Infections through Epstein-Barr Viruses: Target Structure Identified for Therapeutic Approaches

Neuherberg / Munich, October 20, 2009. Scientists of the Department of Gene Vectors at Helmholtz Zentrum München have now shown how a special viral gene regulates the life cycle of B cells infected with Epstein-Barr virus (EBV). The viral protein is a candidate target structure for cancer therapy. (PLoS Pathogens)*

Researchers of the Department of Gene Vectors of Helmholtz Zentrum München have discovered a new role of the gene EBNA-3A in EBV-associated malignant diseases. “In a genome-wide association study we could for the first time identify target genes that were regulated by the viral protein,” Dr. Bettina Kempkes, who led the project, explained.

The Epstein-Barr virus (EBV), a herpesvirus, is of great medical significance – about 95 percent of the population is thought to be latently infected. While the first infection of healthy children appears to be asymptomatic, primary infection in adolescent or adults can cause Pfeiffer gland fever with flu-like symptoms. In addition EBV is associated with cancers like endemic Burkitt's lymphoma, Hodgkin's disease, Nasopharyngeal Carcinoma and gastric carcinoma.

For transplant recipients, whose immune system must be switched off by means of drugs or radiation to prevent rejection of the organ, EBV poses a specific great danger. A reactivation of the latent virus or a primary infection can cause the development of malignant diseases of the immune system, collectively termed post-transplant lymphoproliferative disorder (PTLD). The EBV-infected cells then show a characteristic expression profile of  viral as well as cellular genes.

Quiescent human B cells can be activated and transformed by EBV infection since they gain the ability to proliferate indefinitely  in cell culture . The viral and cellular gene expression profile of these EBV transformed B cells in vitro closely resembles the expression profile of malignant B cells seen in PTLD patients. Thus, EBV transformed B cells provide a highly informative in vitro model to study the pathogenesis of PTLD.

The growth transformation process is regulated in a concerted action by nine viral genes which have different functions. The individual contribution of the viral proteins to the complex process can be investigated through targeted inactivation of individual genes in the viral genome.

In the Department of Gene Vectors, the research group led by Professor Wolfgang Hammerschmidt developed a technique already back in 1998 that enabled scientists to make targeted alterations in the large EBV genome in bacteria cells**. With this technique the research group of Dr. Bettina Kempkes has now switched off the EBNA-3A gene in the viral genome. Transformation studies with these new viruses show that EBNA-3A is substantially involved in the regulation of numerous genes that control biological processes such as apoptosis (programmed cell death) or control the regulation of the cell cycle. The disturbance of these two processes is often the cause of the uncontrolled growth of cancer cells.

Dr. Bettina Kempkes: “EBNA-3A negative B cell lines will be an important cell culture system in the future with which we can investigate whether the promising protein EBNA-3A will be suitable as target molecule for the therapy of EBV-associated diseases.”

Further information

Publications:
*Hertle, M.L., Popp, C., Petermann, S., Maier, S., Kremmer, E., Lang, R., Mages, J., and Kempkes, B. (2009). Differential gene expression patterns of EBV infected EBNA-3A positive and negative human B lymphocytes. PLoS Pathog 5, e1000506.
**Delecluse, H.J., Hilsendegen, T., Pich, D., Zeidler, R., and Hammerschmidt, W. (1998). Propagation and recovery of intact, infectious Epstein-Barr virus from prokaryotic to human cells. Proc Natl Acad Sci U S A 95, 8245-8250.

Helmholtz Zentrum München is the German Research Center for Environmental Health. As leading center oriented toward Environmental Health, it focuses on chronic and complex diseases which develop from the interaction of environmental factors and individual genetic disposition. Helmholtz Zentrum München has around 1680 staff members. The head office of the center is located in Neuherberg to the north of Munich on a 50-hectare research campus. Helmholtz Zentrum München belongs to the Helmholtz Association, Germany’s largest research organization, a community of 16 scientific-technical and medical-biological research centers with a total of 26,500 staff members.

The Department of Gene Vectors investigates the underlying molecular biological mechanisms of a herpesvirus and its interaction with human target cells. A special characteristic of the Epstein-Barr virus (EBV) makes research with this pathogen especially attractive: In vitro the virus very efficiently infects quiescent, i.e. non-proliferating human B cells. The infection is latent, no viruses are produced, but the genetic information of the virus remains stable in the infected cells. These latent infected cells acquire the characteristic of unlimited proliferation and thus reflect aspects of tumor genesis in humans. This model system is unique because it allows scientists to elucidate in vitro the questions of cancer genesis with instruments of molecular and cell biology.

Editor:  Sven Winkler, Helmholtz Zentrum München - Deutsches Forschungszentrum für Gesundheit und Umwelt (GmbH), Ingolstädter Landstraße 1 85764 Neuherberg
Tel.: 089-3187-3946, Fax 089-3187-3324, Internet: www.helmholtz-muenchen.de, E-Mail: presse@helmholtz-muenchen.de