DISTINCT MODULATORY EFFECTS OF BRYOSTATIN-1 AND STAUROSPORINE ON THE BIOSYNTHESIS AND EXPRESSION OF THE HIV RECEPTOR PROTEIN (CD4) BY T-CELLS

A family of structurally related macrocyclic lactones, bryostatins, have recently been shown to display several intriguing pharmacologic properties. Bryostatins are biosynthetic products of bryozoa phyllum of marine animals. To extend the analyses of the biological activities of these highly unusual biosynthetic animal products, we have examined the effect of bryostatin 1 (bryo-1) on the steady-state expression of the human immunodeficiency virus receptor, CD4, by normal peripheral blood T lymphocytes. Incubation of the cells with 5 nM bryo-1 caused a substantial loss of CD4 from the cell surface, as analyzed by flow cytometry using anti-CD4 monoclonal antibody. The modulation of CD4 expression by bryo-1 was not due to a cytotoxicity effect: in the culture conditions where it modulated CD4, bryo-1 also stimulated the expression of the interleukin 2 gene, as indicated by northern blot hybridization. In addition, incubation of the lymphocytes with nanomolar amounts of protein kinase C antagonist, staurosporine, resulted in the inhibition of the bryo-1-induced modulation of CD4 expression. The results of radioimmunoprecipitation analysis of detergent lysates of [S-35] methionine-labeled lymphocytes strongly suggest that bryo-1 inhibits the glycosylation and expression of CD4 in a manner similar to that of tunicamycin.