INTERLEUKIN-12 AND AIDS PATHOGENESIS

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A reciprocal relationship exists between humoral and cell mediated immunity. The response to infectious agents involves a complex interaction between different cells, often regulated in their functions by a network of cytokines. The critical roles of cytokines in the regulation of the immune response and their multiple and often overlapping effects suggest that deficient or abnormal production may results in clinical immunodeficiency. A variety of profound immunological abnormalities have been described in HIV-infected individuals, including not only patients with ARC or AIDS, but also asymptomatic subjects. The central hypothesis of this proposal is that Interleukin-12 (IL-12), a novel cytokine with potent and pleomorphic activities, play an important immunomodulatory role in restoring depressed immune functions in HIV- infected individuals. IL-12 deficiency in HIV-infected individuals may be in part responsible for the deficient cellular immunity, hyper-IgE syndrome, polyclonal B-cell activation and the possible predominance of T helper type 2 (Th2) like responses. Newly developed methods for detecting IL-12 will be used to determine the ability of hematopoietic cells from HIV-infected individuals to produce IL-12 as well as other cytokines, following different stimuli. The in-vitro ability of different HIV strains, viral mutants, as well as cellular products, will be compared in primary monocytes and THP-1 cells, in order to analyze the molecular mechanisms involved in the reduced IL-12 production. T cell clones will be generated in control donors, high risk individuals and HIV-infected patients in the presence of IL-12 or IL-12 antagonists, and we will examine whether IL-12 will favor the differentiation of Th1 like responses, and will affect the pattern of cytokine production in HIV- infected individuals. We will analyze the ability of IL-12 to restore immunological functions in HIV-infected individuals. We will examine its role in the modulation of HIV expression in infected cell lines, and HIV- infected primary cells, and we will compare this effect to that of other cytokines known to up regulate HIV expression in infected cells. The results of these studies will provide new informations about the role of this novel cytokine in the pathogenesis of AIDS, and will be of great use in defining its potential therapeutic role.