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）：艾滋病毒感染对免疫系统产生巨大影响；这些后果包括艾滋病毒的允许性扩张和复制，炎症性损伤以及促进机会性感染发展的严重免疫缺陷。基于这样的理由：促进类似的免疫功能障碍模式的药物可以增强HIV发病机理，我们一直在研究非注射药物对HIV发病机理的影响。使用小鼠/人类嵌合体模型，我们发布了第一个直接证据，表明可卡因增强了HIV复制并改变了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的疾病进展的影响仍然是一个主要的公共卫生问题，但对另一种刺激性甲基苯丙胺（MA）的使用和滥用增加和滥用，最近在HIV-Seronegative和HIV血清阳性人群中都达到了危机比例。实际上，在过去的十年中，艾滋病毒和MA的使用已成为一种“双重流行病”。根据我们以前的工作，以及在HIV - 近亲群体社区中可能被视为公共卫生的必要性，我们假设MA的免疫调节作用将增加对HIV感染和疾病进展的敏感性。为了检验这一假设，我们将利用受试者内的研究设计来研究和定义实验施用的MA在寻求MA依赖性志愿者（HIV - 呼吸阳性或HIV-辅助性）的非治疗中的免疫学影响。具体目的包括：目标1。定义与艾滋病毒感染有关的免疫学参数，在持久使用后，可以在慢性MA使用者中调节，并在受控的临床环境中对静脉内MA进行了实验。目的2。评估自主神经系统（ANS）活性增加的重要性，作为MA可以改变HIV感染性和与HIV相关的免疫参数的潜在机制。最终，定义MA和HIV之间相互作用的基础机制可能导致鉴定出旨在遏制这种独特人群加速疾病进展的新型药物疗法。