IN VIVO DEPLETION OF CD16+ MONOCYTES IN SIV INFECTED MACAQUES

SIV 感染猕猴体内 CD16 单核细胞的耗竭

• 批准号: 8173054
• 负责人: Marcelo J Kuroda
• 金额: $ 6.18万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-05-01 至 2011-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8173054
• 关键词: AIDS neuropathy; Acquired Immunodeficiency Syndrome; Animal Model; Anti-Retroviral Agents; Antibodies; Brain; Brain Diseases; CD16 Antigens; CD8-Positive T-Lymphocytes; Cell Lineage; Cells; Computer Retrieval of Information on Scientific Projects Database; FCGR3B gene; Funding; Grant; HIV; HIV Infections; Heart; Human; Infection; Institution; Kidney; Lymphoid; Macaca; Macaca mulatta; Modeling; Neurologic Dysfunctions; Neuronal Injury; Organ; Pathogenesis; Patients; Plasma; Play; Regimen; Research; Research Personnel; Residual state; Resources; Role; SIV; Source; Tissues; United States National Institutes of Health; Viral; Viral Load result; Virus; Virus Diseases; antiretroviral therapy; cell type; experience; in vivo; killings; macrophage; monocyte; non-compliance; trafficking

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Undetectable levels of virus in the plasma of HIV infected patients can be achieved on seemingly effective antiretroviral therapy. However, patients that have terminated treatment, either because of intolerance or noncompliance, experience a rapid resurgence of viral burden, underscoring the role of reservoirs where the virus hide and persists. One such cellular reservoir is monocyte/macrophage lineage cells. Infected monocytes traffic to tissues and become macrophages, which are a major cell type infected in non-lymphoid organs such as the brain, heart and kidney. A subset of blood monocytes expressing the CD16 antigen expands in HIV infected humans and SIV infected macaques, and preferentially harbor virus. It has been hypothesized that the infection and traffic of CD16+ monocytes play a key role in the pathogenesis of neurologic dysfunction associated with HIV infection. For a direct demonstration of their pathogenic role, however, depletion of these cells will be required. Therefore, we propose to use a SIV/macaque model of neuroAIDS (rhesus monkeys that are SIV infected, CD8 lymphocyte depleted) with an antibody that kills CD16+ monocytes and therefore would block their traffic to tissues. Previously using this animal model, we found that biphasic expansion of CD16+ monocytes during primary infection and during progression to AIDS correlates with brain neuronal injury. The main objective of this project is to determine the effects of CD16+ monocyte depletion on HIV induced brain disease and virus infection in macrophages. Anti-CD16 antibody treatment, if found effective, could be used in combination with the existing antiretroviral regimen to eliminate residual viral reservoirs in HIV infected patients.

该子项目是利用该技术的众多研究子项目之一 资源由 NIH/NCRR 资助的中心拨款提供。子项目及 研究者 (PI) 可能已从 NIH 的另一个来源获得主要资金， 因此可以在其他 CRISP 条目中表示。列出的机构是 中心，不一定是研究者的机构。 通过看似有效的抗逆转录病毒治疗，艾滋病毒感染患者血浆中的病毒水平可以达到不可检测的水平。 然而，由于不耐受或不依从而终止治疗的患者，病毒负荷迅速回升，凸显了病毒隐藏和持续存在的储存库的作用。 一种这样的细胞储库是单核细胞/巨噬细胞谱系细胞。 受感染的单核细胞迁移至组织并变成巨噬细胞，巨噬细胞是脑、心脏和肾脏等非淋巴器官中感染的主要细胞类型。 表达 CD16 抗原的血液单核细胞亚群在感染 HIV 的人类和感染 SIV 的猕猴中扩增，并优先携带病毒。 据推测，CD16+单核细胞的感染和运输在 HIV 感染相关神经功能障碍的发病机制中发挥着关键作用。 然而，为了直接证明它们的致病作用，需要耗尽这些细胞。 因此，我们建议使用神经艾滋病的 SIV/猕猴模型（感染 SIV 的恒河猴，CD8 淋巴细胞耗尽），并使用一种抗体杀死 CD16+ 单核细胞，从而阻止其向组织的运输。 之前使用该动物模型，我们发现 CD16+ 单核细胞在原发感染和艾滋病进展过程中的双相扩张与脑神经元损伤相关。 该项目的主要目标是确定 CD16+ 单核细胞耗竭对 HIV 诱发的脑部疾病和巨噬细胞病毒感染的影响。 如果发现抗 CD16 抗体治疗有效，则可以与现有的抗逆转录病毒治疗方案联合使用，以消除 HIV 感染患者体内残留的病毒库。