Do Psychostimulatory Drugs Enhance Lentivirus Infection?

描述（由申请人提供）：在过去的十年中，甲基苯丙胺（冰毒）的使用与HIV-1感染的发病率上升有关。此外，甲基苯丙胺使用者中迅速进展的HIV-1感染病例强调了确定甲基苯丙胺对HIV-1感染中枢神经系统影响的重要性。这项资助的目的是验证一个假设，即甲基安非他明（可能还有其他精神刺激药物）通过加速感染事件的频率和伴随的逆转录错误的发生率的过程，促进了HIV抗病毒耐药突变体的发展。耐药基因型HIV的出现容易发生在中枢神经系统（CNS），那里的药物浓度可能达不到有效控制HIV复制的最佳水平。同时，由于血脑屏障（BBB）对t细胞运输的限制，中枢神经系统被认为受到免疫系统较少的监视。因此，中枢神经系统是HIV感染、复制、适应和选择的特权位点。此外，中枢神经系统可能是可进入外周细胞室的耐药变异的储存库。该提案有两个具体目标。具体目标1是验证甲基苯丙胺在体外加速耐药慢病毒发展的假设。该目的有四个目标：1 .比较在存在或不存在甲基安非他明的情况下培养的星形胶质细胞和小胶质细胞的AZT耐药FIV的发展速度。目的2：比较在存在或不存在甲基安非他明的情况下培养的星形胶质细胞和小胶质细胞的azt耐药HIV的体外发展速度。目的3：测量甲基安非他明对未感染和慢病毒感染的淋巴细胞、星形胶质细胞和小胶质细胞产生炎症细胞因子的影响，并与这些细胞类型中的病毒表达相关。目的4：确定冰毒是否能增强人类靶细胞的HIV感染，促进细胞增殖并调节CXCR4和/或CCR5的表达。特异性目标#2旨在通过FIV/cat系统的原理验证研究在体内验证这一假设，以评估甲基安非他明对体内AZT耐药性发展的影响。精神刺激药物，包括范围广泛的合法和非法物质，可以改变艾滋病毒的发病机制和影响耐药变异的出现的前景是新的。以前曾有人提出，潜伏在中枢神经系统中的HIV可能有更大的抗药性，但冰毒在这一过程中可能扮演的角色是这一概念的一个新方面。项目描述：中枢神经系统是慢病毒感染的储存库，与外周隔室不同，它允许病毒变异的独立进化，特别是抗病毒耐药突变体。根据我们的观察，我们假设甲基苯丙胺可能会增强中枢神经系统耐药病毒的发展，然后这些病毒可以进入外周隔室。最近在纽约一名冰毒使用者中发生的快速进展的高度耐药HIV-1感染的报告强调了阐明冰毒和HIV-1之间的相互作用以及中枢神经系统耐药发展的重要性。此外，甲基苯丙胺是几种精神药物之一，可能对艾滋病毒感染的中枢神经系统有类似的影响。精神药物可能加速艾滋病毒感染者抗病毒药物耐药性的发展，这是一个重要的公共卫生问题。

DESCRIPTION (provided by applicant): In the last decade, methamphetamine (METH) use has been correlated with a rising incidence of HIV-1 infection. Furthermore, the reported cases of rapidly progressive HIV-1 infection in METH users underscore the importance of determining the influence of METH on infection of the CNS by HIV-1. The purpose of this grant is to test the hypothesis that METH (and possibly other psychostimulatory drugs) enhances the development of antiviral drug resistant mutants of HIV through a process that accelerates the frequency of infection events, and the concomitant incidence of reverse transcription errors. The emergence of drug resistant genotypes of HIV is prone to take place in the central nervous system (CNS) where drug concentrations may be suboptimal for the effective control of HIV replication. At the same time, the CNS is thought to be under less surveillance by the immune system because of restrictions in T-cell trafficking created by the blood-brain-barrier (BBB). Thus, the CNS serves as a privileged site for HIV infection, replication, adaptation and selection. Furthermore, the CNS may be a reservoir for drug-resistant variants that can enter the peripheral compartment. The proposal has two Specific Aims. Specific Aim 1 is to test the hypothesis that METH accelerates the development of drug-resistant lentiviruses in vitro. This Aim has four objectives: #1: Compare the rate of development of AZT resistant FIV for astrocytes and microglia cultured in the presence or absence of METH. Objective #2: Compare the rate of development in vitro of AZT-resistant HIV for astrocytes and microglia cultured in the presence or absence of METH. Objective #3: Measure the effect of METH on inflammatory cytokine production by uninfected and lentivirus-infected lymphocytes, astrocytes and microglia and correlate with virus expression in these cell types. Objective #4: Determine if METH enhances HIV infection of human target cells, promotes cell proliferation and modulates CXCR4 and/or CCR5 expression. Specific Aim #2 is designed to test the hypothesis in vivo via a proof-of-principle study in the FIV/cat system to evaluate the effect of METH on the development of AZT resistance in vivo. The prospect that psychostimulatory drugs, which include a broad range of legal and illegal substances, can alter the pathogenesis of HIV and influence the emergence of drug-resistant variants is novel. The idea that HIV sequestered in the CNS may have more latitude to become drug-resistant has been proposed previously, but the possible role of METH in this process is a new aspect of that concept. PROJECT NARRATIVE: The CNS is a reservoir for lentivirus infection that is distinct from the peripheral compartment and that allows for the independent evolution of virus variants, especially antiviral drug resistant mutants. Based on our observations, we hypothesize that METH may potentiate the development of drug resistant viruses in the CNS, which then can enter the peripheral compartment. The recent report of a rapidly progressive, highly drug resistant HIV-1 infection in a METH user in New York underscores the importance of elucidating the interactions between METH and HIV-1 and the development of drug resistance in the CNS. In addition, METH is one of several psychotropic drugs that may have similar effects on HIV infection of the CNS. The possibility that psychotropic drugs may accelerate the development of antiviral drug resistance in HIV-infected people is an important public health concern.