NEURO-IMMUNE FACTORS IN SIV-INDUCED CNS DYSFUNCTION

SIV 引起的中枢神经系统功能障碍中的神经免疫因素

• 批准号: 6187685
• 负责人: HOWARD S FOX
• 金额: $ 28.34万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-28 至 2004-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6187685
• 关键词: AIDS /HIV neuropathy; Macaca mulatta; antiviral agents; biological models; body movement; body temperature; brain electrical activity; brain mapping; chemokine; cytotoxic T lymphocyte; disease /disorder model; disease /disorder onset; drug resistance; host organism interaction; longitudinal animal study; natural gene amplification; neuroimmunomodulation; neurotoxins; nonhuman therapy evaluation; pathologic process; simian AIDSs; simian immunodeficiency virus; telemetry; virus infection mechanism; virus load

The experiments proposed here are designed to address the relationship between the virus, the host's response to virus, and alterations in CNS functions. We will focus on testing the hypothesis that there is a CTL response in the CNS that serves to help control viral load, but at the cost of damage to the CNS. First, we will investigate the nature and extent of the early CTL response to SIV infection in the CNS. We will asses whether there is a regional specificity of SIV infection or CTL response in the brain. Examination of measures of oxidative stress, a common potential mechanism for many dementing conditions, will assess the potential for these CTL and other events occurring in the host/viral interaction to induce damage to the CNS. Additionally, control of CTL migration by chemokines produced by the infected CNS will be investigated. Second, we will assess the nature of the CTL response in the CNS over time, compare it to the CTL response occurring in the periphery, and relate these findings to the development of CNS functional abnormalities. In order to test whether the level of peripheral viral load plays a role in the maintenance of a CNS immune response, one group of animals will receive anti-viral treatment at two weeks post-viral inoculation, at the peak of peripheral viral load and CTL response. The potential for diminution of the CNS CTL response, versus a perpetuation, will be analyzed to determine the relationship of CNS CTL to peripheral viral load, and their joint relationship to CNS dysfunction and pathology. This will aid in the examination of whether the viral-immune interactions in the CNS compartment can occur independently of those in the blood and lymphoid tissue. Third, we will examine the clonality of CTL responses in the CNS during the acute and chronic infection to assess whether the CNS response is representative of the immune response in the peripheral compartment or whether evidence of local, possibly clonal or oligoclonal amplification occurs within the CNS. We will also use anti-viral therapy and its withdrawal to model the development of viral resistance or failure of effective therapy, and determine the vulnerability of the CNS to re-infection in this setting, and the role CNS CTL play in the response to the rebound viremia.

此处提出的实验旨在解决病毒，宿主对病毒的反应以及中枢神经系统功能的改变之间的关系。 我们将重点介绍中枢神经系统中有CTL响应的假设有助于控制病毒载荷，但以损害中枢神经系统的损害为代价。首先，我们将研究CNS中CTL早期对SIV感染的早期反应的性质和程度。 我们将评估大脑中SIV感染的区域特异性还是CTL反应。 检查氧化应激测量值是许多痴呆条件的常见潜在机制，将评估这些CTL的潜力和其他发生在宿主/病毒相互作用中的事件，以诱导CNS损害。此外，将研究由感染中枢神经系统产生的趋化因子迁移的CTL迁移。 其次，我们将随着时间的推移评估中枢神经系统中CTL响应的性质，将其与外围发生的CTL响应进行比较，并将这些发现与CNS功能异常的发展相关。 为了测试周围病毒负荷水平是否在维持CNS免疫反应中起作用，在外周病毒负荷和CTL反应的峰值处，一组动物将在病毒后两周内接受抗病毒治疗。 将分析CNS CTL响应减少的潜力，而不是永久性，以确定CNS CTL与外围病毒载荷的关系，以及它们与CNS功能障碍和病理学的关节关系。 这将有助于检查中枢神经系统中CNS中的病毒免疫相互作用可以独立于血液和淋巴组织中的病毒相互作用。 第三，我们将检查急性和慢性感染期间中枢神经系统中CTL反应的克隆性，以评估中枢神经系统反应是否代表了外围区室中免疫反应的代表性，还是局部，可能是克隆或可能发生的，可能发生克隆或寡聚的证据。 我们还将使用抗病毒疗法及其撤离来模拟病毒抗性或有效治疗失败的发展，并确定中枢神经系统在这种情况下重新感染的脆弱性，以及CNS CTL在响应反弹病毒血症中的作用。