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J Virol, May 1998, p. 4371-4378, Vol. 72, No. 5
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.

Cell-to-Cell Contact as an Efficient Mode of Epstein-Barr Virus Infection of Diverse Human Epithelial Cells

Shosuke Imai,1 Jun Nishikawa,1,2 and Kenzo Takada1,*

Department of Virology, Cancer Institute, Hokkaido University School of Medicine, Sapporo 060,1 and First Department of Internal Medicine, Yamaguchi University School of Medicine, Ube 755,2 Japan

Received 2 December 1997/Accepted 4 February 1998

We show clear evidence for direct infection of various human epithelial cells by Epstein-Barr virus (EBV) in vitro. The successful infection was achieved by using recombinant EBV (Akata strain) carrying a selective marker gene but without any other artificial operations, such as introduction of the known EBV receptor (CD21) gene or addition of polymeric immunoglobulin A against viral gp350 in culture. Of 21 human epithelial cell lines examined, 18 became infected by EBV, as ascertained by the detection of EBV-determined nuclear antigen (EBNA) 1 expression in the early period after virus exposure, and the following selection culture easily yielded a number of EBV-infected clones from 15 cell lines. None of the human fibroblasts and five nonhuman-derived cell lines examined was susceptible to the infection. By comparison, cocultivation with virus producers showed approx 800-fold-higher efficiency of infection than cell-free infection did, suggesting the significance of direct cell-to-cell contact as a mode of virus spread in vivo. Most of the epithelial cell lines infectable with EBV were negative for CD21 expression at the protein and mRNA levels. The majority of EBV-infected clones established from each cell line invariably expressed EBNA1, EBV-encoded small RNAs, rightward transcripts from the BamHI-A region of the virus genome, and latent membrane protein (LMP) 2A, but not the other EBNAs or LMP1. This restricted form of latent viral gene expression, which is a central issue for understanding epithelial oncogenesis by EBV, resembled that seen in EBV-associated gastric carcinoma and LMP1-negative nasopharyngeal carcinoma. The results indicate that direct infection of epithelial cells by EBV may occur naturally in vivo, and this could be mediated by an unidentified, epithelium-specific binding receptor for EBV. The EBV convertants are viewed, at least in terms of viral gene expression, as in vitro analogs of EBV-associated epithelial tumor cells, thus facilitating analysis of an oncogenic role(s) for EBV in epithelial cells.

* Corresponding author. Mailing address: Department of Virology, Cancer Institute, Hokkaido University School of Medicine, N15 W7, Kita-ku, Sapporo 060, Japan. Phone: 81-11-706-5071. Fax: 81-11-717-1128. E-mail: kentaka{at}med.hokudai.ac.jp.

J Virol, May 1998, p. 4371-4378, Vol. 72, No. 5
0022-538X/98/$04.00+0
Copyright © 1998, American Society for Microbiology. All rights reserved.


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