Epstein-Barr virus BamHI W repeat number limits EBNA2/EBNA-LP coexpression in newly infected B cells and the efficiency of B-cell transformation: a rationale for the multiple W repeats in wild-type virus strains.

Abstract:

:The genome of Epstein-Barr virus (EBV), a gammaherpesvirus with potent B-cell growth-transforming ability, contains multiple copies of a 3-kb BamHI W repeat sequence; each repeat carries (i) a promoter (Wp) that initiates transformation by driving EBNA-LP and EBNA2 expression and (ii) the W1W2 exons encoding the functionally active repeat domain of EBNA-LP. The W repeat copy number of a virus therefore influences two potential determinants of its transforming ability: the number of available Wp copies and the maximum size of the encoded EBNA-LP. Here, using recombinant EBVs, we show that optimal B-cell transformation requires a minimum of 5 W repeats (5W); the levels of transforming ability fall progressively with viruses carrying 4, 3, and 2 W repeats, as do the levels of Wp-initiated transcripts expressed early postinfection (p.i.), while viruses with 1 copy of the wild-type W repeat (1W) and 0W are completely nontransforming. We therefore suggest that genetic analyses of EBV transforming function should ensure that wild-type and mutant strains have equal numbers (ideally at least 5) of W copies if the analysis is not to be compromised. Attempts to enhance the transforming function of low-W-copy-number viruses, via the activity of helper EBV strains or by gene repair, suggested that the critical defect is not related to EBNA-LP size but to the failure to achieve sufficiently strong coexpression of EBNA-LP and EBNA2 early postinfection. We further show by the results of ex vivo assays that EBV strains in the blood of infected individuals typically have a mean of 5 to 8 W copies, consistent with the view that evolution has selected for viruses with an optimal transforming function.

journal_name

J Virol

journal_title

Journal of virology

authors

Tierney RJ,Kao KY,Nagra JK,Rickinson AB

doi

10.1128/JVI.06059-11

subject

Has Abstract

pub_date

2011-12-01 00:00:00

pages

12362-75

issue

23

eissn

0022-538X

issn

1098-5514

pii

JVI.06059-11

journal_volume

85

pub_type

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