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Analysis of the Epstein-Barr virus (EBV) latent membrane protein 1 (LMP-1) gene and promoter in Hodgkin's disease isolates: selection against EBV variants with mutations in the LMP-1 promoter ATF-1/CREB-1 binding site.

AbstractAIMS:
To study the distribution of Epstein-Barr virus (EBV) variants containing mutations in the latent membrane protein 1 (LMP-1) oncogene and promoter in EBV associated Hodgkin's disease and infectious mononucleosis compared with previous findings in asymptomatic EBV carriers.
METHODS:
Sequence analysis of the EBV LMP-1 promoter and gene in isolates from Danish patients with Hodgkin's disease (n = 61) and infectious mononucleosis (n = 10).
RESULTS:
Viruses (previously designated group D) that contain two mutations in the activating transcription factor/cAMP response element (ATF/CRE) in the LMP-1 promoter, which are known to decrease promoter activity greatly, were significantly less frequent in Hodgkin's disease than in both infectious mononucleosis (p = 0.0081) and asymptomatic EBV carriers (p = 0.0084). In some cases, the LMP-1 gene contained mutations in a recently identified cytotoxic T cell (CTL) epitope. Most viral isolates contained mutations shown to increase nuclear factor kappa B (NF-kappa B) activation and had one of two newly identified C-terminal activation regions 3 (CTAR-3) deleted. The exon 1 Xho-I restriction site in the LMP-1 gene could be lost through a range of different mutations.
CONCLUSIONS:
These findings indicate selection pressure against EBV strains with weak LMP-1 promoter activity in Hodgkin's disease and thus provide further strong circumstantial evidence for the pathogenic role of EBV (and LMP-1) in this disease. Mutation of the CTL epitope suggests immune selection of EBV strains. Many EBV isolates contain functionally important mutations in the LMP-1 gene. Loss of the Xho-I restriction site should not be used as a marker of specific LMP-1 variants.
AuthorsK Sandvej, B S Andresen, X G Zhou, N Gregersen, S Hamilton-Dutoit
JournalMolecular pathology : MP (Mol Pathol) Vol. 53 Issue 5 Pg. 280-8 (Oct 2000) ISSN: 1366-8714 [Print] England
PMID11091852 (Publication Type: Comparative Study, Journal Article, Research Support, Non-U.S. Gov't)
Chemical References
  • Activating Transcription Factor 1
  • DNA-Binding Proteins
  • EBV-associated membrane antigen, Epstein-Barr virus
  • Epitopes, T-Lymphocyte
  • Genetic Markers
  • NF-kappa B
  • Nuclear Proteins
  • Trans-Activators
  • Transcription Factors
  • Viral Matrix Proteins
  • CREB-Binding Protein
  • CREBBP protein, human
Topics
  • Activating Transcription Factor 1
  • Base Sequence
  • CREB-Binding Protein
  • DNA-Binding Proteins
  • Epitopes, T-Lymphocyte (genetics)
  • Genetic Markers
  • Herpesvirus 4, Human (genetics)
  • Hodgkin Disease (immunology, virology)
  • Humans
  • Infectious Mononucleosis (immunology, virology)
  • Molecular Sequence Data
  • Mutation
  • NF-kappa B (genetics)
  • Nuclear Proteins (genetics)
  • Polymerase Chain Reaction
  • Promoter Regions, Genetic (genetics)
  • Sequence Analysis, DNA
  • T-Lymphocytes, Cytotoxic (ultrastructure)
  • Trans-Activators (genetics)
  • Transcription Factors (genetics)
  • Viral Matrix Proteins (genetics)

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