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

评估感染 SIV 的猕猴中 ZIKV 合并感染的风险

• 批准号: 10397539
• 负责人: Megan A O'Connor
• 金额: $ 6.75万
• 依托单位: UNIVERSITY OF WASHINGTON
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-04-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10397539
• 关键词: AIDS/HIV problem; Acquired Immunodeficiency Syndrome; Acute; Adult; Animal Model; Animals; Area; Autopsy; Blood; Cells; Child; Clinical; Congenital neurologic anomalies; Dengue; Dengue Infection; Disease; Disease Outbreaks; Disease Progression; Drug or chemical Tissue Distribution; FCGR3B gene; Female; Flavivirus; Flavivirus Infections; Flow Cytometry; Frequencies; Geography; Goals; HIV; HIV Infections; Histopathology; Human; Immune; Immune response; Immunocompromised Host; In Vitro; Individual; Infant; Infection; Inflammation; Inflammatory; Knowledge; Macaca; Macaca nemestrina; Measurement; Measures; Mediating; Mentors; Modeling; Monitor; Natural History; Neuraxis; Outcome; Pathogenesis; Pathology; Patients; Peripheral Blood Mononuclear Cell; Persons; Phenotype; Population; Predisposition; Pregnancy; Pregnant Women; Primates; Reporting; Research; Resources; Risk; Route; SIV; Sampling; Surveillance Methods; Testing; Tissues; Training; Universities; Vertical Disease Transmission; Viral; Viral Load result; Viral Pathogenesis; Virus Replication; Washington; West Nile virus; Woman; Work; Yellow fever virus; ZIKV infection; Zika Virus; adaptive immune response; antiretroviral therapy; cellular targeting; co-infection; congenital zika syndrome; cytokine; global health; human disease; in vivo; insight; monocyte; nervous system disorder; neuropathology; nonhuman primate; programs

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.

项目摘要 超过3600万人感染艾滋病毒，黄病毒流行地区在地理上有很大重叠 感染尽管发生了大规模的黄病毒爆发，但人们严重缺乏关于 黄病毒感染可能对艾滋病毒感染者（PLWH）产生的影响。目前还不清楚艾滋病毒合并感染的影响 对黄病毒感染的临床后果有影响，目前在人类中的研究受到低患者 数字和不一致的纳入艾滋病毒疾病状态的黄病毒病的解释。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， 用于评估人类黄病毒感染对艾滋病毒感染者的影响。然而，没有确定的艾滋病毒- 存在ZIKV共感染动物模型。在这项建议中，我们将研究艾滋病毒合并感染的自然史， 黄病毒，以了解风险，原因和临床结果在PLWH。在NHPs上，我们展示了 CD 16+单核细胞是ZIKV的主要体内血液靶标，并且在人类中发现了类似的结果。 单核细胞频率在HIV感染期间增加，尽管ART降低了HIV感染者的总频率， 对于人来说，CD 16+单核细胞仍然升高。我们将调查艾滋病毒感染促进 通过降低抗病毒先天性和适应性免疫应答， 炎症和扩大感染的细胞靶，包括单核细胞。艾滋病病毒侵入中枢 神经系统（CNS）中的ZIKV是由CD 16+单核细胞介导的，因此单核细胞也可以起到将ZIKV传播到 中枢神经系统和促进神经系统疾病。因此，HIV感染可促进ZIKV发病， 通过扩大细胞靶池和诱导炎症来抑制神经侵袭。此外，我们假设， 增强的ZIKV发病机制发生在PLWH中，我们将使用SIV的NHP模型进行实验测试 感染具体地，在目标1中，我们将评估来自SIV感染动物的细胞是否支持更大的ZIKV 复制的在目的2中，我们将确定ZIKV发病机制是否在SIV感染的猕猴中增强。我们 将确定SIV感染是否促进ZIKV侵入CNS，并确定ZIKV的先天和 适应性免疫反应对应于增强的感染。这些研究将提供重要的见解 在HIV人群中增强ZIKV发病机制的潜在风险，并确定PLWH是否具有 ZIKV相关病理的风险更大。本K 01的目标是支持开发我的 自己的独立研究计划，重点是了解病毒合并感染对PLWH的影响。为了 为了实现这一目标，我将扩展我以前的培训，使用HIV和ZIKV人类感染的NHP模型， 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 中心，并将与我的导师，德博拉富勒博士和迈克尔盖尔博士密切合作。