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Epstein-Barr Virus in Nasal Lymphomas Contains Multiple Ongoing
Mutations in the EBNA-1 Gene
M.I. Gutiérrez,
G. Spangler,
D. Kingma,
M. Raffeld,
I. Guerrero,
O. Misad,
E.S. Jaffe,
I.T. Magrath, and
K. Bhatia
From the Lymphoma Biology Section, Pediatric Oncology Branch,
Molecular Pathology Section, Pathology Branch, National Cancer
Institute, National Institutes of Health, Bethesda, MD; and the Centro
de Investigación en Cancer "Maes-Heller" and Instituto
Nacional de Enfermedades Neoplásicas, Lima, Perú.
We have described 5 major subtypes of Epstein-Barr virus (EBV) based
on variations in EBNA-1 sequences. These include P-ala (identical to
the prototype B95.8 virus), P-thr, V-pro, V-leu, and V-val. Normal
individuals often carry multiple EBV subtypes, the most common being
P-ala, whereas EBV-associated tumors examined to date always contain a
single subtype, which only on rare occasion is P-ala. The
primary hypotheses that these observations generate are as follows: (1)
Each of these EBV subtypes are naturally occurring, and in normal
individuals the multiplicity of subtypes results from multiple
infections. (2) EBV subtypes in normal individuals are generated in
vivo from a single infecting virus subtype by mutations in EBNA-1. The
second hypothesis essentially excludes the possibilities that the
nonrandom association of certain subtypes with lymphomas is secondary
to the geographic distribution of EBV subtypes and, if proven correct,
could provide strong support for a direct role of EBV in tumorigenesis.
In this report, we provide evidence for the latter hypothesis. We show
that the P-ala EBV subtype present in most nasal lymphomas undergoes
and accumulates multiple mutations consistent with the generation of
variant species of EBNA-1 in vivo. This phenomenon is similar to the
generation of quasispecies in RNA viruses and is the first description
of in vivo generation of subtypes in DNA viruses. In RNA-based viruses, including human immunodeficiency virus and hepatitis C
virus, the emergence of quasispecies is linked to
replication infidelity and significantly influences disease processes
through its effect on viral tropism, the emergence of viruses resistant
to the host defenses or to therapy, and pathogenicity. The present data
thus raise important questions relating to the mechanisms whereby these mutations are generated in EBV and their relevance to the pathogenicity of EBV-associated lymphomas.
Blood, Vol. 92 No. 2 (July 15), 1998:
pp. 600-606
© 1998 by the American Society of Hematology.
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