Retinoids and Substances of Abuse in HIV-1 Infection

HIV-1 感染中的类视黄醇和滥用物质

• 批准号: 6627806
• 负责人: WALTER ROYAL
• 金额: $ 34.14万
• 依托单位: MOREHOUSE SCHOOL OF MEDICINE
• 依托单位国家: 美国
• 财政年份: 2002
• 资助国家: 美国
• 起止时间: 2002-05-15 至 2007-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6627806
• 关键词: HIV infections; cell line; clinical research; cocaine; cytokine; human immunodeficiency virus 1; human subject; immunomodulators; leukocyte activation /transformation; monocyte; morphine; neuropathology; nuclear factor kappa beta; opiate alkaloid; opioid receptor; patient oriented research; phagocytes; posttranslational modifications; receptor expression; retinoids; substance abuse related disorder; tumor necrosis factor alpha; virus replication; vitamin receptor

DESCRIPTION: (provided by applicant) Neurologic disease in HIV infection has been associated with damage to nervous system tissue induced by pro-inflammatory cytokines and other soluble factors that are released by activated mononuclear phagocytes (MP). In this proposal, we will examine mechanisms by which retinoids suppress pro-inflammatory activity in immune cells from individuals with HIV infection and in immune cell lines. Retinoids, which are vitamin A-related compounds, have been demonstrated to suppress such immune activity, and, in studies of m -1 infection, can suppress replication of virus in infected mononuclear cell lines. Among individuals with HIV-1 (HIV) infection, vitamin A deficiency has been associated with an increased risk of developing HIV-related complications. However, in most cases, the administration of vitamin A in clinical trials has not been associated with improvement in HIV-related clinical parameters. Our prior studies demonstrate that 1) parameters of vitamin A metabolism in plasma are lower among HIV-infected individuals than among non-infected subjects and suggest that such abnormalities can be observed in CSF; 2) plasma retinol levels are lower in seronegative patients with chronic inflammatory neurologic disease than in control subjects with non-inflammatory neurologic disease and treatment of these individuals with an immunomodulatory agent is associated with specific effects on retinoid receptor subtype expression patterns; 3) retinoid compounds suppress pro-inflammatory cytokine production by peripheral blood immune cells and cell lines and that, in the cell lines, retinoid-induced suppressive activity can be inhibited by simultaneous exposure of the cells to morphine or cocaine. Therefore, we propose the following aims for this proposal: 1) to examine the expression of pro-inflammatory cytokine (TNF-a) by mononuclear cells from opiate users and non-drug users with or without a history of HIV infection; 2) to examine the effects of specific retinoid receptor activation on the immune effects elicited in retinoid-exposed mononuclear cell lines; 3) to examine the effects of substances of abuse (morphine and cocaine) on specific immune responses induced by retinoid receptor agonists and receptor antagonists in mononuclear cell lines; and 4) and to assess the role of inhibition of nuclear NF-KB binding in the effects of retinoids and substances of abuse on pro-inflammatory cytokine production by the patient cells and by the mononuclear cell lines. These studies will broaden our understanding of the immune effects of retinoid compounds in individuals with HIV infection, and may lead to effective approaches to the treatment of the infection and its complications with vitamin A.

描述：（由申请人提供）HIV 感染引起的神经系统疾病已 与神经系统组织损伤有关 促炎细胞因子和其他可溶性因子 激活的单核吞噬细胞（MP）。在本提案中，我们将研究 类维生素A抑制免疫系统促炎活性的机制 来自艾滋病毒感染者和免疫细胞系的细胞。类维生素A， 维生素 A 相关化合物已被证明可以抑制这种现象 免疫活性，并且在 m -1 感染的研究中，可以抑制复制 受感染的单核细胞系中的病毒。 HIV-1 (HIV) 感染者 感染，维生素 A 缺乏与感染风险增加有关 出现与艾滋病毒相关的并发症。然而，在大多数情况下， 临床试验中服用维生素 A 尚未发现与 HIV相关临床参数的改善。我们之前的研究表明 1) 血浆中维生素A代谢参数较低 HIV 感染者的比例高于未感染者，这表明 脑脊液中可观察到异常； 2）血浆视黄醇水平较低 患有慢性炎症性神经系统疾病的血清阴性患者比 患有非炎症性神经系统疾病的对照受试者和治疗 这些具有免疫调节剂的个体与特定的 对类维生素A受体亚型表达模式的影响； 3) 类视黄醇化合物 抑制外周血免疫细胞产生促炎细胞因子 和细胞系，并且在细胞系中，类维生素A诱导的抑制 细胞同时暴露于吗啡或 可卡因。因此，我们提出本提案的以下目标：1） 通过单核细胞检查促炎细胞因子（TNF-a）的表达 来自阿片类药物使用者和有或没有艾滋病毒病史的非吸毒者的细胞 感染; 2) 检查特定视黄醇受体激活的影响 对类维生素A暴露的单核细胞系引起的免疫效应的影响； 3） 检查滥用物质（吗啡和可卡因）对人的影响 类维生素A受体激动剂和受体诱导的特异性免疫反应 单核细胞系中的拮抗剂； 4) 并评估其作用 类视黄醇和物质作用中抑制核 NF-KB 结合 滥用患者细胞产生的促炎细胞因子和 单核细胞系。这些研究将加深我们对 类视黄醇化合物对 HIV 感染者的免疫影响，并且可能 从而找到治疗感染及其相关疾病的有效方法 维生素A引起的并发症。