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Member Information
Gary H. Cohen, PhD
Professor and Chair
Department of Microbiology, School of Dental Medicine
Office Phone: 215-898-5914
Office Fax: 215-898-8385
Email: cohen@biochem.dental.upenn.edu
Website(s):
Education: PhD 1964, University of Vermont
Keywords: Herpesvirus, virus entry, glycoproteins, cellular receptors
Research and/or Clinical Interests:
My research focuses on the mechanism of herpes simplex virus entry into host cells and the roles played by the viral glycoproteins and their cellular receptors.
Summary:
My goal is to understand events that mediate herpes simplex virus (HSV) entry into susceptible cells and promote viral pathogenesis. The two serotypes, HSV-1 (oral) and HSV-2 (genital) establish lifelong latent infections within sensory ganglia. Periodically, the virus reactivates and causes recurrent infections. Together with my colleague and collaborator, Dr. Roselyn Eisenberg, our laboratory focuses on glycoprotein gD, an essential virion component which interacts with cellular receptors to trigger HSV entry. We previously defined four functionally important regions on gD. Antibodies to these sites neutralize virus infectivity and mutations in these sites destroy gD function. gD is the receptor binding protein of HSV and can utilize more than one cell receptor for entry. One of these, called HveA (herpes virus entry mediator A) is a member of the TNF receptor superfamily. A second one, called HveC (also known as poliovirus related receptor 1) is a member of the immunoglobulin superfamily. HveC bears no obvious structural similarity to HveA and it is likely that the two proteins are distributed differently in human tissues and have distinct normal cellular functions.
A major goal is to localize the gD binding domains on each receptor and to localize gD binding domains on each receptor. We express the ectodomains of gD and receptors in a baculovirus expression system. By ELISA, gel filtration, and surface plasmon resonance (biacore), gD binds directly to HveA and to HveC with micromolar affinity. Mutant forms of gD show changes in affinity for one receptor or both. For example, deletion of functional region 4 increases the affinity of gD for HveA and HveC, indicating that region 4 normally modulates the gD-receptor interaction.
What is the significance of gD-receptor binding for triggering the next steps of virus entry? Our current working hypothesis is that the interaction leads to a conformational change in one or both proteins and it is this altered structure that triggers later steps. What is the structure of gD and the gD/receptor complex? The answers to these and other questions are being sought.
Representative Publications:
Whitbeck, J.C., C. Peng, H.Lou, R. Xu, S.H. Willis, M. Ponce de Leon, A.V. Nicola, R.I. Montgomery, M.S. Warner, A.M. Soulika, J.D. Lambris, P.G. Spear, G.H. Cohen, and R.J. Eisenberg. 1997. Herpes simplex virus glycoprotein D binds directly to HVEM, a mediator of HSV entry. J. Virol. 71: 6083-6093.
Geraghty, R. J., C. Krummenacher, G. H. Cohen, R. J. Eisenberg, and P. G. Spear. 1998. Entry of alphaherpesviruses mediated by poliovirus receptor-related protein 1 and poliovirus receptor. Science 280:1618-1620.
Krummenacher, C., A. V. Nicola, J. C. Whitbeck, H. Lou, W. Hou, J. D. Lambris, R. J. Geraghry, P. G. Spear, G. H. Cohen, and R. J. Eisenberg. 1998. Herpes simplex virus glycoprotein D can bind to Poliovirus Receptor Related Protein 1 (PRR1/HveC) or Herpes Virus Entry Mediator (HVEM/HveA), two structurally unrelated mediators of virus entry. J. Virol. 72: 7064-7074.
Willis, S. H., A. H. Rux, C. Peng, J. C. Whitbeck, A. V. Nicola, H. Lou, W. Hou, L. Salvador, R. J. Eisenberg and G. H. Cohen. 1998. Examination of the kinetics of herpes simplex virus (HSV) glycoprotein D to the herpes virus entry mediator (HveA) using surface plasmon resonance. J. Virol. 72:5937-5947.
Rux, A. H., S. H. Willis, A. V. Nicola, W. Hou, H. Lou, C. Peng, G. H. Cohen, and R. J. Eisenberg. 1998. Functional region IV of glycoprotein D from herpes simplex virus modulates binding to the Herpes Virus Entry Mediator (HVEM/HveA). J. Virol. 72:7091-7098.
