Acquired immune deficiency syndrome (AIDS) is caused by infection with the human immunodeficiency virus (HIV-1). Infection with HIV- 1 is associated with B cell hyperactivity, loss of cell mediated immune function and frequently, defective antibody production. This proposal is based on the hypothesis that soluble envelope glycoproteins of HIV-1 exert significant immunological influences and thereby contribute to the overall immune dysfunction in HIV infection. We have previously shown that a whole viral extract of HIV-1 influences functions of both T and B lymphocytes of normal volunteers. Preliminary results have now shown that purified HIV- 1 envelope glycoprotein, gp160 can induce terminal differentiation in normal B lymphocytes and gp120 can suppress normal T cell functions in vitro. A B cell stimulatory subregion has ben identified in the activity was found to be localized in the carboxyl terminal of the gp41 region of the envelope. Studies proposed are aimed at identifying B cell stimulatory epitopes of HIV-1, understanding mechanisms at the cellular and sub-cellular level of the stimulatory and suppressive influences of HIV proteins and lastly to identify the immunosuppressive molecules of HIV-1. Virally mediated or modulated effects will include study of lymphocyte activation viz. membrane potential changes, calcium mobilization, second messengers, activation of protein kinase C and expression of cellular genes. We propose to test synthetic peptides spanning the B cell stimulatory subregion to delineate the B cell stimulatory epitope of HIV-1. With these studies, we hope to gain insight into the pathogenic mechanisms of immune dysfunction caused by HIV-1. These studies are important for developing a unified hypothesis incorporating the stimulatory and inhibitory properties of HIV-1 and also have implications for ongoing vaccine trials with HIV-1 envelope proteins and in the development of therapeutic approaches for other immunologic disorders.
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