Available evidence indicates that the pathogenicity of HIV is in large part caused by its ability to suppress immune function. Suppression appears not to result solely from infection of cells of the immune system; rather it appears that interaction of the viral envelope protein with its receptor(s), most notably CD4, leads to active transduction of immunosuppressive signals.
The aim of this Program Application is to fund 4 integrated projects which explore the molecular basis of HIV suppression of immunologic function. Funds are also requested for a cytometry/reagent core which will support studies performed in the 4 projects. Project 1, entitled """"""""gp120 induced CD4 modulation of antigen receptor function"""""""", will define the role of specific protein kinases in CD4-ligation mediated inactivation of CD3 signaling. Once defined, the molecular basis by which the implicated kinases regulated CD3 will be determined. Project 2, entitled """"""""CD4 function in physiologic activation of T cells"""""""", will define the signaling by CD4 during CD4 dependent activation of T cells by antigen presenting cells (APC). Studies will utilize T cells which are dependent on CD4 for activation along with antigen presenting cells which express wild type or mutant Ia which lack CD4 binding sites. Comparative biochemical analysis of signaling in response to these APC will allow definition of the signal transducing role of CD4 in physiologic T cell activation. The mechanisms by which gp120 perturbs this response will be defined. Project 3, entitled """"""""gp120 and thymocyte maturation"""""""", will explore the possibility that T-cell lymphopenia in AIDS is caused in part by gp120 inducing, via CD4, deletion of developing T cells in the thymus. The molecular basis of signaling of this response will be defined. Project 4, entitled """"""""The effects of gp120 and gp41 on macrophage function"""""""", will define the suppressive effects of viral glycoproteins on binding, phagocytosis and killing of M. avium and listeria. AIDS patients are particularly at risk for infection by M. avium but not listeria, thus studies of differential effects will be particularly useful. One biologic parameters are established, the role of specific second messenger systems in suppression will be defined. The studies will employ analytic methods ranging from conventional assays of lymphocyte activation and macrophage function, to gene expression, to molecular analyses of protein phosphorylation, lipid metabolism and Ca++ mobilization. Cell systems to be employed include normal human cells and lymphomas, hCD4 transfected mouse T hybridomas and hCD4 transgenic mice. Definition of the molecular bases by which viral glycoproteins exercise immunosuppressive effects should open avenues for pharmacologic intervention in AIDS to bolster immune competence and reveal potential counterindications for the use of gp120 vaccines.
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