INHIBITION OF EPSTEIN-BARR VIRUS RECEPTOR INTERACTION

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Infection of humans by Epstein-Barr virus results in significant morbidity and during immunosuppression can result in fatal B cell lymphoproliferative disease. The rapid accumulation of knowledge concerning the earliest events in EBV/host cell interaction presents an opportunity to develop antiviral reagents which interfere with EBV attachment to its cellular receptor (CR2). This proposal will examine whether soluble forms of recombinant CR2 or the viral attachment protein, gp350/220, are capable of blocking infection of EBV in vivo. These studies will take advantage of a newly developed model of EBV-induced lymphoproliferative disease in the immunodeficient mouse (SCID) to analyze the antiviral properties of soluble CR2 and gp350/220 as well as synthetic peptide gp350/220 analogues. Studies are also planned to examine the molecular basis of EBV interaction with CR2 as well as with its natural ligand, C3dg. Soluble CR2 and gp350/220 will be subjected to systematic sitedirected mutagenesis to identify crucial amino acid residues which mediate virus-CR2 interaction. Quantitative binding assays carried out with immobilized proteins or in solution will be used to assess the relative functional activity of individual CR2 and gp350/220 mutants. The secondary structure of CR2 and gp350/220 mutants will be analyzed by CD or NMR spectroscopy. A long term goal of these studies is to determine the three-dimensional structure of CR2 and the CR2/gp350/220 and CR2/C3dg complexes using X-ray crystallography or NMR spectroscopy. The solution of the ligand/receptor structure should allow the rationale design of therapeutic agents which block EBV binding without interfering with normal B cell function.