SIGNAL TRANSDUCTION VIA THE CD4 MOLECULE

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This proposal describes the characteristics of a monoclonal antibody, termed 6B10, that binds to a portion of the CD4 molecule involved in the binding of the HIV/AIDS virus. The binding of 6B10 to CD4+ T cells also results in the generation of biochemical signals important in lymphocyte activation, namely the mobilization of intracellular calcium (CA++). This occurs in the absence of the CD3/TCR complex suggesting that the CD4 molecule is directly involved in the transduction of these biochemical signals. 6B10 also inhibited OKT3/CD3-induced T cell proliferation and OKT3/CD3- induced Ca++ mobilization. This suggests that signal transduction by CD4 may be important in the regulation of T cell proliferation. Since 6B10 binds to a region of CD4 involved in HIV binding, it is therefore hypothesized that HIV may initiate Ca++ mobilization. If HIV affects T cell function in a manner similar to that seen by 6B10, this would suggest involvement of HIV in T cell activation and may help explain the pathogenesis of some of the qualitative abnormalities of CD4+ T cells seen in patients with AIDS. This hypothesis will be investigated by comparing the effects of HIV to 6B10 in terms of their ability to induce changes in Ca as well as affect T cell proliferation, IL-2 production and IL-2 receptor expression. The region of the CD4 molecule important in the generation of these biochemical signals will also be determined. This will be done using site-directed mutagenesis to alter portions of the cDNA coding for the intracytoplasmic tail of the CD4 molecule. Mutant cDNA's will be inserted in the CD4- T cell line, Jurkat, and studied in terms of Ca++ mobilization as well as in IL-2 production and IL-2 receptor expression. The understanding of how the CD4 molecule affects the biochemical events of lymphocyte activation may lead to an improved understanding of the interactions between HIV and CD4 involved in the pathogenesis of the immunodeficiency seen in patients with AIDS.