This proposal is designed to test the hypothesis that cocaine and the newly described cocaine-alcohol metabolite, cocaethylene, have synergistic effects on HIV infection in vivo and in vitro. This proposal capitalizes on the high incidence of cocaine use and AIDS in Dade County, Florida. The cohort for the proposed studies will be selected from the Miami Outreach Project, a study designed to determine the extent and risk of HIV infection associated with crack cocaine use. Ongoing epidemiological studies of crack cocaine and HIV in Miami currently assess the history, nature, frequency and social context of drug use and sexual behaviors. The increased incidence and progression of AIDS in drug users may result from a number of different factors, including 1.) needle sharing, 2.) multiple sexual partners, 3.) drug-induced impairment of the immune system, and 4.) activation of HIV-1 by co-infection with HTLV-I or II. This proposal seeks funds to provide evidence for a direct action of cocaine and cocaethylene on HIV expression, infectivity and replication. Using a standardized interview instrument, 100 African-American women, who are HIV seropositive, will be divided into two subgroups based on the frequency of cocaine use: 1.) cocaine users with elevated cocaine/cocaethylene and 2.) subjects who are very infrequent users with low to negligible levels of these compounds. Detection of drug and metabolite levels will be confirmed in toxicology screens by GC/MS analysis. Virus load will be determined in plasma and PBMNCs obtained from these subjects to determine if there is increased virus replication associated with specific drug use patterns. Bioprofile studies using HIV-1 isolated from blood lymphocytes and monocyte/macrophages will determine the influence of drug use on tropisms of the isolates. A comparison of the virulence of the HIV-1 isolates and stimulatory effects of cocaine, cocaethylene, and ethanol on HIV replication in these cells will also be determined. Statistical analysis will assess the effects of drug use frequency, route of administration (IV vs. non-IV), and numbers of sexual partners on virus load, bioprofile, and disease progression. The effects of the cocaine and cocaethylene on different phases of the virus life cycle including expression, virus production, assembly, infectivity, and tropism will be evaluated in molecular viral studies. Using a uniquely developed recombinant pseudovirus system with envelope sequences derived from HIV isolated from the drug users, the direct effects of cocaine and cocaethylene on the phases of HIV replication will be assessed.

Agency
National Institute of Health (NIH)
Institute
National Institute on Drug Abuse (NIDA)
Type
Research Project (R01)
Project #
1R01DA007909-01
Application #
3214495
Study Section
Sociobehavioral Subcommittee (DAAR)
Project Start
1992-07-15
Project End
1997-06-30
Budget Start
1992-07-15
Budget End
1993-06-30
Support Year
1
Fiscal Year
1992
Total Cost
Indirect Cost
Name
University of Miami School of Medicine
Department
Type
Schools of Medicine
DUNS #
City
Miami
State
FL
Country
United States
Zip Code
33146
Duncan, Robert; Shapshak, Paul; Page, J Bryan et al. (2007) Crack cocaine: effect modifier of RNA viral load and CD4 count in HIV infected African American women. Front Biosci 12:1488-95
Chiappelli, Francesco; Shapshak, Paul; Younai, Fariba et al. (2006) Cellular immunology in HIV-1 positive African American women using alcohol and cocaine. Front Biosci 11:2434-41
Duran, Elda M; Shapshak, Paul; Worley, Jason et al. (2005) Presenilin-1 detection in brain neurons and FOXP3 in peripheral blood mononuclear cells: normalizer gene selection for real time reverse transcriptase pcr using the deltadeltaCt method. Front Biosci 10:2955-65
Shapshak, Paul; Duncan, Robert; McCoy, Clyde B et al. (2005) Quantification of HIV GAG RNA using real time reverse transcriptase PCR. Front Biosci 10:135-42
Fujimura, Robert K; Khamis, Imad; Shapshak, Paul et al. (2004) Regional quantitative comparison of multispliced to unspliced ratios of HIV-1 RNA copy number in infected human brain. J NeuroAIDS 2:45-60
Minagar, Alireza; Shapshak, Paul; Duran, Elda M et al. (2004) HIV-associated dementia, Alzheimer's disease, multiple sclerosis, and schizophrenia: gene expression review. J Neurol Sci 224:3-17
Shapshak, Paul; Duncan, Robert; Minagar, Alireza et al. (2004) Elevated expression of IFN-gamma in the HIV-1 infected brain. Front Biosci 9:1073-81
Kuljis, Rodrigo O; Shapshak, Paul; Alcabes, Philip et al. (2002) Increased density of neurons containing NADPH diaphorase and nitric oxide synthase in the cerebral cortex of patients with HIV-1 infection and drug abuse. J NeuroAIDS 2:19-36
Minagar, Alireza; Shapshak, Paul; Fujimura, Robert et al. (2002) The role of macrophage/microglia and astrocytes in the pathogenesis of three neurologic disorders: HIV-associated dementia, Alzheimer disease, and multiple sclerosis. J Neurol Sci 202:13-23
Shapshak, P; Segal, D M; Crandall, K A et al. (1999) Independent evolution of HIV type 1 in different brain regions. AIDS Res Hum Retroviruses 15:811-20

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