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Edward K. Wagner
Professor, Molecular Biology and Biochemistry
School of Biological Sciences

PH.D., Massachusetts Institute of Technology
Fellow, American Association for the Advancement of Science
Member, American Academy of Microbiology
Molecular biology of herpes simplex virus in productive infection and latency. Regulation of herpes simplex virus gene expression. Molecular analysis of herpes simplex virus pathogenesis.
The herpes viruses are large DNA containing viruses which replicate in the nucleus of the cells they infect. They are remarkable for a number of reasons. First, they have a very strictly controlled replication 'program' in which specific groups of viral genes are expressed in sequence. This program begins with the appropriation of cellular transcriptional machinery followed by conversion of the cell into a vehicle for the efficient replication of their genome which contains on the order of 100 genes, and, finally, the production of new virus with the ability to spread to other tissues. Second, this replication pattern can be interrupted in certain favored cells in which a latent infection can occur. During the latent phase of infection the interaction between the earliest viral gene products and host cell proteins which would lead to productive infection are interrupted, and only those viral genes necessary for the maintenance of the viral genome in the infected cell are required. However, stress can trigger a reactivation event where one or more latent phase viral gene products can re-establish the productive replication cycle. Thus, an individual can serve as a reservoir of infection for years or decades after initial infection. Third, the reactivation event takes place in spite of host immune defense, but the interaction between viral gene products and host immunity limits the extent of viral replication so that reactivation is generally a relatively benign process with little sequelae.

Despite this well controlled interaction between virus and host, human herpesvirus infections can lead to significant medical problems. Some human herpesviruses have been statistically implicated as causative agents of cancer. Herpesviruses can be venereally transmitted. Some herpesviruses are immunosuppressive. Further, immunosuppression by infections with human immunodeficiency viruses (HIV) or treatment with immunosuppressive drugs prior to organ transplants can lead to disseminated herpes virus infections and death.

The bulk of research in Dr. Wagner's laboratory is directed towards obtaining a full molecular description of the control of gene expression and gene function during productive and latent infection with herpes simplex virus (HSV). This is among the best characterized representative of the herpes viruses as a group. The virus is neurotropic and establishes latent infections in sensory nerve ganglia. Prior work from this laboratory have established many of the molecular parameters describing HSV gene expression during the replication cycle. DNA sequence and RNA transcription analysis have allowed identification of specific viral functions throughout the genome. More recently, the molecular mechanisms and DNA sequence elements involved in controlling the expression of individual viral genes and the basis for their temporal control are being extensively analyzed. Such work involves both the defined mutagenesis of DNA sequence elements controlling individual viral genes, and the generation of recombinant viruses which contain such mutated elements for the study of their function.

These approaches have also been directed towards study of the molecular basis of HSV latency. The latent state can be divided into discrete stages of infection, each of which is characterized by a specific transcriptional program. Establishment of latency in neurons involves a tissue specific blockage of the generalized process of transcriptional activation which normally occurs as the first step in productive infection. Following establishment of the latent infection only one viral promoter is active and it controls the expression of a complexly processed series of viral mRNA species which are required for efficient reactivation of HSV from the latent state, although they have no readily discernable effect on the lytic phase of infection itself.

Workers in the laboratory are currently engaged in 'engineering' modifications of the viral genome so to further our understanding the molecular trigger of the reactivation process as well as the mechanism of action of these latency specific gene products. We are also investigating the nature of genetic elements important in programmed expression of viral genetic information important in productive infection. Towards this aim, we have just developed an HSV DNA microarray that can be used to rapidly assay global patterns of viral and cellular gene expression during productive and abortive infection. Such studies relate to specific questions concerning viral replication and tissue specific gene expression, and also are important in developing approaches towards utilization of viral tissue specificity as a means of introducing foreign genes into specific tissues.
Wagner, E.K. 1999. Herpes Simplex Virus--Molecular Biology. in "Encyclopedia of Virology, 2nd ed.", (R.G. Webster and A. Granoff, eds.), Academic Press, London, pp. 686-697.
William C. Yang, G.V. Devi-Rao, Peter Ghazal, Edward Wagner and Steven J. Triezenberg. 2002. General And Specific Alterations In Programming Of Global Viral Gene Expression During Infection By Vp16 Activation-Deficient Mutants Of Herpes Simplex Virus Type 1. J. Virol. In press.
Wagner, E.K. , Garcia Ramirez, J.J., Stingley, S.W, Aguilar, J.S., Buehler, L., Devi-Rao, G.B., and Ghazal, P. 2002. Practical Approaches To Long Oligonucleotide-Based DNA Microarray: Lessons From Herpes Viruses, Progress in Nucleic Acids Research 71:445-492
Santiago Aguilar, Douglas Roy, Peter Ghazal, Edward Wagner. 2002. Dimethyl sulfoxide blocks Herpes Simplex Virus-1 productive infection in vitro acting at different stages with positive cooperativity: application of micro-array analysis. BMC Infectious Diseases 2:9 []
Stingley, S.W., Garcia Ramirez, J.J., Aguilar, J.S., Simmen, K., Sandri-Goldin, R.M., Ghazal, P. and Wagner, E.K. 2000. Global Analysis of HSV type 1 Transcription using an Oligonucleotide-based DNA Microarray, J. Virol, 74:9916-9927.
Petroski, M., Devi-Rao, G.B., Rice, M.K. and E.K. Wagner. 2001. The downstream activation sequence of the strict late Herpes Simplex Virus Type 1 UL38 promoter interacts with hTAFII70, a component of TFIID. Virus Genes, 22:299-310
Lieu, P.T. and Wagner, E.K. 2000. The kinetics of VP5 mRNA expression is not critical for viral replication in cultured cells. J. Virol 74:2770-2776
Tran, R.K., Lieu, P.T, Aguilar, J.S., Wagner, E.K. and D. C. Bloom. 2002. Altering the expression kinetics of VP5 results in altered virulence and pathogenesis of HSV-1 in mice, J. Virol 76:2199-205
Lieu, P.T. and Wagner, E.K. 2000. Two Leaky-Late HSV-1 Promoters Differ Significantly in Structural Architecture. Virology 272: 191-203.
Basic Virology. (M. Hewlett, co-author) (ISBN 0632042990). Blackwell Science, Boston. 1999.
American Society for Microbiology
American Society for Virology
University of California
3228 McGaugh Hall
Mail Code: 3900
Irvine, CA 92697
(949)824-5370, 6953
(949) 824-8551
Updated 04/18/2005

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