Lab members:
Linda van Dyk - Principal Investigator
Taylor Armstrong - Professional research assistant; taylor.armstrong@uchsc.edu
Lisa Williams - Microbiology Graduate student; lisa.williams@uchsc.edu
Erin Buckingham - Microbiology Graduate student; erin.buckingham@uchsc.edu
Kevin Diebel - Molecular Biology Graduate student; kevin.diebel@uchsc.edu
Katherine Lee - Post-doctoral fellow; katherine.lee@uchsc.edu
Jessica Lagana - Undergraduate assistant

Lab contact info:
van Dyk lab, MS8333
12800 E. 19th Ave., P18-9103
P.O. Box 6511
Aurora, CO 80045
lab: 303 724-4271
fax: 303 724-4226

Research Program:
Herpesviruses are forever. They are a large family of viruses that share the ability to establish a lifelong latent infection within their hosts. The latent infection is never cleared, but is controlled by the host immune system. This is evident upon immunosuppression of infected individuals, in whom the virus infection reactivates. A hallmark of the gammaherpesviruses is their ability to establish latent infection within the lymphoid system of the host. This balance between the host immune system and viral latency is complex and is dependent on both host and viral genes. The gammaherpesviruses include the human pathogens Epstein Barr virus and Kaposi's sarcoma associated herpesvirus (KSHV), as well as murine gammaherpesvirus 68 (gamma-HV68). Each of these viruses uses B lymphocytes as a major reservoir of latency and is associated with B cell malignancies and also with chronic inflammatory diseases. The focus of my lab is on gammaherpesvirus pathogenesis, particularly on virus and host mechanisms to regulate latency and reactivation.

Gamma-HV68 and KSHV both encode homologs of the host cyclins. Exogenous expression of the viral cyclins promotes cell cycle progression and leads to cellular transformation. Infection of normal mice with a mutant HV68 deficient in viral cyclin expression results in a profound decrease in reactivation from latency and associated chronic disease. The mechanism of viral cyclin action in reactivation from latency is being investigated by use of in vivo complementation, molecular biological studies, and proteomic analysis. The viral cyclins interact with host tumor suppressor proteins, including the retinoblastoma protein and the cyclin dependent kinase inhibitor, p18Ink4c. The relationship between tumor suppressors and virus infection is being investigated at the level of both whole animal and molecular interactions.
The gammaherpesviruses establish latency in B lymphocytes, and virally transformed cells demonstrate altered B cell signaling. It is thought that this ability to derail B cell signaling is important to establishment of latency and evasion of host immune detection. The role of host B cell signaling in establishment of latency is being investigated by infection of mice and cell lines deficient in particular B cell signaling components. Finally, one of the means by which gammaherpesviruses may control infected host cells is by virus encoded miRNAs. Our lab is investigating the role of viral miRNAs on cell cycle, tumor suppressors and signaling of infected host B cells.

Funding agencies:
National Cancer Institute, Burroughs Wellcome Fund, Center for AIDS Research, Cancer League of Colorado

Key Publications:

• Pfeffer, S., Sewer, A., Lagos-Quintant, M., Sheridan, R., Sander, C., Grasser, F.A., van Dyk, L.F., Kiong Ho, C., Shuman, S., Chien, M.,Russo, J.J., Ju J., Randall, G., Lindenbach, B.D., Rice, C.M., Simon, V., Ho, D.D., Zavolan, M., and Tuschl, T. 2005. Identification of microRNAs of the herpesvirus family. Nature Methods 2:269-276.
• Loh, J., Huang, Q., Petros, A.M., Nettesheim, D., van Dyk, L.F., Labrada, L., Speck, S.H., Levine, B., Olojniczak, E.T., and Virgin, H.W. 2005. A surface groove essential for viral bcl-2 function during chronic infection in vivo. PLoS Pathogens 1(1): e10.
• van Dyk LF, Virgin HW 4th, Speck SH. 2003. Maintenance of gammaherpesvirus latency requires viral cyclin in the absence of B lymphocytes. J. Virology 77:5118-5126.
• Gangappa, S., van Dyk, L.F., Jewett, T.J., Speck, S.H., and Virgin, H.W. IV. 2002. Identification of the in vivo role of a viral bcl-2. J. Exp. Med. 195:1-11.
• Tibbetts, S. A., van Dyk, L. F., Speck, S. H., and Virgin, H. W. Virgin IV. 2002. Immune Control of the Number and Reactivation Phenotype of Cells Latently Infected with a Gammaherpesvirus. J. Virology 76:7125-7132.
• van Dyk, L.F., Virgin, H.W.IV, and Speck, S.H. 2000. The Murine Gammaherpesvirus 68 v-Cyclin is a Critical Regulator of Reactivation from Latency. J. Virology 74:7451-7461.
• van Dyk, L.F. Hess, J.L., Katz, J.D., Jacoby, M., Speck, S.H., and Virgin, H.W.IV. 1999. The Murine Gammaherpesvirus 68 v-Cyclin Gene is an Oncogene that Promotes Cell Cycle Progression in Primary Lymphocytes. J. Virology 73:5110-5122.
• Grakoui, A., van Dyk, L.F., Dowdy, S.F., and Allen, P.M. 1998. Molecular Basis for the Lack of T Cell Proliferation Induced by an Altered Peptide Ligand. International Immunol. 10:969-979.
• *Lissy, N.A., *van Dyk, L.F., Becker-Hapak, M., Vocero-Akbani, A., Mendler, J., and Dowdy, S.F. 1998. TCR Antigen-Induced Cell Death Occurs from a Late G1 Phase Cell Cycle Check Point. Immunity 8:57-65. *These authors contributed equally to this study.

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