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.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
5R01DA012113-02
Application #
2898296
Study Section
Human Development Research Subcommittee (NIDA)
Program Officer
Sharp, Charles
Project Start
1998-08-01
Project End
2001-05-31
Budget Start
1999-06-01
Budget End
2000-05-31
Support Year
2
Fiscal Year
1999
Total Cost
Indirect Cost
Name
Temple University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
City
Philadelphia
State
PA
Country
United States
Zip Code
19122
Raymond, Andrea D; Hasham, Muneer; Tsygankov, Alexander Y et al. (2007) Herpesvirus saimiri terminal membrane proteins modulate HIV-1 replication by altering Nef and Tat functions. Curr HIV Res 5:79-86
Raymond, Andrea D; Hasham, Muneer; Tsygankov, Alexander Y et al. (2006) H. saimiri tyrosine-kinase interacting protein inhibits Tat function: a prototypic strategy for restricting HIV-1-induced cytopathic effects in immune cells. Virology 352:253-67
Turner, Lorianne Stehouwer; Tsygankov, Alexander Y; Henderson, Earl E (2006) StpC-based gene therapy targeting latent reservoirs of HIV-1. Antiviral Res 72:233-41
Raymond, Andrea D; Hasham, Muneer G; Tsygankov, Alexander Y et al. (2004) Herpesvirus saimiri-encoded proteins Tip and StpC modulate human immunodeficiency virus type 1 replication in T-cell lines and lymphocytes independently of viral tropism. Virology 324:60-6
Steele, Amber D; Henderson, Earl E; Rogers, Thomas J (2003) Mu-opioid modulation of HIV-1 coreceptor expression and HIV-1 replication. Virology 309:99-107
Wetzel, Michele A; Steele, Amber D; Henderson, Earl E et al. (2002) The effect of X4 and R5 HIV-1 on C, C-C, and C-X-C chemokines during the early stages of infection in human PBMCs. Virology 292:6-15
Le, Y; Wetzel, M A; Shen, W et al. (2001) Desensitization of chemokine receptor CCR5 in dendritic cells at the early stage of differentiation by activation of formyl peptide receptors. Clin Immunol 99:365-72
Li, B Q; Wetzel, M A; Mikovits, J A et al. (2001) The synthetic peptide WKYMVm attenuates the function of the chemokine receptors CCR5 and CXCR4 through activation of formyl peptide receptor-like 1. Blood 97:2941-7
Szabo, I; Wetzel, M; McCarthy, L et al. (2001) Interactions of opioid receptors, chemokines, and chemokine receptors. Adv Exp Med Biol 493:69-74
Wetzel, M A; Steele, A D; Eisenstein, T K et al. (2000) Mu-opioid induction of monocyte chemoattractant protein-1, RANTES, and IFN-gamma-inducible protein-10 expression in human peripheral blood mononuclear cells. J Immunol 165:6519-24