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

基本信息

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
项目类别：
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

项目摘要

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.

项目概要超过 3600 万人感染艾滋病毒，黄病毒流行地区存在很大的地理重叠感染。尽管发生了大规模的黄病毒爆发，但人们对黄病毒的认识严重缺乏黄病毒感染可能对艾滋病毒感染者（PLWH）产生影响。目前尚不清楚 HIV 合并感染有何影响对黄病毒感染的临床后果有影响，目前对人类的研究受到患者人数少的限制数量以及将艾滋病毒疾病状况纳入黄病毒病解释中的不一致。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，是理想的模型用于评估人类黄病毒感染对艾滋病毒感染者的影响。然而，目前尚无确定的 HIV- 存在 ZIKV 共感染动物模型。在本提案中，我们将研究 HIV 合并感染的自然史黄病毒以了解 PLWH 的风险、原因和临床结果。之前在 NHP 中，我们展示了 CD16+单核细胞是 ZIKV 的主要体内血液靶标，并且在人类中也发现了类似的结果。 HIV 感染期间单核细胞频率增加，尽管 ART 降低了 HIV 感染者的总频率人中，CD16+单核细胞仍然升高。我们将研究艾滋病毒感染促进的假设通过降低抗病毒先天和适应性免疫反应、增加对黄病毒感染的易感性炎症和扩大感染的细胞目标，包括单核细胞。 HIV侵入中枢神经系统 (CNS) 由 CD16+ 单核细胞介导，因此单核细胞也可能将 ZIKV 传播到中枢神经系统并促进神经系统疾病。因此，HIV 感染可以促进 ZIKV 的发病机制，通过扩大细胞靶标库并诱导炎症来进行神经侵袭。此外，我们假设 ZIKV 发病机制增强发生在 PLWH 中，我们将使用 SIV 的 NHP 模型对此进行实验测试感染。具体来说，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 发病机制是否在感染 SIV 的猕猴中得到增强。我们将确定SIV感染是否促进ZIKV侵入CNS并确定先天和与增强的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研究 HIV 人群中 ZIKV 发病机制增强的潜在风险，并确定 PLWH 是否患有出现 ZIKV 相关疾病的风险更大。 K01 的目标是支持我的发展转型自己的独立研究计划专注于了解病毒混合感染对艾滋病病毒感染者的影响。为了为了实现这一目标，我将使用 HIV 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中心，并将与我的导师 Deborah Fuller 博士和 Michael Gale 博士密切合作。