Department Affiliation: Pharmacology and Molecular Sciences
Degree: Ph.D., University of Chicago
Rank: Professor
Telephone Number: 410-955-8680
Fax Number: 410-955-3023
E-mail address: wgibson@jhmi.edu
School of Medicine Address: 312A Physiology Building, 725 N. Wolfe St., Baltimore, MD 21205
Herpesvirus proteins: Studies of their expression, structure and function using genetic, biochemical, and immunological approaches to identify new antiviral targets
Our group is studying the structure and molecular interactions of herpesvirus proteins with the objective of understanding their role during virus replication. The long term goal of the work is to uncover new targets for antiviral drug development, and to better define the events involved in virus assembly and maturation. Our research has focused on cytomegalovirus (CMV), which has the largest genome (~230 kb) among the known herpesviruses and a sexually transmissible agent that can cause severe problems among individuals with suppressed (e.g., anti-cancer chemotherapy; organ transplantation) or dysfunctional (e.g., HIV-infected) immune systems. Two areas of ongoing research are:
- Biochemical, enzymatic, physical, and genetic characterization of the viral maturational proteinase -- a current target for pharmaceutical development of antiviral drugs. The CMV proteinase represents a new mechanistic class of serine proteinases, is essential for virus replication, and is being pursued as a potential target for antiviral drug development. We are investigating the molecular biology of how this key enzyme functions in the virus-infected cell, and whether its precursor form may have different structural and enzymatic properties than the smaller proteolytic domain. These questions bear on understanding the biological function of this key regulatory enzyme, and maximally exploiting it as an antiviral target.
- Molecular, physical, and biological description of CMV capsid formation. The herpes simplex virus (HSV) capsid is one of the largest structures that has been demonstrated to self-assemble. This same process has not been reproduced with cytomegalovirus -- a closely related virus containing homologs of all four HSV capsid proteins. We are interested in this difference and the implication that CMV requires additional host or viral functions to build its protein shell. The involvement or requirement for protein modification in this process is of particular interest, and the significance of several site-specific phosphorylations are being investigated.
Recent Publications:
- Casaday, R.J., Bailey, J.R., Kalb, S.R., Brignole, E.J., Loveland, A.N., Cotter, R.J., and Gibson, W. Assembly protein precursor (pUL80.5 homolog) of simian cytomegalovirus is phosphorylated at a glycogen synthase kinase 3 site and its downstream "priming" site: Phoaphorylation affects interaction of protein with itself and with major capsid protein, J. Virol. 78:13501-13511, 2004. Pub Med Reference
Gibson, W. Assembly and maturation of the capsid. In, Cytomegaloviruses: Molecular Biology and Immunology. Ed, M. Reddehase. Horizon Scientific Press, Norwich UK., In press, 2005.
McCartney, S.A., Brignole, E.J., Kolegraff, K.N., Loveland, A.N., Ussin, L.M., and Gibson, W. Chemical rescue of I-site cleavage in living cells and in vitro discriminates between the cytomegalovirus protease, assemblin, and its precursor, pUL80a, J. Biol. Chem. 280:33206-33212, 2005. Pub Med Reference
Loveland, A.N., Chan, C.-K., Brignole, E.J., and Gibson, W. Cleavage of human cytomegalovirus protease pUL80a at internal and cryptic sites is not essential but enhances infectivity, J. Virol. 79:12961-12968, 2005. Pub Med Reference
- Wang, J., Loveland, A.N., Kattenhorn, L.M., Ploegh, H.L., and Gibson, W. High-molecular-weight protein (pUL48) of human cytomegalovirus is a competent deubiquitinating protease: Mutant viruses altered in its active-site cysteine or histidine are viable, J. Virol. 80:6003-6012, 2006. Pub Med Reference
- Loveland, A.N., Nang, L., Nguyen, N.L., Brignole, E.J., and Gibson, W. The amino-conserved domain of human cytomegalovirus UL80a proteins is required for key interactions during early stages of capsid formation and virus production, J. Virol. 81:620-628, 2007. Pub Med Reference
- Margulies, B.J. and Gibson, W. The chemokine receptor homologue encoded by UL27 of human cytomegalovirus is heavily glycosylated and is present in infected human foreskin fibroblasts and enveloped virus particles, Virus Research 123:57-71, 2007. Pub Med Reference
- Brignole, E.J. and Gibson, W. Enzymatic activities of human cytomegalovirus maturational protease assemblin and its precursor (pPR, pUL80a) are comparable: Maximal activity of pPR requires self-interaction through its scaffolding domain, J Virol. 81:4091-4103, 2007. Pub Med Reference
Other graduate programs in which Dr. Gibson participates:
