Retinoids and Substances of Abuse in HIV-1 Infection

描述：(申请人提供)神经系统疾病在HIV感染中有 与对神经系统组织造成的损伤有关 促炎细胞因子和其他可溶性因子由 活化的单核巨噬细胞(MP)。在这份提案中，我们将研究 维甲酸抑制免疫系统促炎活性的机制 来自HIV感染者和免疫细胞系的细胞。维甲酸， 它们是与维生素A相关的化合物，已经被证明可以抑制这种 免疫活性，在m-1感染的研究中，可以抑制复制 病毒在感染的单核细胞系中。在感染HIV-1(HIV)的个人中 感染，缺乏维生素A会增加罹患 出现与艾滋病毒相关的并发症。然而，在大多数情况下， 在临床试验中服用维生素A并不与 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 感染艾滋病毒的人比未感染的人更多，并表明这样的 脑脊液中可观察到异常；2)血浆视黄醇水平在 血清阴性的慢性炎症性神经疾病患者比 非炎症性神经系统疾病的对照研究及治疗 这些带有免疫调节剂的个体与特定的 对维甲酸受体亚型表达模式的影响；3)维甲酸化合物 抑制外周血免疫细胞产生促炎细胞因子 和细胞系，在细胞系中，维甲酸诱导的抑制 同时将细胞暴露于吗啡或其他物质可抑制细胞活性。 可卡因。因此，我们提出这项建议的目的如下：1) 检测单个核细胞促炎性细胞因子-α的表达 有或没有HIV病史的鸦片使用者和非吸毒者的细胞 感染；2)检测特异性维甲酸受体激活的影响 维甲酸诱导的单个核细胞免疫效应的研究 检查滥用物质(吗啡和可卡因)对 维甲酸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；以及4)并评估 维甲酸类物质对核内核因子-KB结合的抑制作用 滥用患者细胞产生的促炎细胞因子 单核细胞系。这些研究将扩大我们对 维甲酸类化合物对HIV感染者的免疫作用，并可能 导致有效的方法来治疗感染和其 维生素A的并发症

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.