Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
MOLECULAR MUTANTS OF EBV AND MEDICAL CONSEQUENCES (MEETING ABSTRACT)
Causes, Cures and Consequences of Lymphoproliferative Diseases--A Symposium to Honor George and Eva Klein. May 9-11, 1991, Omaha, NE, 1991.. Unique Identifier : AIDSLINE ICDB/92679938 Patton DF; No affiliation given
Abstract:
Recent work has begun to expose the importance of EBV in mucosal epithelium. Epithelia appear to provide a permissive site for EBV in which replicative/lytic cycle genes are prominent. Variants of the prototypic EBV genome exist and are associated with diverse in vitro and in vivo properties. At least two and probably three biotypes exist (EBV1, EBV2, EBV3) as well as a variety of defective EBV. Defective EBV consist of a variety of genomic deletions and rearrangements which probably do not include EBNA2 at all, cannot transform B cells but instead disrupt latency of EBV-transformed B cells in vitro, are found only in association with standard (parent) virus and, thus far, have been found in association with replicating EBV in epithelia. Work in our lab has focused on identification of the defective EBV in clinical samples. The first well-characterized defective EBV was found in an endemic Burkitt's lymphoma derived from Jijoye called P3HR-1. The defective genome called 'hetDNA' consists of a largely deleted, recombined, palindromic sequence. In vitro, these hetDNA are able to induce replicative cycles in latently infected B cell lines; this biologic effect maps to the rearrangement of standard bamHI segments W and Z, two fragments normally separated by 55 kb. The BamWZ rearrangement allows for the upregulation of the BamHI Z gene product called ZEBRA which is a transactivator of the EBV lytic cycle. ZEBRA, a DNA binding protein, also has sequence similarity to c-fos and binds the AP-1 site. We have looked for evidence of hetDNA in human lesions by performing polymerase chain reaction (PCR) amplification of the abnormal WZ junction. We have also looked for expression of ZEBRA in tissues as a marker for the EBV lytic cycle and possibly for hetDNA. We have shown by PCR and DNA sequencing that the BamWZ rearrangement characteristic of hetDNA is found in the human lesion oral hairy leukoplakia (OHL). OHL is an epithelial lesion found mostly in HIV-infected individuals but contains abundant replicating EBV. Preliminary results show that the BamWZ rearrangement is present in other epithelial specimens such as tongue scrapings of HIV-infected patients without OHL, and in a thymic carcinoma containing replicating EBV. Using monospecific (gift of Miller) and monoclonal (gift of Young) antibodies to ZEBRA, we have identified high levels of ZEBRA expression in epithelial and post-transplant B-cell tumors containing EBV. In summary, EBV clearly has several significant and interrelated variants which may have clinical significance yet to be identified. Traditional reliance on B cell transformation as the diagnostic test for the virus has prohibited detection of variants that may thrive in the mucosal epithelial setting of the immunocompetent host. Use of PCR and other methods will permit detection of less common variants which effect EBV pathogenesis but do not easily transform B cells unless in the setting of immunodeficiency. Understanding interactions of variants will hopefully lead to rational and effective therapy against EBV.
Keywords: B-Lymphocytes/PHYSIOLOGY Burkitt's Lymphoma/*GENETICS Chromosome Deletion DNA-Binding Proteins/*GENETICS/METABOLISM DNA, Neoplasm/GENETICS Gene Amplification Gene Expression Gene Rearrangement Genes, fos/GENETICS Genome, Viral Herpesvirus 4, Human/*GENETICS/PHYSIOLOGY Human Polymerase Chain Reaction Trans-Activators/GENETICS Up-Regulation (Physiology) Virus Replication ABSTRACT 920630
M9261015
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Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
