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.

这个子项目是许多研究子项目中的一个 由NIH/NCRR资助的中心赠款提供的资源。子项目和 研究者（PI）可能从另一个NIH来源获得了主要资金， 因此可以在其他CRISP条目中表示。所列机构为 研究中心，而研究中心不一定是研究者所在的机构。 通过看似有效的抗逆转录病毒疗法，可以使艾滋病毒感染者血浆中的病毒水平达到无法检测的水平。 然而，由于不耐受或不依从而终止治疗的患者会经历病毒负荷的快速复苏，这强调了病毒隐藏和持续存在的水库的作用。 一种这样的细胞储库是单核细胞/巨噬细胞谱系细胞。 受感染的单核细胞运输到组织并成为巨噬细胞，巨噬细胞是在非淋巴器官如脑、心脏和肾中感染的主要细胞类型。 表达CD 16抗原的血液单核细胞亚群在HIV感染的人和SIV感染的猕猴中扩增，并优先携带病毒。 据推测，CD 16+单核细胞的感染和运输在与HIV感染相关的神经功能障碍的发病机制中起关键作用。 然而，为了直接证明它们的致病作用，需要去除这些细胞。 因此，我们建议使用具有杀死CD 16+单核细胞的抗体的神经AIDS的SIV/猕猴模型（SIV感染的恒河猴，CD 8淋巴细胞耗尽），因此将阻断它们向组织的运输。 以前使用这种动物模型，我们发现，在原发性感染和进展到艾滋病的过程中，CD 16+单核细胞的双相扩增与脑神经元损伤相关。 本项目的主要目的是确定CD 16+单核细胞耗竭对HIV诱导的脑疾病和巨噬细胞中的病毒感染的影响。 如果发现抗CD 16抗体治疗有效，则可与现有的抗逆转录病毒方案联合使用，以消除HIV感染患者中残留的病毒储库。