Sequence polymorphisms between latent membrane proteins LMP1 and LMP2A do not correlate in EBV-associated reactive and malignant lympho-proliferations

The latent membrane proteins LMP1 and LMP2A are co-expressed in most malign ancies associated with Epstein-Barr virus (EBV), In contrast with the trans forming LMP1 oncoprotein, LMP2A is expressed in lymphocytes of healthy EBV carriers and considered to maintain viral latency. Critical for these LMP2A functions are a transmembranous epitope recognized by specific cytotoxic T lymphocytes (CTLs) and the N-terminal immunoreceptor tyrosine-based activa tion motif (ITAM), blocking B cell receptor signaling. To characterize ITAM and CTL motifs of LMP2A and to correlate them with C-terminal variants of LMPI including the 30-bp deletion variant (LMP1 Delta), comparative sequenc e analysis was performed on 76 samples from patients with reactive and mali gnant lympho-proliferation (infectious mononucleosis, n = 21; tonsillar hyp erplasia, n = 16, chronic lymphoproliferation, n = 9; Hodgkin's disease, n = 8; Non-Hodgkin's lymphoma, n = 5; AIDS-related large-cell lymphoma, n = 1 7). The CTL motif was conserved in all but 2 cases (C-426-->S). The ITAM mo tif was characterized by strictly conserved YXXL sequences in all cases, wi th a sequence polymorphism in between. The B95.8 prototype was found in 17% (13/76) of cases, while in 72% a variant with 3 point mutations (166796 C- ->A, 166805 C-->A, 166810 C-->T) was detected; 11% had 1 or 2 of these muta tions in addition to G-->A at 166793. In the C terminus of LMP1, a hypervar iable region including LMP1 Delta was described in 61% of cases. There was no significant association of a particular LMP2A variant with either malign ant phenotype or LMP1 Delta, demonstrating that the functional domains of L MP2A are conserved and that the sequence polymorphisms in LMP1 and LMP2A ar e independent. (C) 1999 Wiley-Liss, Inc.