Linda F. van Dyk

Assistant Professor Ph.D., Southwestern Medical Center

Current Research

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 controlled by the host immune system: immunosuppression results in reactivation of lytic infection. A hallmark of the gammaherpesviruses is their ability to establish latent infection within the lymphoid system of the host. Gammaherpesviruses persist for life within cells of the immune system, the very system responsible for their clearance. 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 (gHV68). Each of these viruses use B lymphocytes as a major reservoir of latency and are associated with B cell malignancies.

The focus of my lab is on gammaherpesvirus pathogenesis, particularly on virus and host mechanisms to regulate latency and reactivation.

The availability of gHV68 as a murine model of gammaherpesvirus pathogenesis provides the following benefits: 1) a genetically manipulable virus, 2) a genetically manipulable host system with a wealth of genetic alterations and strain variations, and 3) the ability to study pathogen/host interactions over the entire course of viral infection.

gHV68 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 gHV68 deficient in viral cyclin expression (v-cyclin KO) is equivalent to wild-type virus in lytic infection, but results in a profound defect in reactivation from latency and associated chronic disease. The mechanism of viral cyclin action in maintenance and reactivation from latency is being investigated by use of in vivo complementation and molecular biological studies. 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. 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 and signaling of infected host B cells. Finally, 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.

Lab Members: Linda van Dyk, Taylor Armstrong, Erin Buckingham, Kevin Diebel, Katherine Lee, Andrea Suarez and Lisa Williams

Recent Publications

Click Here For An Updated List Of Dr. van Dyk's Publications

Loh J, Huang Q, Petros AM, Nettesheim D, van Dyk LF, Labrada L, Speck SH, Levine B, Olejniczak ET, Virgin HW 4th. A surface groove essential for viral Bcl-2 function during chronic infection in vivo. PLoS Pathog. 2005 Sep;1(1):e10.

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.

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.