The goal of this study is to analyze the biological significance of the interferon and cytokine systems in SIV induced immunodeficiency syndrome. We have previously shown that interferon induced inhibition of murine leukemia virus (MuLV) replication occurs at the level of virus assembly and that the interferon treatment leads to a formation of defective particles. Our recent results show that HIV infection in T-cells is sensitive to the antiviral effect of interferon, however, whether the interferon induced block of HIV replication is identical to that seen with MuLV is not clear as yet. In addition, we have recently shown that in retrovirus induced murine immunodeficiency, the regulated expression of interferon genes is altered. In the present proposal, we shall use the SIV induced immunodeficiency model to examine the roles which interferons and cytokines associated with the interferon system (e.g. TNF, I1-1 and IL-6) play in the life- cycle and pathophysiology of SIV infection and examine the following questions: 1) What is the role of interferon and TNF in the SIV replication and induction of AIDS symptoms? Does the infection with SIV effect the inducible expression of the interferon genes and cytokines closely related to the interferon system (e.g. TNF, I1-1, beta 2 - IL-6)? Does the interferon system contribute to the suppression of SIV infection in vivo? or to SIV induced pathogenicity; 2) Does the SIV infection in monkey lead to the production a) of an acid-labile alpha-interferon, such as seen in AIDS patients or b) a novel acid-stable interferon that has been found to be induced by co-cultivation of visna virus infected macrophages with T-cells. If these two interferons can be induced in vitro system, they will be characterized on the RNA levels by using the available cloned DNA probe and on the protein levels with the available antibodies. If the analysis will indicate a novel interferon protein(s), the cDNA will be cloned and characterized. We believe that the SIV system will enable us to compare in molecular terms the effect of interferon in retroviral infection both in vitro and in vivo and allow us to evaluate the complex role of the cytokine system in retroviral infection and induce immunosuppression. These data should prove a firm production for the understanding of pathogenicity of HIV infection in AIDS syndrome in man.
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