D. Wade Gibson

Image of Dr. Wade Gibson

D. Wade Gibson

Primary Appointment: 
Pharmocology and Molecular Sciences
Secondary Appointment: 
(410) 955-8680

725 N. Wolfe Street
Physiology 312-A 
Baltimore MD 21205

Research topic: 

Herpes virus proteins: synthesis, structure, and function during replication

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 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 is an important sexually transmissible agent that can cause severe problems among naturally or therapeutically immunosuppressed (e.g., dysfunctional immune system, AIDS, anti-cancer chemotherapy; organ transplantation). Areas of interest and active research include:

  • Biochemical, enzymatic, physical, and genetic characterization of the viral maturational protease -- a current target for pharmaceutical development of antiviral drugs. The CMV protease represents a new mechanistic class of serine proteases, 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 its 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 and are being investigated. 
  • Determine how incoming DNA-containing nucleocapsids are transported from the plasma membrane to the nucleus, and how progeny DNA-containing nucleocapsids are transported out of the nucleus. Once through the plasma membrane, herpesviruses appear to move in a directed way to nuclear pores and release their DNA cargo into the nucleus. A different process of crossing the nuclear membrane is used by progeny nucleocapsids as they mature into infectious particles. We are identifying and studying the viral and cellular proteins that mediate these processes, with the promise of uncovering novel targets for drugs that can interfere with virus replication at these steps. A newly discovered ubiquitin-specific cytseine protease that is encoded by the virus and becomes part of the infectious particle may be involved in these processes and that connection is being investigated.
Selected Publications: 

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) 

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) 

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)

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)

Loveland, A. N., Nguyen, N. L., Brignole, E. J., and Gibson, W.  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) 

Brignole, E. J., and Gibson, W.  Enzymatic activities of human cytomegalovirus maturational protease assemblin and its precursor (pUL80a) are comparable:  Maximal activity of pPR requires self-interaction through its scaffolding domain.  J Virol. 81:4091-103 (2007). 

Gibson, W.  Human cytomegalovirus:  Molecular biology.  In, Encyclopedia of Virology, 3rd Edition (Eds., B.W.J. Mahy and M.H.V. Van Regenmortel), Oxford: Elsevier, Vol. 2, pp485-490 (2008).

Gibson, W.  Structure and Formation of the Cytomegalovirus Virion.  In, Human Cytomegalovirus (Eds., T. Shenk and M.F. Stinski), Current Topics in Microbiology and Immunology, Springer Press, 325:187-204 (2008). 

Nguyen, N.L., Loveland, A.N, and Gibson, W.  Nuclear localization sequences in cytomegalovirus capsid assembly proteins (UL80 proteins) are required or virus production: Inactivating NLS1, NLS2, or both affects replication to strikingly different extents. J. Virol. 82:5381-5389 (2008). 

Kim, E.T., Oh, S.E., Lee, Y.-O., Gibson, W., and Ahn, J.-H.  Cleavage specificity of the UL48 deubiquitinating protease activity of human cytomegalovirus and the growth of an active site mutant virus in cultured cells. J. Virol., 83:12046-56 (2009). 

Fernandes, S.M., Brignole, E.J. and Gibson, W.  Cytomegalovirus capsid protease: Biological substrates are cleaved more efficiently by full-length enzyme (pUL80a) than by the catalytic domain (assemblin). J. Virol. 85:3526-3534 (2011).

Gibson, W. and Bogner, E. Morphogenesis of the cytomegalovirus virion and subvirus particles.  In,  Cytomegaloviruses:  From Molecular Pathogenesis to Intervention (Ed., M. Reddehase), Caister Academic Press, (2012).

Gibson, W. Cytomegalovirus assemblin.  In, Handbook of Proteolytic Enzymes, 3rd Edition (Eds. N. Rawlings and G. Salvesen), Elsiver (2013).

Kalu, N.N., Desai, P., Shirley, C.M., Avery, R., Jones, R.J., Gibson, W., Dennis, P., Ambinder, R.F. Nelfinavir inhibits maturation and export of herpes simplex virus type 1. J. Virol. 2014 Feb 26. [Epub ahead of print] 

Tullman, J.A., Harmon, M.-E., Delannoy, M. 1   and Gibson, W. Recovery of an HMWP/hmwBP (pUL48/pUL47) Complex from Virions of Human Cytomegalovirus: Subunit Interactions, Oligomer Composition, Deubiquitylase Activity. J. Virol. 2014 May 1 [Epub ahead of print].