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: 8358140
• 负责人: Marcelo J Kuroda
• 金额: $ 5.78万
• 依托单位: TULANE UNIVERSITY OF LOUISIANA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2012-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8358140
• 关键词: AIDS neuropathy; Acquired Immunodeficiency Syndrome; Adverse effects; Animals; Anti-Retroviral Agents; Antibiotics; Antibodies; Brain; CD16 Antigens; CD8-Positive T-Lymphocytes; Cell Lineage; Cells; Chronic; Clinical; Control Groups; Dose; FCGR3B gene; Funding; Generic Drugs; Grant; HIV; HIV Infections; Heart; Human; Infection; Intravenous; Kidney; Macaca; Macaca mulatta; Minocycline; Modeling; Monkeys; National Center for Research Resources; Neurologic Dysfunctions; Oral; Organ; Outcome; Pathogenesis; Patients; Plasma; Play; Primates; Principal Investigator; Reporting; Research; Research Infrastructure; Resources; Role; SIV; Safety; Source; Testing; Tissues; United States National Institutes of Health; Viral Load result; Virus; antiretroviral therapy; cell type; cost; experience; in vivo; killings; macrophage; monocyte; nervous system disorder; non-compliance; prospective; response; trafficking

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. 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 persist. 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 originally proposed to use the SIV/macaque model of neuroAIDS (rhesus monkeys that are SIV infected, CD8 lymphocyte depleted) with a depleting anti-CD16 antibody that kills CD16+ monocytes and therefore would block their traffic to tissues. Unfortunately, desirable CD16 monocytes depletion was not achieved with this antibody as we originally expected. And no difference in the outcome of the neurological disorder was observed comparing to the control group. Therefore we decided to take another approach for the next monkey study. It has been recently reported that in SIV macaque models of AIDS, neuroprotective and antiretroviral effects of minocycline, an oral antibiotic, have been demonstrated. Possible neuroprotective mechanisms of minocycline include the inhibition of CD16+ monocytes and/or the reduction of monocyte turnover and traffic, as suggested in other studies. Through the in vivo modulation of monocyte responses during SIV infection, we will evaluate more precisely, in a prospective manner, the role of increased monocyte turnover and CD16+ monocytes, and also be able to determined whether the decreased monocyte turnover will have any effect of AIDS progression. Oral minocycline, a widely used generic antibiotic with a good safety record in humans and animals, has been tested extensively in many experimental animals including monkeys. No adverse effects or side effects at the tested doses were observed even following chronic daily administration in macaques (60 days). The daily dose we propose to administer orally is the usual (low) clinical dose of intravenous minocycline. Overall, no adverse effects are anticipated from the treatment.

这个子项目是许多利用资源的研究子项目之一 由NIH/NCRR资助的中心拨款提供。子项目的主要支持 而子项目的主要调查员可能是由其他来源提供的， 包括其它NIH来源。 列出的子项目总成本可能 代表子项目使用的中心基础设施的估计数量， 而不是由NCRR赠款提供给子项目或子项目工作人员的直接资金。 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CD16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，CD16+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，我们最初提出使用神经AIDS的SIV/猕猴模型（SIV感染的恒河猴，CD8淋巴细胞耗尽），使用耗尽性抗CD16抗体，该抗体杀死CD16+单核细胞，因此将阻断它们向组织的运输。 不幸的是，如我们最初预期的那样，用该抗体没有实现期望的CD16单核细胞耗竭。与对照组相比，观察到神经系统疾病的结局无差异。因此，我们决定采取另一种方法进行下一项猴子研究。最近有报道称，在SIV猕猴艾滋病模型中，米诺环素（一种口服抗生素）的神经保护和抗逆转录病毒作用已得到证实。 米诺环素可能的神经保护机制包括抑制CD 16+单核细胞和/或减少单核细胞更新和运输，如其他研究所示。 通过在SIV感染过程中单核细胞反应的体内调节，我们将以前瞻性的方式更精确地评估单核细胞更新和CD 16+单核细胞增加的作用，并且还能够确定单核细胞更新减少是否会对AIDS进展产生任何影响。 口服米诺环素是一种广泛使用的通用抗生素，在人类和动物中具有良好的安全记录，已在包括猴子在内的许多实验动物中进行了广泛的测试。 即使在猕猴中长期每日给药（60天）后，在试验剂量下也未观察到不良反应或副作用。 我们建议口服的每日剂量是静脉注射米诺环素的常用（低）临床剂量。 总体而言，预计治疗不会产生不良反应。