OPIOIDS EFFECTS ON HIV1 REPLICATION AND REACTIVATION

描述：（申请人摘要） HIV-1感染和静脉注射阿片类药物滥用之间的关联已经被证实。 确立了习 虽然这些病例中的感染主要与 通过使用针头传播病毒，药物本身所起的作用 在HIV-1诱导的疾病进展中的作用尚不清楚。 假设， 阿片类药物可以调节HIV-1的复制和激活， 潜伏病毒 三种策略将用于检查药物的效果 滥用作为艾滋病发展的辅助因素。 (1)中的HIV-1复制 对照和阿片样物质处理的植物血凝素（PHA）刺激的外周血 将比较血液淋巴细胞（PBL）;（2）潜伏HIV-1的再活化 在对照和阿片样物质处理的慢性感染细胞系ACH-2和 U1 HIV将进行比较;（3）我们将确定阿片类药物是否调节 细胞因子、趋化因子和趋化因子受体的表达 已知在调节T细胞嗜性或 巨噬细胞/单核细胞（M）嗜性HIV-1菌株。 初步数据支持a 海洛因和吗啡在HIV复制和再激活中的作用。 HIV-1 通过测量逆转录酶的积累来监测复制。 转录酶（RT）活性和合胞体诱导后共培养 CD 4阳性SupT 1细胞。 海洛因治疗增加了RT的积累 活性和PHA处理的PBL的合胞体诱导。 海洛因也 在慢性感染的T细胞系ACH-2中增强HIV-1表达。 这些初步结果表明，一旦发生HIV-1感染， 可以增加HIV-1的扩散。 这种影响至少可以解释 在一定程度上，对于HIV-1诱导的疾病在i. v. 吸毒者 此外，我们还使用RNase保护试验， 表明阿片类药物可以调节趋化因子和趋化因子受体 已知对HIV-1感染很重要。 在这里，我们建议审查 海洛因、吗啡、美沙酮和可卡因对HIV-1复制的影响， 延迟再激活。 此外，特异性阿片受体的作用 将使用高度选择性的 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.