STUDY OF MHC & CTL IN OPIATE-DEPENDENT MONKEYS WITH AIDS

描述：(改编自申请者摘要)猿猴免疫缺陷病毒 (SIV)感染猕猴提供了最好的非人类灵长类动物模型 研究艾滋病。这些研究人员将利用SIV/猕猴模型来 确定NEF特异性细胞毒性T淋巴细胞(CTL)是否在 体内新病毒变种的筛选。调查人员还将测试 病毒特异性CTL克隆可持续整个病程的假说 病毒感染的可能性。此外，他们将确定MHC是否 恒河猴在体内可以起到抵抗SIV感染的作用。 最后，他们将调查鸦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 体内感染艾滋病病毒的病程。这些研究将使用以下方法进行 从美国国立卫生研究院支持的一项正在进行的研究中获得的血液样本，旨在确定 阿片依赖如何改变SIV smm9诱导的40例艾滋病的进展 恒河猴。 在特定目标1中，他们将检验以下假设：特定于nef的CTL 应答选择新的病毒变异体，这些新变异体逃脱CTL 承认。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，而对环境施加选择压力 CTL表位更为宽松。 在特定目标2中，他们将测试CTL克隆产生的假设 在SIV感染过程的早期持续整个过程 疾病。麦克迈克尔博士的团队有初步数据表明， 在SIV感染期间，T细胞可以存活。这与之前的情况有些不同 调查结果。 在特定的目标3中，他们将测试某些MHC等位基因可以 影响SIVsmm9体内感染的病程。由于MHC的产品 基因结合病原体衍生的多肽，并将它们呈递给T细胞，它已经被 暗示这些高度多态的分子可能会影响 个人对艾滋病病毒做出反应。最近的研究表明 某些人类白细胞抗原分子可能在长期内发挥重要作用 非进步者。 在特定的目标4中，他们将检验阿片类药物可以影响CTL的假设 或HTL反应，这些反应反过来可以决定疾病的进程 感染。尽管有证据表明CTL和HTL在HIV中的作用 感染，对个人进行长期研究一直是困难的 在这种情况下，病毒的感染时间、剂量和性质在 相关动物模型。在这群动物中，他们将能够确定 鸦片类药物是否会影响对艾滋病病毒的细胞免疫反应。

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.