AIDS and Opiates: A Monkey Model

描述（由申请人提供）：IV药物滥用是一个突出的风险因素 艾滋病可信的支持可以发现，阿片类药物对艾滋病没有影响 进展，或恶化，或抑制。在一项试验性的猴子研究中，我们 发现艾滋病的进展被吗啡依赖减缓。我们有 随后，发起了一个大。(20恒河猴/组，吗啡vs生理盐水）研究， 证实这一观察。此竞争性续约申请针对的是 继续这一努力。猴子已经服用阿片类药物和病毒1-1/2年了。 艾滋病的进展速度与我们的模型不能判断，直到3-4年后病毒 感染因此，现在就知道阿片类药物依赖是否正在改变还为时过早。 艾滋病在这项研究中。迄今为止，只有2只对照猴死于 艾滋病平均病毒滴度在组间没有差异，这表明它们的 进展率将是相似的;然而，服用阿片类药物的猴子显示病毒免疫 相互作用可以解释为保护。因此，我们计划继续 研究直至达到进展率终点， 试验动物和对照动物之间的差异（如果存在）将是明显的（预测在 （二）建议补助金）。病毒滴度和突变率， 诸如宿主修复DNA损伤的能力等因素都是 与各种相关的免疫措施结合使用。这些 分析预计将产生重要的相互依存的相关因素，艾滋病 这将有助于确定进展结果。上覆第二 假设也在探索中，即，一个维护良好的 阿片类药物依赖会延缓神经艾滋病的发展神经病理学有 据报道，在海洛因成瘾者中， 当前的相关问题。我们将继续检查猴子的CSF， 这一目的是为了看看阿片类药物是否会改变这种病毒和免疫状态。 隔室，以及血脑屏障完整性是否受到影响。初步 数据表明阿片类药物确实改变了CSF中的炎症。另外， 淋巴结组织正在检查去甲肾上腺素能神经的完整性 同时采取病毒和免疫措施。各种各样的验尸报告 也计划从形态学的角度评估躯体和神经病理学， 病毒检测、细胞因子谱和炎症，以寻找定量的 以及暴露于吗啡与盐水的动物的质量差异。这 一位医生正在努力让琳达·张医生使用MR 光谱学来检测神经组织的细胞损失。最后，许多 将使用上述类型的测试，沿着神经内分泌测试 在第4年处死猴子之前， 加剧病毒的产生。这些研究将检验一个反假设， 我们的“保护性”假设也就是说，阿片类药物戒断的压力 通过诱导艾滋病病毒的产生来加剧艾滋病？最后，我们希望这些 研究，以提高对阿片类药物是否以及如何改变 艾滋病的进展。

DESCRIPTION (provided by applicant): IV-drug abuse is a prominent risk factor in AIDS. Credible support can be found that opiates have no effect on AIDS progression, or are exacerbatory, or inhibitory. In a pilot monkey study, we found that AIDS progression was slowed by morphine dependency. We have subsequently initiated a large. (20 rhesus/group, morphine vs saline) study to confirm this observation. This competitive renewal application is directed at continuing this effort. Monkeys have been on opiates and virus for 1-1/2 yr. AIDS progression rate with our model cannot be judged until 3-4 yr post-virus infection. So, it is too soon to know whether opiate dependency is altering AIDS progression in this study. To date, only 2 control monkeys have died from AIDS. Mean viral titers do not differ between groups, which suggests that their progression rates will be similar; yet, monkeys on opiates show viral-immune interactions interpretable as being protective. Thus, we plan to continue this study until an endpoint in rates of progression is reached where differences between test and control animals, if they exist, will be obvious (predicted in yr-2 of the proposed grant). Viral titers and mutation rates, and potentially contributing factors like the ability of the host to repair DNA damage are all being followed in conjunction with a variety of relevant immune measures. These analyses are expected to yield important interdependent correlates of AIDS progression that will help qualify the progression outcome. An overlying second hypothesis is also being explored, i.e., that a well-maintained opiate-dependency will retard progression of neuro-AIDS. Neuropathology has been reported as elevated in heroin addicts, making this a particularly relevant current issue. We will continue examining CSF from our monkeys for this purpose to see if opiates alter viral and immune status in this compartment, and whether blood brain barrier integrity is affected. Preliminary data suggest that opiates do alter inflammation in the CSF. Also, biopsied lymph-node tissues are being examined for noradrenergic nerve integrity simultaneous with viral and immune measures. A variety of postmortem tests are planned, too, to assess somatic and neural pathology in terms of morphology, viral detection, cytokine profiles, and inflammation to look for quantitative and qualitative differences in animals exposed to morphine versus saline. This effort is being extended by a subcontract to Dr. Linda Chang to use MR Spectroscopy to test neural tissues for cell loss. Finally, many of the aforementioned types of tests, along with neuroendocrine tests, are to be used before monkeys are sacrificed in yr-4, to see whether opiate-withdrawal exacerbates virus production. These studies will test a counterhypothesis to our 'protective' hypothesis. That is, does the stress of opiate withdrawal exacerbate AIDS by inducing AIDS virus production? In the end, we expect these studies to improve knowledge about whether and how opiates modify the progression of AIDS.