STUDY OF MHC & CTL IN OPIATE DEPENDENT MONKEYS WITH AIDS

MHC的研究

• 批准号: 2873843
• 负责人: David I Watkins
• 金额: $ 35.28万
• 依托单位: UNIVERSITY OF WISCONSIN-MADISON
• 依托单位国家: 美国
• 财政年份: 1999
• 资助国家: 美国
• 起止时间: 1999-09-30 至 2003-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2873843
• 关键词: Macaca mulatta; alleles; cellular immunity; cytotoxic T lymphocyte; drug addiction; helper T lymphocyte; major histocompatibility complex; molecular cloning; opiate alkaloid; simian AIDSs; simian immunodeficiency virus; virus infection mechanism

DESCRIPTION: (Adapted from Applicant's Abstract) Simian immunodeficiency virus (SIV) infection of macaques provides the best non-human primate model for studying AIDS. These investigators will utilize the SIV/macaque model to determine whether nef-specific cytotoxic T lymphocytes (CTL) play a role in selection for new virus variants in vivo. The investigators will also test the hypothesis that clones of virus-specific CTL can persist for the entire course of the virus infection. Additionally, they will determine whether the MHC of the rhesus macaque can play a role in resistance to SIV infection in vivo. Finally, they will investigate whether opiates can influence the generation of AIDS virus-specific CTL or helper T lymphocyte (HTL) responses during the course of AIDS virus infection in vivo. These studies will be carried out using blood samples obtained from an ongoing NIH-supported study aimed at determining how opiate-dependency alters progression of AIDS induced by SIV smm9 in 40 rhesus macaques. In Specific Aim 1 they will test the hypothesis that the nef-specific CTL response selects for new viral variants and that these new variants escape CTL recognition. They have recently generated preliminary data indicating that CTLs exert considerable selective pressure on nef, whereas selective pressure on env CTL epitopes was more relaxed. In Specific Aim 2 they will test the hypothesis that clones of CTL generated early in the course of SIV infection persist for the entire course of the disease. Dr. McMichael's group have preliminary data suggesting that clones of T cells can persist during SIV infection. This is somewhat contrary to previous findings. In Specific Aim 3 they will test the hypothesis that certain MHC alleles can influence the course of SIVsmm9 infection in vivo. Since products of the MHC genes bind pathogen-derived peptides and present them to T cells, it has been suggested that these highly polymorphic molecules might influence how an individual makes a response to the AIDS virus. Recent studies have indicated that certain HLA molecules may play an important role in long-term non-progressors. In Specific Aim 4, they will test the hypothesis that opiates can influence CTL or HTL responses which can, in turn, determine the course of disease after infection. Although evidence exists for the role CTLs and HTLs in HIV infection, it has been difficult to carry out long term studies in individuals in which time of infection, and dose and nature of the virus are known in a relevant animal model. In this cohort of animals they will be able to determine whether opiates can influence the cellular immune response to the AIDS virus.

描述：（改编自申请人的摘要）猿猴免疫缺陷病毒 (SIV)猕猴的感染提供了最好的非人灵长类动物模型， 研究艾滋病。这些研究人员将利用SIV/猕猴模型， 确定nef特异性细胞毒性T淋巴细胞（CTL）是否在 在体内选择新的病毒变体。调查人员还将测试 假设病毒特异性CTL的克隆可以持续整个过程 病毒感染。此外，他们将确定是否MHC的 恒河猴体内可起到抵抗SIV感染的作用。 最后，他们将研究阿片类药物是否会影响 艾滋病病毒特异性CTL或辅助性T淋巴细胞（HTL）反应， 艾滋病病毒在体内的感染过程。这些研究将使用 从NIH支持的一项正在进行的研究中获得的血液样本， 阿片类药物依赖如何改变40例SIV smm 9诱导的艾滋病进展 恒河猴 在具体目标1中，他们将检验nef特异性CTL 应答选择新的病毒变体，并且这些新变体逃避CTL 识别.他们最近产生的初步数据表明，CTL 对nef施加相当大的选择压力，而对env施加选择压力， CTL表位较为宽松。 在《特定目标2》中，他们将检验CTL克隆产生 在SIV感染的早期持续整个病程， 疾病麦克迈克尔博士的研究小组有初步数据表明， T细胞在SIV感染期间可以持续存在。这与此前的 调查结果。 在《特定目标3》中，他们将检验某些MHC等位基因可以 影响体内SIVsmm 9感染的过程。因为MHC的产物 基因结合病原体衍生肽并将其呈递给T细胞， 表明这些高度多态的分子可能会影响 一个人对艾滋病病毒做出反应。最近的研究表明 某些HLA分子可能在长期免疫中起重要作用。 不进步者。 在具体目标4中，他们将检验阿片类药物可以影响CTL的假设。 或HTL反应，这反过来又可以决定疾病的过程后， 感染尽管有证据表明CTL和HTLs在HIV中的作用， 感染，很难在个体中进行长期研究 其中感染时间、病毒的剂量和性质是已知的， 相关动物模型。在这组动物中，他们将能够确定 阿片类药物是否会影响细胞对艾滋病病毒的免疫反应。