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Epstein-Barr virus strains with latent membrane protein-1 deletions:
prevalence in the Italian population and high association with human
immunodeficiency virus-related Hodgkin's disease
R Dolcetti, P Zancai, V De Re, A Gloghini, B Bigoni, B Pivetta, S De Vita, A Carbone and M Boiocchi
Division of Experimental Oncology 1, Centro di Riferimento Oncologico,
Aviano, Italy.
Six Epstein-Barr virus (EBV)-related lymphoproliferative disorders were
investigated to verify whether the EBV strain harbored by neoplastic cells
had the same EBNA-2 and latent membrane protein-1 (LMP-1) DNA sequences of
the virus carried by normal lymphocytes of the same patients. Within each
case, the analysis of neoplastic lymph nodes, reactive lymphadenopathies,
and/or EBV+ spontaneous lymphoblastoid cell lines gave concordant results
with respect to type-specific EBNA-2 region and LMP-1 gene. In particular,
five cases showed the same deletion in the 3' end of the LMP-1 gene in both
normal and neoplastic cells. We also determined the prevalence of LMP-1
deletions in a large series of normal peripheral blood mononucleated cells
(PBMCs) from Italian individuals. The analysis showed that 50% (9 of 18) of
PBMCs from human immunodeficiency virus (HIV)-seronegative donors carried a
30-bp deletion in the C-terminal portion of the LMP-1 gene, whereas a
nondeleted fragment was amplified in about 44% (8 of 18) of the cases. Only
one sample (5.6%) showed the amplification of a full-length LMP-1 band
together with a deleted fragment. Similarly, PBMCs from HIV- infected
patients showed an almost equivalent prevalence of full-length (17 of 37,
46%) and deleted (16 of 37, 43.2%) LMP-1 fragments, whereas about 11% of
samples (4 of 37) showed evidence of double infections. Of note, deletions
in the LMP-1 gene were detected with similar prevalence values in EBV+
Hodgkin's disease (HD) (13 of 30, 43.3%) and non- Hodgkin's lymphoma (NHL)
(2 of 5, 40%) cases from HIV-seronegative patients and in HIV-related, EBV+
NHLs (4 of 7, 57.1%). Conversely, a 30-bp LMP-1 deletion was found in 10 of
12 HIV-associated HD cases (83%), a prevalence significantly higher than
that detected in HIV- unrelated HD (P = .01). These findings indicate that:
(1) the same EBV strain carrying LMP-1 deletions is harbored by normal and
neoplastic cells of patients with EBV+ disorders, ruling out that these
mutations might result from immunoselection phenomena; (2) in the Italian
population, the prevalence of LMP-1 deletion mutants is comparable to that
of EBV strains with full-length LMP-1; (3) HIV-induced immunosuppression is
not associated with an increased prevalence of LMP- 1 deletions in PBMCs;
and (4) HIV-related HD cases, but not those of HIV-seronegative Italian
patients, are closely correlated with the presence of LMP-1 deletions,
suggesting that infection with these strains may increase the risk of
developing HD in the HIV setting.
Volume 89,
Issue 5,
pp. 1723-1731,
03/01/1997
Copyright © 1997 by The American Society of Hematology
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