HIV, Drug Abuse and Neurotoxicity

甲基苯丙胺和3，4-亚甲基二氧基甲基苯丙胺(MDMA)是两种最常见的俱乐部 毒品，在年轻一代中很受欢迎。这些非法物质被数百万人使用 每年都有人使用，他们的使用在同性恋人群中更受欢迎。甲基苯丙胺和 已知MDMA会引起神经毒性，包括改变大脑结构，特别是在 与抑郁和认知问题相关的区域。有间接证据表明 甲基苯丙胺和MDMA可能影响HIV-1阳性吸毒者的病程 明显表现为HIV-1感染率升高、病毒载量增加以及神经性炎症 在吸毒者中。多巴胺(DA)、多巴胺转运体(DT)、酪氨酸羟化酶(TH)和 氧化应激标志物在甲基苯丙胺和MDMA介导的神经毒性中得到了很好的证实。 然而，细胞因子和趋化因子的作用尚不清楚。另一方面，众所周知，艾滋病毒 引起艾滋病毒相关性痴呆症(HAD)和非法物质，特别是鸦片类药物已有记录 使这些影响更加复杂。对两种HIV蛋白(tat和gp120)进行了详细的研究。 诱导能力HAD。然而，病毒VPR和Nef，虽然牵连，但没有得到很好的研究，因为他们的 在HAD中扮演的角色。此外，关于两者之间可能的协同作用，可用的信息有限。 一方面是甲基苯丙胺和MDMA，另一方面是不同的病毒毒素。在本提案中，我们将 细胞因子和趋化因子在甲基苯丙胺和MDMA介导的神经毒性中的作用 找出同时使用两种药物是否会增加神经毒性。我们将确定艾滋病毒vpr的作用和 NEF在神经毒性方面的研究相对较少。我们还将确定是否有 非法药物和病毒毒素之间的协同作用以及是否可以通过使用 拮抗剂和siRNA。这些体外发现将扩展到体内实验，在这些实验中 将探索甲基苯丙胺或MDMA和病毒毒素对HIV TAT、Nef和gp120的影响 转基因小鼠。

Methamphetamine and 3, 4- methylenedioxymethamphetamine (MDMA) are two most common club drugs, and are very popular among younger generation. These illicit substances are used by millions of people every year and their use is more popular among gay population. Both methamphetamine and MDMA are known to cause neurotoxicity including changes in structure of the brain, especially in the areas associated with depression and cognitive problems. There is indirect evidence that Methamphetamine and MDMA might affect course of the disease among HIV-1 positive drug-users as evident by higher incidence of HIV-1 infection and increased viral load and as well as neuroinflammation among drug users. Role of dopamine (DA), dopamine transporter (DT), tyrosine hydroxylase (TH) and oxidative stress markers is well established in methamphetamine and MDMA-mediated neurotoxicity. However role of cytokine and chemokine remains under explored. On the other hand HIV is known to cause HIV-associated dementia (HAD) and illicit substances especially opiates have been documented to compound these effects. Two HIV proteins (Tat and gp120) have been studied in great detail for their ability to induce HAD. However, viral Vpr and Nef, though implicated, but not very well studied for their role in HAD. Furthermore, there is only limited information available regarding possible synergy between methamphetamine and MDMA on one hand and different virotoxins on the other. In this proposal we will determine role of cytokines and chemokine in methamphetamine and MDMA-mediated neurotoxicity and find out whether concurrent use of 2 drugs increases neurotoxicity. We will determine role of HIV Vpr and Nef in neurotoxicity which has been relatively unexplored. We will also determine whether there is synergy between illicit drugs and virotoxins and whether neurotoxic effect can be abrogated by use of antagonist and siRNA. These in vitro findings will be extended to in vivo experiments wherein combined effect of methamphetamine or MDMA and virotoxins will be explored in HIV Tat, Nef and gp120 transgenic mice.