AIDS and Opiates: A Monkey Model

描述(由申请人提供)：静脉注射药物滥用是一个突出的危险因素 在艾滋病方面。可以找到可信的证据，阿片剂对艾滋病没有影响 进展，或恶化，或抑制。在一项试验性的猴子研究中，我们 研究发现，对吗啡的依赖减缓了艾滋病的进展。我们有 随后发起了一场规模较大的。(20只恒河猴/组，吗啡与生理盐水)研究 证实了这一观察结果。此竞争性续订申请针对的是 继续这一努力。猴子服用鸦片类药物和病毒已有一年半的时间。 我们的模型中的艾滋病进展率要到病毒感染后3-4年才能判断 感染。因此，现在就知道鸦片依赖是否正在改变还为时过早。 艾滋病在这项研究中的进展。到目前为止，只有2只对照猴死于 艾滋病。平均病毒滴度在不同组之间没有差异，这表明他们的 进展率将相似；然而，服用鸦片类药物的猴子表现出病毒免疫 相互作用可以解释为保护性的。因此，我们计划继续这样做 研究直到达到进展率的终点，在那里差异 如果存在的话，测试动物和对照动物之间的差异将是显而易见的(在 拟议赠款的YR-2)。病毒滴度和变异率，以及潜在的 宿主修复DNA损伤的能力等促成因素都是 并配合各种相关的免疫措施。这些 预计分析将得出重要的相互依存的艾滋病相关因素 将有助于限定进展结果的进展。更高的一秒 还在探索一种假设，即一个维护良好的 阿片类药物依赖将延缓神经艾滋病的进展。神经病理学有 据报道在海洛因成瘾者中升高，这使得这一点特别 相关的当前问题。我们将继续检查我们猴子的脑脊液 这一目的是为了观察阿片剂是否会改变病毒和免疫状态 以及血脑屏障的完整性是否受到影响。初步 数据表明，鸦片类药物确实会改变脑脊液中的炎症。还有，活组织检查 正在对淋巴结组织进行去甲肾上腺素能神经完整性检查 同时采取病毒和免疫措施。各种各样的尸检是 还计划从形态上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 以及暴露在吗啡和生理盐水中的动物的质量差异。这 正在通过分包合同将努力扩展到Linda Chang博士，以使用MR 光谱学测试神经组织的细胞丢失。最后，许多 将使用上述类型的测试以及神经内分泌测试。 在YR-4处死猴子之前，观察阿片类药物是否戒断 加剧了病毒的产生。这些研究将检验一种反假设 我们的“保护性”假说。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而加剧艾滋病？最后，我们期待着这些 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.