We were the first to report that HIV proteins express unique, immunoregulatory activities that may be extra-infectious mediators of the pathogenesis of AIDS. Next we studied the molecular mecnanisms underlying the effects of viral proteins in the development of the immnunodeficiency and neuropathological complications of AIDS. Also we had a long-standing interest in the role of i.v., recreational drugs as co-factors in susceptibility to and progression of HIV infections. These interests merged in a series of studies demonstrating that opioids potentiate several immunopathogenic mechanisms mediated by HIV proteins. Thus our preliminary results support the success of this proposal. Several experimental approaches will be used to determine the molecular mechanism underlying the synergy between HIV proteins and opioids. Human lymphocytes will be cultured with HIV proteins + morphine to look for further potentiation of the shift from Th-1 to Th-2 lymphocyte predominance that we showed was mediated by HIV proteins alone. This will be accomplished by examining both gene expression and production of Th-1 and Th-2 defining cytokines. Further we shall determine whether opioids synergize with HIV proteins in vitro to induce apoptosis of lymphocytes or purified microglia and astrocytes from rat brains to determine the effects of opioids and HIV proteins on the immune system and the CNS respectively. Control experiments using the mu-specific opioid antagonists, naloxone and beta funaltrexamine, will assure the specificity of opioid-mediated effects. In vivo confirmation of our in vitro CNS findings will be undertaken using our established rat mode1 wherein HIV proteins + excitatory amino acid agonists + morphine will be stereotactically injected into the dorsal hippocampus. Brain slices will be examined for gross and microscopic pathology. Identification of markers for apoptosis as well as expression of specific cytokine genes will be determined in brain sections by direct hybridization and a new, in situ, PCR method. Lastly we shall follow-up on the exciting new findings that the beta-chemokines and their receptors affect susceptibility to and progression of HIV infections. Recently, we reported that morphine modulates the expression of the beta-chemokines and their receptors. Now we shall determine the molecular mechanisms underlying these effects. Subsequent experiments will compare and contrast clinical materials from HIV- and HIV+ adults and neonates and the neuropathological studies will subsequently use human CNS tissues. Our studies on opioids as co-factors in HIV infections may yield novel therapies for the treatment of opioid-addicted, HIV-infected patients.

National Institute of Health (NIH)
National Institute on Drug Abuse (NIDA)
Research Project (R01)
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Human Development Research Subcommittee (NIDA)
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Sharp, Charles
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State University of New York at Buffalo
Internal Medicine/Medicine
Schools of Medicine
United States
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Ludwig, Linda B; Ambrus Jr, Julian L; Krawczyk, Kristie A et al. (2006) Human Immunodeficiency Virus-Type 1 LTR DNA contains an intrinsic gene producing antisense RNA and protein products. Retrovirology 3:80
Nair, Madhavan P N; Reynolds, Jessica L; Mahajan, Supriya D et al. (2005) RNAi-directed inhibition of DC-SIGN by dendritic cells: prospects for HIV-1 therapy. AAPS J 7:E572-8
Mahajan, Supriya D; Schwartz, Stanley A; Aalinkeel, Ravikumar et al. (2005) Morphine modulates chemokine gene regulation in normal human astrocytes. Clin Immunol 115:323-32
Nair, Madhavan P N; Mahajan, Supriya D; Schwartz, Stanley A et al. (2005) Cocaine modulates dendritic cell-specific C type intercellular adhesion molecule-3-grabbing nonintegrin expression by dendritic cells in HIV-1 patients. J Immunol 174:6617-26
Mahajan, Supriya D; Aalinkeel, Ravikumar; Reynolds, Jessica L et al. (2005) Morphine exacerbates HIV-1 viral protein gp120 induced modulation of chemokine gene expression in U373 astrocytoma cells. Curr HIV Res 3:277-88
Nair, Hari Krishnan; Rao, Kesava V K; Aalinkeel, Ravikumar et al. (2004) Inhibition of prostate cancer cell colony formation by the flavonoid quercetin correlates with modulation of specific regulatory genes. Clin Diagn Lab Immunol 11:63-9
Aalinkeel, Ravikumar; Nair, Madhavan P N; Sufrin, Gerald et al. (2004) Gene expression of angiogenic factors correlates with metastatic potential of prostate cancer cells. Cancer Res 64:5311-21
Nair, Madhavan P N; Mahajan, S; Hewitt, R et al. (2004) Association of drug abuse with inhibition of HIV-1 immune responses: studies with long-term of HIV-1 non-progressors. J Neuroimmunol 147:21-5
Nair, Madhavan P N; Schwartz, Stanley A; Mahajan, Supriya D et al. (2004) Drug abuse and neuropathogenesis of HIV infection: role of DC-SIGN and IDO. J Neuroimmunol 157:56-60
Chadha, Kailash C; Schwartz, Stanley A; Nair, Madhavan P N et al. (2003) Serum interferon inhibitor declines in patients with HIV-1 infection after a change in antiretroviral therapy. Immunol Invest 32:299-312

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