In Vivo Modeling of Methamphetamine and HIV Interactions

甲基苯丙胺和艾滋病毒相互作用的体内模型

• 批准号: 7286836
• 负责人: GAYLE COCITA BALDWIN
• 金额: $ 18.75万
• 依托单位: UNIVERSITY OF CALIFORNIA LOS ANGELES
• 依托单位国家: 美国
• 财政年份: 2006
• 资助国家: 美国
• 起止时间: 2006-09-05 至 2009-07-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7286836
• 关键词: Acute; Address; Adrenergic Antagonists; Affect; Autonomic nervous system; B-Lymphocytes; Cell physiology; Cell surface; Cells; Chimera organism; Chronic; Clinical; Clinical Research; Cocaine; Cocaine Abuse; Communities; Dendritic Cells; Dependence; Development; Disease Progression; Epidemic; Goals; HIV; HIV Infections; HIV Receptors; HIV Seropositivity; Heterosexuals; Human; Immune; Immune System Diseases; Immune system; Immunity; Immunologic Deficiency Syndromes; Immunologics; Immunosuppression; Immunosuppressive Agents; Individual; Inflammatory; Injection of therapeutic agent; Injury; Interferon Type II; Lead; Leukocytes; Mediating; Mediator of activation protein; Methamphetamine; Modeling; Mus; Opportunistic Infections; Pathogenesis; Pattern; Peptides; Peripheral Blood Mononuclear Cell; Pharmacotherapy; Phytohemagglutinins; Pike fish; Population; Populations at Risk; Predisposition; Production; Propranolol; Public Health; Publishing; Rate; Relative (related person); Research Design; Research Personnel; Safety; Serum; T-Lymphocyte; Testing; Therapeutic immunosuppression; Time; Work; base; chemokine; chemokine receptor; cohort; cytokine; design; drug of abuse; functional disability; in vivo; in vivo Model; intravenous administration; macrophage; men; men who have sex with men; monocyte; novel; peripheral blood; programs; response; volunteer

DESCRIPTION (provided by applicant): HIV infection produces sweeping effects on the immune system; the consequences of these include the permissive expansion and replication of HIV, inflammatory injury and a profound immunodeficiency that facilitates the development of opportunistic infections. Based on the rationale that agents that promote a similar pattern of immune dysfunction could enhance HIV pathogenesis we have been investigating the impact of non-injection drugs of abuse on HIV pathogenesis. Using a mouse/human chimera model, we published the first direct evidence that cocaine enhances HIV replication and alters the expression and function of human immune cells in vivo. Although the impact of cocaine abuse on disease progression in HIV-positive individuals continues to be a major public health concern, increases in the use and abuse of another stimulant, methamphetamine (MA), has recently reached crisis proportions in both the HIV- seronegative and the HIV seropositive population. In effect, HIV and the use of MA have become a "double epidemic" over the past decade. Based on our previous work and what may be viewed as a public health imperative in the HIV-seropositve community, we have hypothesized that the immune modulating effects of MA will increase susceptibility to HIV infection and disease progression. To test this hypothesis, we will utilize a within-subjects study design to investigate and define the immunologic impact of experimentally administered MA in non-treatment seeking MA-dependent volunteers, who are either HIV-seropositive or HIV-seronegative. The specific aims include: Aim 1. To define immunologic parameters, pertinent to HIV infection, that may be modulated in chronic MA users following protracted use and following experimental administration of intravenous MA in a controlled clinical setting. Aim 2. To evaluate the significance of increased autonomic nervous system (ANS) activity as a potential mechanism by which MA may alter HIV infectivity and HIV-relevant immune parameters. Ultimately, defining the mechanisms underlying the interaction between MA and HIV may lead to the identification of novel pharmacotherapies designed to curb the accelerated disease progression in this unique population.

描述（由申请人提供）：HIV 感染对免疫系统产生全面影响；这些后果包括艾滋病毒的扩张和复制、炎症损伤以及促进机会性感染发展的严重免疫缺陷。基于促进类似免疫功能障碍模式的药物可能增强艾滋病毒发病机制的基本原理，我们一直在研究滥用非注射药物对艾滋病毒发病机制的影响。使用小鼠/人类嵌合体模型，我们发表了第一个直接证据，证明可卡因可增强 HIV 复制并改变体内人类免疫细胞的表达和功能。尽管可卡因滥用对艾滋病毒阳性个体疾病进展的影响仍然是一个主要的公共卫生问题，但另一种兴奋剂甲基苯丙胺 (MA) 的使用和滥用最近在艾滋病毒血清阴性和艾滋病毒阳性个体中都达到了危机程度。 HIV 血清阳性人群。实际上，艾滋病毒和 MA 的使用在过去十年中已成为“双重流行病”。根据我们之前的工作以及 HIV 血清阳性社区的公共卫生必要性，我们假设 MA 的免疫调节作用将增加对 HIV 感染和疾病进展的易感性。为了检验这一假设，我们将利用受试者内研究设计来调查和定义实验性给予 MA 对非治疗寻求 MA 依赖志愿者（HIV 血清阳性或 HIV 血清阴性）的免疫学影响。具体目标包括： 目标 1. 确定与 HIV 感染相关的免疫参数，这些参数可以在长期使用 MA 的长期使用者中以及在受控临床环境中进行静脉 MA 实验给药后进行调节。目标 2. 评估自主神经系统 (ANS) 活性增加作为 MA 改变 HIV 感染性和 HIV 相关免疫参数的潜在机制的重要性。最终，明确 MA 和 HIV 之间相互作用的机制可能会导致确定新的药物疗法，旨在遏制这一独特人群中疾病的加速进展。