OPIOIDS EFFECTS ON HIV1 REPLICATION AND REACTIVATION

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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.