OPIOIDS EFFECTS ON HIV1 REPLICATION AND REACTIVATION

阿片类药物对 HIV1 复制和重新激活的影响

基本信息

批准号：
6175567
负责人：
EARL E HENDERSON
金额：
$ 24.08万
依托单位：
TEMPLE UNIV OF THE COMMONWEALTH
依托单位国家：
美国
项目类别：
财政年份：
1998
资助国家：
美国
起止时间：
1998-08-01 至 2003-05-31
项目状态：
已结题

项目摘要

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.

描述：（申请人的摘要） HIV-1感染与静脉注射阿片类药物滥用之间的关联已经存在已确立的。尽管在这些情况下感染主要与通过使用针头传播病毒，药物本身的作用在HIV-1诱导的疾病进展中，基本上未知。假设接受测试是阿片类药物调节HIV-1复制和重新激活潜在病毒。将使用三种策略来检查药物的影响滥用作为辅助进展的辅助因子。（1）HIV-1复制对照和阿片类药物处理的植物凝血素（PHA）刺激的周围将比较血液淋巴细胞（PBL）；（2）潜伏HIV-1的重新激活在对照和阿片类药物治疗的长期感染细胞系ACH-2和将比较U1HIV；（3）我们将确定阿片类药物是否调节细胞细胞因子，趋化因子和趋化因子受体的表达已知在调节T细胞 - 嗜热或 HIV-1的巨噬细胞/单核细胞（M） - 热带菌株。初步数据支持海洛因和吗啡在HIV复制和重新激活中的作用。 HIV-1 通过测量反向的积累来监测复制转录酶（RT）活性和合成诱导与与 CD4阳性SUPT1细胞。海洛因治疗增强了RT的积累 PHA处理的PBL的活性和合成诱导。海洛因也是在慢性感染的T细胞系ACH-2中增强的HIV-1表达。这些初步结果表明，一旦发生HIV-1感染，海洛因可以增加HIV-1的增殖。这种效果至少可以说明在某种程度上，在静脉注射中，HIV-1诱导的疾病的进展更快吸毒者。此外，我们已经使用RNase保护测定法证明阿片类药物可以调节趋化因子和趋化因子受体已知对于HIV-1感染很重要。在这里，我们建议检查海洛因，吗啡，美沙酮和可卡因对HIV-1复制的影响潜伏期重新激活。此外，特定阿片类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对手。