Do Psychostimulatory Drugs Enhance Lentivirus Infection?

精神刺激药物会增强慢病毒感染吗？

• 批准号: 7419096
• 负责人: LAWRENCE E MATHES
• 金额: $ 22.5万
• 依托单位: OHIO STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2007
• 资助国家: 美国
• 起止时间: 2007-09-15 至 2009-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7419096
• 关键词: Astrocytes; Blood - brain barrier anatomy; CCR5 gene; CXCR4 gene; Case Study; Cell Proliferation; Cells; Central Nervous System Agents; Central Nervous System Infections; Development; Drug resistance; Event; Evolution; Feline Immunodeficiency Virus; Felis catus; Frequencies; Genotype; Grant; HIV; HIV Infections; HIV-1; HIV-1 drug resistance; Human; Immune system; In Vitro; Incidence; Infection; Inflammatory; Legal; Lentivirus Infections; Lymphocyte; Measures; Medical Surveillance; Methamphetamine; Microglia; Neuraxis; New York; Pathogenesis; Peripheral; Pharmaceutical Preparations; Process; Production; Psychotropic Drugs; Public Health; Purpose; Range; Rate; Reporting; Reverse Transcription; Role; Site; Subfamily lentivirinae; System; T-Lymphocyte; Testing; Thinking; Time; Variant; Viral Drug Resistance; Virus; Zidovudine resistance; base; cell type; concept; cytokine; design; drug resistant virus; in vivo; mutant; novel; trafficking

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.

描述（由申请人提供）：在过去十年中，甲基苯丙胺（METH）的使用与HIV-1感染发病率的上升有关。此外，METH使用者中快速进展的HIV-1感染病例报告强调了确定METH对HIV-1感染CNS的影响的重要性。这项资助的目的是检验METH（以及可能的其他精神刺激药物）通过加速感染事件频率以及伴随的逆转录错误发生率的过程增强HIV抗病毒药物耐药性突变体的发展的假设。HIV耐药基因型的出现倾向于发生在中枢神经系统（CNS）中，其中药物浓度对于有效控制HIV复制而言可能是次优的。与此同时，CNS被认为受到免疫系统的监视较少，因为血脑屏障（BBB）限制了T细胞的运输。因此，CNS作为HIV感染、复制、适应和选择的特权位点。此外，CNS可能是耐药变异体的储存库，这些变异体可以进入外周室。该提案有两个具体目标。具体目的1是检验METH在体外加速耐药慢病毒发展的假设。该目标有四个目标：第一名：比较在METH存在或不存在的情况下培养的星形胶质细胞和小胶质细胞的AZT抗性FIV的发展速率。目的#2：比较在METH存在或不存在的情况下培养的星形胶质细胞和小胶质细胞的AZT耐药HIV的体外发展速率。目标三：测量METH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的炎性细胞因子产生的影响，并与这些细胞类型中的病毒表达相关。目的#4：确定METH是否增强人类靶细胞的HIV感染，促进细胞增殖并调节CXCR 4和/或CCR 5表达。具体目标#2旨在通过FIV/猫系统中的原理验证研究在体内检验假设，以评价METH对体内AZT耐药性发展的影响。包括广泛的法律的和非法物质的精神刺激药物可以改变艾滋病毒的发病机制并影响耐药变体的出现，这一前景是新颖的。以前已经提出了在CNS中隔离的HIV可能有更多的自由度变得耐药的想法，但是METH在这个过程中可能的作用是这个概念的一个新方面。项目叙述：CNS是慢病毒感染的储库，其不同于外周区室，并且允许病毒变体（特别是抗病毒药物抗性突变体）的独立进化。根据我们的观察，我们假设METH可能会增强CNS中耐药病毒的发展，然后这些耐药病毒可以进入外周室。最近的一份报告显示，纽约的一名METH使用者感染了一种进展迅速、高度耐药的HIV-1，这突出说明了阐明METH和HIV-1之间的相互作用以及CNS中耐药性发展的重要性。此外，METH是可能对CNS的HIV感染具有类似作用的几种精神药物之一。精神药物可能加速艾滋病毒感染者产生抗病毒药物耐药性的可能性是一个重要的公共卫生问题。