BIOCHEMISTRY OF CCR5/CXCR4/GP120 SIGNAL TRANSDUCTION

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This proposal seeks to address two current hypotheses regarding the role of chemokines and their receptors in viral disease pathogenesis. The first hypothesis is that the chemokine receptors bear discrete structural features which recognize the bind a conformationally protected feature on the gp120 molecule (exposed after CD4 binding). Interaction at this binding site directly leads to the fusion event mediated by gp41. The second hypotheses is that chemokines responding to virally infected cells are essential to shape the immune response by recruitment of specific host defense cells in a coordinated fashion. In the case of HIV-1 infection, identification of the chemokine response in the lung may be of significance in understanding the pulmonary consequences of the infection. Two specific aims are proposed as means to gather additional information regarding these hypotheses. Aim 1 will identify and characterize single chain antibodies from a phage display library which specifically recognize the gp120/CD4 complex in an effort to identify more precisely the co-receptor binding sites for R5 and X4 envelope glycoproteins. Aim 2 will examine the role of chemokines in viral host defense in the lung using a transgenic mouse bearing an inducible chemokine antagonist or lacking a Th1 polarized receptor CXCR3. Information gathered in this proposal may be of importance in the development of therapeutic strategies to control HIV disease.