Herpes Simplex Virus (HSV) is a common human pathogen causing significant morbidity and mortality. Recent evidence suggests that HSV utilizes the fibroblast growth factor (FGF) and its receptor for cellular entry and subsequent infection. Preliminary evidence from our laboratory suggests that a specific form of the FGF receptor is important for HSV infection. It is the long term goal of this proposal to study the interaction of HSV with the FGF receptor and develop novel methods of antiviral therapy. Initial experiments will determine what forms of the FGF receptor interact with HSV and the role of the receptor as a viral binding site or some other mechanism for viral penetration. The FGF receptors present in HSV-permissive cells will be identified and studied for response to various FGF ligands (acidic FGF, basic FGF, hst/KS FGF, and int-2). Viral binding and early viral protein synthesis (a marker of viral penetration) will be studied as a function of receptor type expressed. The role of the receptor tyrosine kinase activity will be studied by expressing tyrosine kinase inactive mutants of the receptor and testing their susceptibility to HSV infection. Also tyrosine phosphorylation of proteins in response to HSV infection will be studied. Further the viral proteins that interact with the receptor will be identified by using the receptor as an affinity reagent. In order to define the structural features of the FGF receptor important for HSV infection, soluble forms of the receptor will be expressed and tested for viral binding. The ability of these proteins to inhibit HSV infection will be compared to their ability to inhibit FGF stimulation. Preliminary evidence from our laboratory suggests that it may be possible to dissociate FGF binding from the site necessary for viral interaction thereby producing specific antiviral agents. It is the final goal of this proposal to prepare the principal investigator for a career in basic science. Through formal course work, seminars, meetings, scientific discussions and an intensive research experience, the applicant hopes to establish the foundation essential for independent scientific investigation.
