enhanced in SIV-infected macaques. We will determine whether SIV infection promotes invasion of ZIKV into the CNS and determine the innate and adaptive immune responses corresponding to enhanced infection. These studies will provide significant insights into the potential risk of enhanced ZIKV pathogenesis in the HIV population and determine if PLWH have a greater risk of ZIKV-associated pathologies. The goal of this K01 is to support the transition of developing my own independent research program focused on understanding the impact of viral co-infections in PLWH. In order to achieve this goal I will expand upon my previous training using NHP models of HIV and ZIKV human infection, will leverage the resources at the University of Washington and the Washington National Primate Research Center, and will work closely with my mentors, Dr. Deborah Fuller and Dr. Michael Gale.