Opoid and Retinoid Interactions in the HIV-1 Transgenic Rat

描述（由申请人提供）：HIV-1转基因大鼠，包含复制缺陷的HIV-1基因组，发展出许多人类HIV疾病的免疫学和临床表现，包括神经系统受累。HIV感染中的神经系统疾病与激活的单核细胞释放的促炎细胞因子和其他可溶性因子诱导的神经系统组织损伤有关。这些影响在阿片类药物使用者中被观察到增强。类维生素a已被证明可以抑制这种免疫活性，并且在HIV-1感染的研究中，可以抑制病毒在感染的单核细胞系中的复制。维生素A的细胞效应是通过特异性结合维甲酸受体（RAR）和类维甲酸X受体（RXR）介导的。我们之前已经证明RAR和RXR的激活可以抑制人类细胞系的促炎细胞因子（TNF-a）的产生，吗啡可以抑制RXR介导的TNF-a抑制。RXR的激活也增加了mu阿片受体（MOR）的表达。这些观察结果的临床意义和这些影响背后的机制尚不清楚。因此，在这项拨款中，我们将使用HIV-1转基因大鼠模型来研究类维生素a的作用。本研究的目的是：(1)评估类维甲酸激动剂和拮抗剂以及吗啡对体外HIV-1转基因大鼠单核细胞促炎反应的影响；(2)观察类视黄醇激动剂、拮抗剂和吗啡的激活和暴露对转基因和对照大鼠免疫细胞MOR表达的影响；(3)观察类维甲酸激动剂、拮抗剂和吗啡对转基因和对照大鼠免疫细胞HIV-1基因表达的影响；(4)观察维生素A缺乏和吗啡对HIV-1转基因大鼠和对照大鼠临床状态的影响。这些研究将有助于更好地理解类维生素a代谢和阿片类药物在艾滋病毒感染的发病机制中的作用，更具体地说，在吸毒者神经系统疾病的发生中。

DESCRIPTION (provided by applicant): The HIV-1 transgenic rat, which incorporates a replication-defective HIV-1 genome, develops a number of the immunological and clinical manifestations of human HIV disease, including nervous system involvement. Neurological disease in HIV infection has been associated with damage to nervous system tissue induced by proinflammatory cytokines and other soluble factors that are released by activated mononuclear cells. These effects have been observed to be enhanced in opioid users. Retinoids have been demonstrated to suppress such immune activity, and, in studies of HIV-1 infection, can suppress replication of virus in infected mononuclear cell lines. The cellular effects of vitamin A are mediated by specific binding to retinoic acid receptor (RAR) and retinoid X receptor (RXR). We have previously demonstrated that RAR and RXR activation can suppress proinflammatory cytokine (TNF-a) production by human cell lines and that morphine can inhibit RXR-mediated TNF-a suppression. RXR activation also increased mu opioid receptor (MOR) expression. The clinical implications of these observations and the mechanisms that underlie these effects are unclear. Therefore, in this grant we will examine the effects of retinoids using the HIV-1 transgenic rat model. The aims of this proposal are to (1) To assess the effects of retinoid agonists and antagonists and morphine on proinflammatory responses by mononuclear cells from the HIV-1 transgenic and control rats in vitro; (2) To examine the effects of activation and exposure to retinoid agonists and antagonists and morphine on MOR expression by immune cells from transgenic and control rats; (3) To examine the effects of retinoid agonists and antagonists and morphine on HIV-1 gene expression by immune cells from transgenic and control rats; and (4) To examine the effects of vitamin A deficiency and morphine on the clinical status of HIV-1 transgenic and control rats. These studies will be useful for better understanding the role of retinoid metabolism and opioids in the pathogenesis of HIV infection in general and, more specifically, in the occurrence of nervous system disease in drug users.