The long time goal of this study is to evaluate the biological role of cytokines in the pathogenesis of human acquired immunodeficiency syndrome (AIDS) and associated neoplasia. During the present funding period, we have shown that interferon (IFN) can inhibit HIV replication at multiple levels. Thereby IFN is able not only to limit de novo infection and virus replication in persistently infected cells but can also block the transactivation of HIV provirus mediated by HSV infection. We have also shown that a cell, which can synthesize high levels of IFN as a response to HIV-1 infection is nonpermissive to HIV-1 infection. In the present proposal, which is an extension of these studies, we want to analyze the molecule mechanism by which IFN affects different types of HIV infection and determine whether the IFN system has the ability to prevent or down modulate the activation of HIV provirus induced by different cytokines. We will focus on the following questions: 1) What are the molecular mechanisms by which IFN inhibits HIV-1 replication in T-cells and macrophages? 2) What are the characteristics of kappaB binding proteins stimulated by inflammatory cytokines in HIV-1 infected cells? 3) What is the molecule mechanism by which kappaB directed transcription is suppressed in IFN producing cells? and 4) What is the molecular nature of the block in inducible expression of IFN alpha genes in HIV infected cells? We believe that our present results, together with the results of the proposed study, will allow us to evaluate in molecular terms, the complex role of the IFN system in HIV infection as well as to clarify some of the pathways by which IFNs and cytokines may interact with each other. This study should also provide a more rational foundation for the use of IFN and cytokine therapy in HIV infection in man. The fact that IFN can inhibit activation of HIV provirus induced by HSV-1 as well as to abort HIV infection, indicates that in vivo IFN may have a much broader spectrum of effects than we anticipated. It also suggest that the present strategies for clinical use of IFN may be reevaluated and IFN applied in much earlier stages of HIV infection.
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