Retinoids and Substances of Abuse in HIV-1 Infection

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DESCRIPTION: (provided by applicant) Neurologic disease in HIV infection has been associated with damage to nervous system tissue induced by pro-inflammatory cytokines and other soluble factors that are released by activated mononuclear phagocytes (MP). In this proposal, we will examine mechanisms by which retinoids suppress pro-inflammatory activity in immune cells from individuals with HIV infection and in immune cell lines. Retinoids, which are vitamin A-related compounds, have been demonstrated to suppress such immune activity, and, in studies of m -1 infection, can suppress replication of virus in infected mononuclear cell lines. Among individuals with HIV-1 (HIV) infection, vitamin A deficiency has been associated with an increased risk of developing HIV-related complications. However, in most cases, the administration of vitamin A in clinical trials has not been associated with improvement in HIV-related clinical parameters. Our prior studies demonstrate that 1) parameters of vitamin A metabolism in plasma are lower among HIV-infected individuals than among non-infected subjects and suggest that such abnormalities can be observed in CSF; 2) plasma retinol levels are lower in seronegative patients with chronic inflammatory neurologic disease than in control subjects with non-inflammatory neurologic disease and treatment of these individuals with an immunomodulatory agent is associated with specific effects on retinoid receptor subtype expression patterns; 3) retinoid compounds suppress pro-inflammatory cytokine production by peripheral blood immune cells and cell lines and that, in the cell lines, retinoid-induced suppressive activity can be inhibited by simultaneous exposure of the cells to morphine or cocaine. Therefore, we propose the following aims for this proposal: 1) to examine the expression of pro-inflammatory cytokine (TNF-a) by mononuclear cells from opiate users and non-drug users with or without a history of HIV infection; 2) to examine the effects of specific retinoid receptor activation on the immune effects elicited in retinoid-exposed mononuclear cell lines; 3) to examine the effects of substances of abuse (morphine and cocaine) on specific immune responses induced by retinoid receptor agonists and receptor antagonists in mononuclear cell lines; and 4) and to assess the role of inhibition of nuclear NF-KB binding in the effects of retinoids and substances of abuse on pro-inflammatory cytokine production by the patient cells and by the mononuclear cell lines. These studies will broaden our understanding of the immune effects of retinoid compounds in individuals with HIV infection, and may lead to effective approaches to the treatment of the infection and its complications with vitamin A.