Affiliation of authors: Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Hong Kong.
Correspondence to: Ka-Fai To, F.R.C.P.A., Department of Anatomical and Cellular Pathology, Prince of Wales Hospital, The Chinese University of Hong Kong, Shatin, NT Hong Kong (e-mail: kfto{at}cuhk.edu.hk).
In their recent article, Gutiérrez et al. (1) identified three EpsteinBarr virus (EBV) variants in the BZLF1 promoter Zp (Zp-P [considered the prototypical sequence], Zp-V3, and Zp-V4) and postulated that these might result in different lytic potentials and be differentially expressed among individuals with nonmalignant and malignant diseases. Hong Kong and Southern China are considered to be endemic regions, with the EBV variants that are different from other localities.
We analyzed EBV type and sequence variations in EBV Zp domains by direct DNA sequencing in a total of 95 EBV-associated lesions (96 isolates) from individuals from Hong Kong and Southern China (Table 1). Eighty-seven of 95 (91.6%) lesions contained type A EBV. Eight (8.4%) lesions contained type B EBV, all of which carried Zp-V3. Of the 88 type A EBV isolates, 31 (35.2%) contained Zp-P and 53 (60.2%) contained Zp-V3. From 36 nonmalignant samples with type A EBV, 19 (52.8%) contained Zp-P, and 16 (44%) contained Zp-V3. From 51 malignant samples, we obtained 52 EBV isolates with type A EBV, of which 12 (23.1%) contained Zp-P and 37 (71.2%) contained Zp-V3. In addition, from one nonmalignant and three malignant samples with type A EBV, we identified four novel Zp-P variants. Three variants differed from Zp-P at one position only: Zp-V1_104 (-104C-A), isolated from a healthy carrier; Zp-V1_105 (-105C-T), isolated from a natural killer (NK)/T-cell lymphoma; and Zp-V1_119 (-119G-A), isolated from a nasopharyngeal carcinoma (NPC). All these substitutions occurred within the ZIIIB domain of Zp, which can strongly bind ZEBRA (Z, EB replication activator) and contribute to the transactivation of Zp (2). A fourth variant (Zp-V3+118), isolated from an NPC, contained four nucleotide substitutions relative to Zp-P, three of which were identical to those found in Zp-V3 (1), and the fourth a C to T substitution at position -118. This position is also within the functional domain of ZIIIB. It is noteworthy that this variant with four nucleotide substitutions was different from the Zp-V4 variant described by Gutiérrez et al. (1). Taken together, these results suggest that the ZIIIB domain may be a mutational hotspot.
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In our locality, the distribution of EBV variants with respect to Zp in various EBV-associated conditions is distinct from other geographic regions. Although Zp-V3 is detectable in nonmalignant samples, it is statistically significantly associated with NPC. Whether these variants have a functional consequence remains to be determined. However, the possible link(s) between different variants and lytic potential or latency-to-lytic cycle switch requires further investigation.
NOTES
Supported by Research Grants Committee Earmarked Grant CU4301/99M, Hong Kong Special Administrative Region of the Peoples Republic of China.
REFERENCES
1 Gutierrez MI, Ibrahim MM, Dale JK, Greiner TC, Straus SE, Bhatia K. Discrete alterations in the BZLF1 promoter in tumor and non-tumor-associated Epstein-Barr virus. J Natl Cancer Inst 2002;94:175763.
2 Flemington E, Speck SH. Autoregulation of Epstein-Barr virus putative lytic switch gene BZLF1. J Virol 1990;64:122732.[ISI][Medline]
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