Chin Med J (Taipei) 1998;61:S111.

Sequence Variability in EBNA-1 May Reflect Variable Pathogenicity of EBV Subtypes

Magrath IT, Gutierrez M, Bhatia K.

National Cancer Institute, Maryland, USA

Abstract

We have shown that there are at least 5 subtypes of EBV detectable in normal individuals, based on sequence analysis of EBNA-1, an EBV latent gene responsible for viral genome maintenance In latently infected cells. Interestingly, the most frequently detected subtype (P-ala) in normal individuals is the least frequently detected subtype in EBV associated tumors. Moreover, we have not observed one subtype, V-leu, in normal individuals, although this is present in a high fraction of Burkitt's lymphomas. V-Ieu differs only at a single amino acid (487) from a subtype that does occur in normal cells, suggesting that V-leu arises by mutation in V-pro. The possibility that most of the EBNA-1 mutations are generated in the infected individual, rather than representing separate infecting viral strains, is supported by the observation that several EBNA-1 subtypes may be present in a single subject, but some subtypes (V-pro and V-val) never occur in the absence of others (P-ala or P-thr). In contrast to normal individuals, in Burkitt's lymphoma and nasopharyngeal carcinomas we have been able to detect only a single subtype. Recently, we provided strong additional evidence that EBNA-1 subtypes are generated in vivo after infection with a single variant. In nasal NK/T cell lymphomas from Latin America, we identified multiple mutations in EBNA-1, although the virus was monoclonal at another locus within the LMP-1 gene. Within individual tumors, incremental mutation of EBNA-1 was demonstrated by molecular cloning of EBNA-1 fragments. Interestingly, although mutations we have not previously observed were found in these tumors, the most frequent mutations were those associated with the five variant subtypes we have previously described,. Thus, NK/T cell lymphoma differs markedly from other EBV associated tumors with respect to the sequence variation in EBNA-1, and appears to provide an environment in which EBNA-1 mutation is fostered, or more readily tolerated. Our data also imply that EBNA-1 mutation may have relevance to the viral host range, to the pathogenesis of EBV associated mutation, and could even be relevant to the clinical consequences of EBV infection. In this respect, EBNA-1 mutation resembles the generation of quasi-species in RNA viruses.

[Chin Med J (Taipei) 1998;61:S111.]