Identification of SIV replication and reservoirs in the CNS

CNS 中 SIV 复制和储存库的识别

基本信息

批准号：
10669027
负责人：
PHILIP J SANTANGELO
金额：
$ 78.54万
依托单位：
UNIVERSITY OF LOUISIANA AT LAFAYETTE
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：
2020-09-19 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10669027
关键词：
Acute Address Anatomy Anti-Retroviral Agents Area Blood Blood - brain barrier anatomy Brain Cell Lineage Cell Separation Cell physiology Cells Central Nervous System Chronic Phase Clinic Collection Data Data Analyses Detection Development Dose Environment Evaluation Flow Cytometry Future Goals Gut Mucosa HIV HIV Infections Image Imaging Techniques Imaging technology ImmunoPET Infection Interruption Intervention Ionomycin Kinetics Label Laboratories Light Link Location Lymphoid Macaca Macaca nemestrina Mannitol Maps Microscopic Microscopy Modeling Molecular Monitor Monkeys Monoclonal Antibodies Nature Nervous System Trauma Neurologic Symptoms Organ Penetration Peptides Pharmaceutical Preparations Plasma Positron-Emission Tomography Primates Process Production Proteins Protocols documentation Radioisotopes Research Residual state SIV Secondary to Signal Transduction Site Sorting Source Stains Supporting Cell Systemic infection Techniques Technology Testing Time Tissues Transferrin Viral Viral reservoir Virus Virus Diseases Virus Latency Virus Replication X-Ray Computed Tomography acute infection antiretroviral therapy blood-brain barrier crossing cell type chronic infection confocal imaging imaging system in vivo lymph nodes monocyte neuroAIDS nonhuman primate reproductive tract response tool transcriptome sequencing translation to humans viral rebound

项目摘要

Abstract Even though highly potent antiretroviral therapy (ART) has the ability to reduce viral replication to undetectable levels in the plasma in simian immunodeficiency virus (SIV) infected monkeys, our recently developed viral env directed immunoPET/CT imaging technology has been able to detect foyers of continued SIV signals even after prolonged ART. However, the ability of this non-invasive technique to map SIV signal in the CNS have thus far been elusive. In this application we propose to focus on the development of probes and strategies to specifically address SIV signals in the CNS, by optimizing the technology to enable SIV specific PET probes to cross the blood brain barrier and mark cells expressing SIV env in vivo. Towards this goal we will use the pigtailed macaque model infected with SIVsmB670/SIVmac239-17E-Fred developed and validated by the team of Dr. Clements as one of the most reliable models of neuroHIV. Leveraging the strength and technological advances available at the New Iberia Research Center and Georgia Tech, we will map the seeding of reservoirs in the CNS during acute infection and monitor the kinetic of viral signals post-acute infection using a combination of immunoPET/CT, light-sheet and confocal imaging techniques, as well as sorting of infected cells to document the nature and function of cells remaining active in the early chronic phase of CNS SIV infection. Next we will document the dynamics of viral kinetics in the CNS relative to total body upon ART initiation, as well as post- ART interruption. Data generated from these highly detailed analyses will delineate which cells retain persistent viral replication under ART (if any) and more importantly evaluate the contribution of CNS viral reservoirs to the early viral rebound in vivo. The in depth analysis of this data will also provide important steps towards the development of cure strategies that include the CNS.

抽象的即使高度有效的抗逆转录病毒疗法（ART）具有将病毒复制降低到无法检测到的能力我们最近开发的病毒Env的邻胺免疫缺陷病毒（SIV）感染猴子的血浆水平定向免疫集/CT成像技术即使在长期艺术。但是，到目前为止，这种非侵入性技术在中枢神经系统中绘制SIV信号难以捉摸。在此应用中，我们建议专注于探针和策略的制定通过优化技术以使SIV特定的PET探针越过CNS中的SIV信号血脑屏障和标记体内表达SIV ENV的细胞。为了实现这一目标，我们将使用辫子被SIVSMB670/SIVMAC239-17E-FRED感染的猕猴模型由Dr.团队开发和验证 Clements是神经hiv的最可靠模型之一。利用力量和技术进步我们将在新的伊比利亚研究中心和佐治亚理工学院购买，我们将绘制储层的播种急性感染期间的中枢神经系统，并通过组合结合免疫集/CT，灯页和共聚焦成像技术，以及对感染细胞进行分类以记录在中枢神经系统SIV感染的早期慢性期，细胞的性质和功能保持活跃。接下来我们会记录中枢神经系统中病毒动力学的动力学，相对于艺术启动时的全体身体，以及艺术中断。这些高度详细的分析产生的数据将描绘出细胞保留持久性的数据在ART下的病毒复制（如果有），更重要的是评估中枢神经系统病毒储层对体内早期病毒反弹。对该数据的深入分析还将提供重要的步骤制定包括中枢神经系统在内的治疗策略。