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. Herpesviruses are subdivided by genomic and
biological properties. A hallmark of the
gammaherpesviruses is their ability to establish latent
infection within the lymphoid system of the host. Gammaherpesviruses
persist for a lifetime 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 all parameters of
lytic infection, but results in a profound defect in
reactivation from latency. Infection of B cell-deficient
mice with this v-cyclin KO results in failure to
maintain lifelong latency (the hallmark of herpesviruses).
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 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.
Selected Publications
Van Dyk, L. F., Virgin, H.W. IV, and Speck,
S. H. 2003. The Murine Gammaherpesvirus 68 v-Cyclin is Essential for
Long-term Maintenance of Viral Latency and Provides Evidence for Cell Type
Specific Maintenance Mechanisms. J.
Virology 77:5118-5126.
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.
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.
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.
Van Dyk, L.F., Wise, T.W., Moore, B.B., and
Meek, K. 1996. Immunoglobuin DH Recombination Signal Sequence Targeting: Effect
of DH Coding and Flanking Regions and Recombination Partner. J. Immunol. 157:
4005-4015.
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