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

K Sandvej¹, B S Andresen³, X-G Zhou¹, N Gregersen² and S Hamilton-Dutoit¹

¹ Laboratory of Immunopathology, Institute of Pathology, Kommunehospitalet, DK-8000 Aarhus C, Denmark
² Research Unit for Molecular Medicine, Aarhus University Hospital and Faculty of Health Science, DK-8200, Aarhus N, Denmark
³ Institute of Human Genetics, Aarhus University, DK-8000, Aarhus C, Denmark

Correspondence to:
Dr Sandvej Kristian.Sandvej{at}aas.auh.dk

Aims—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 B (NF-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.

Key Words: Epstein-Barr virus • Hodgkin's disease • latent membrane protein 1 • promoter mutations

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