SIGNALLING FUNCTION OF CD4 AND ITS ROLE IN MODIFYING T-CELL ACTIVATION

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To investigate the biological and immunological consequences of HIV-CD4 interactions, we have initiated studies to analyze the functional changes which occur secondary to the binding of either virus, virus envelope, or antibodies to CD4 on the surface of normal T-cells. The initial studies are to evaluate a variety of monoclonal antibodies to CD4 and other cell surface molecules, along with envelope proteins and purified HIV to determine whether these reagents either co-stimulate or inhibit T-cell receptor initiated T-cell activation. We have found that different epitopes on the CD4 molecule, as defined by monoclonal antibodies, are able to transmit different signals to the T-cell. Some sites are very potent at inhibiting T-cell activation when presented in solution, where as others evoke strong stimulatory -activity in the context of a crosslinked simultaneous signal from the T-cell receptor. These functional differences may represent differences in the type or quality of signal generated in response to distinct epitopes on the CD4 molecule. When the effects of HIV are analyzed in the same systems, activities similar to those of monoclonal antibodies to CD4 are apparent. However, the functional effects of virus and envelope are much broader and extend beyond interactions that can be assigned to an exclusive effect on the CD4 molecule. These stimulatory and inhibitory activities may depend on envelope sites outside of the virus CD4 binding region or even be secondary to other proteins present on the viral surface. We are also currently studying the biochemical signaling generated. by different antibodies to CD4. Recent observations suggest that crosslinking of CD4 can potentiate increases in intracellular calcium concentrations possibly secondary to protein kinase activation. Our goal is to define and understand the molecular and biochemical differences between CD4 generated negative and positive signalling. These pathways presumably are routes by which HIV can modify the function of the host T-cell.