OPIOIDS EFFECTS ON HIV1 REPLICATION AND REACTIVATION

描述：(申请人摘要) HIV-1感染与静脉注射阿片类药物滥用之间的联系一直是 已经成立了。尽管这些病例中的感染主要与 通过针头传播病毒，药物本身所起的作用 在HIV-1诱导的疾病中，进展在很大程度上是未知的。假设是为了 阿片类药物调节HIV-1复制和重新激活 潜伏病毒。将使用三种策略来检查药物的效果 在艾滋病的发展过程中，虐待是辅助因素。(1)HIV-1在中国复制 对照和阿片类药物治疗植物血凝素(PHA)刺激的外周血细胞 将比较血淋巴细胞(PBL)；(2)潜伏的HIV-1的重新激活 在对照组和阿片类药物处理的慢性感染细胞系ACH-2和 将对U1HIV进行比较；以及(3)我们将确定阿片类药物是否调节 细胞因子、趋化因子及趋化因子受体的表达 已知在调节感染方面很重要，通过嗜T细胞或 嗜巨噬细胞/单核细胞(M)的HIV-1毒株。初步数据支持 海洛因和吗啡在艾滋病毒复制和再激活中的作用。HIV-1 通过测量反向累积来监测复制 共培养后转录酶活性和合胞体的诱导 CD4阳性的SupT1细胞。海洛因治疗增加了RT的积聚 PHA处理的外周血淋巴细胞的活性和合胞体的诱导。海洛因也 增强慢性感染T细胞株ACH-2中HIV-1的表达。 这些初步结果表明，一旦出现HIV-1感染，海洛因 会增加HIV-1的增殖。这种影响至少可以解释 部分原因是由于HIV-1诱导的疾病在静脉注射中进展更快。 吸毒者。此外，我们还使用了RNase保护分析来 证明阿片类药物可以调节趋化因子及其受体 已知对HIV-1感染很重要。在这里，我们建议研究 海洛因、吗啡、美沙酮和可卡因对HIV-1复制和免疫功能的影响 延迟重新激活。此外，特异性阿片受体的作用 更改中涉及的类型将使用高度选择性确定 激动剂和拮抗剂。

DESCRIPTION: (Applicant's Abstract) An association between HIV-1 infection and intravenous opioid abuse has been established. Though infection in these cases is linked primarily to transmission of virus through needle use, the role the drugs themselves play in HIV-1-induced disease progression is largely unknown. The hypothesis to be tested is that opioids modulate HIV-1 replication and reactivation of latent virus. Three strategies will be used to examine the effect of drugs of abuse as cofactors on the progression of AIDS. (1) HIV-1 replication in control and opioid-treated phytohemagglutinin (PHA)-stimulated peripheral blood lymphocytes (PBLs) will be compared; (2) reactivation of latent HIV-1 in control and opioid-treated chronically infected cell lines ACH-2 and U1HIV will be compared; and (3) we will determine whether opioids modulate the expression of cellular cytokines, chemokines and chemokine receptors known to be important in regulating infection by either T cell-tropic or macrophage/monocyte (M)-tropic strains of HIV-1. Preliminary data support a role for heroin and morphine in HIV replication and reactivation. HIV-1 replication was monitored by measuring the accumulation of reverse transcriptase (RT) activity and syncytia induction after coculture with CD4-positive SupT1 cells. Heroin treatment enhanced the accumulation of RT activity and syncytia induction by PHA-treated PBLs. Heroin also potentiated HIV-1 expression in chronically infected T cell line ACH-2. These preliminary results suggest that once HIV-1 infection occurs, heroin can increase the proliferation of HIV-1. This effect may account, at least in part, for the more rapid progression of HIV-1-induced disease in i.v. drug abusers. In addition, we have used RNase protection assays to demonstrate that opioids can modulate chemokine and chemokine receptors known to be important for HIV-1 infection. Here we propose to examine the effects of heroin, morphine, methadone and cocaine on HIV-1 replication and latency reactivation. Furthermore, the role of specific opioid receptor types involved in the changes will be determined using highly selective agonists and antagonists.