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Journal of Virology, September 2005, p. 11990-12001, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.11990-12001.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.

The Extracellular Domain of Herpes Simplex Virus gE Is Indispensable for Efficient Cell-to-Cell Spread: Evidence for gE/gI Receptors

Katarina Polcicova,{dagger} Kim Goldsmith,{ddagger} Barb L. Rainish, Todd W. Wisner, and David C. Johnson*

Department of Molecular Microbiology & Immunology, Oregon Health & Science University, Portland, Oregon 97239

Received 2 May 2005/ Accepted 29 June 2005

Herpes simplex virus (HSV) spreads rapidly and efficiently within epithelial and neuronal tissues. The HSV glycoprotein heterodimer gE/gI plays a critical role in promoting cell-to-cell spread but does not obviously function during entry of extracellular virus into cells. Thus, gE/gI is an important molecular handle on the poorly understood process of cell-to-cell spread. There was previous evidence that the large extracellular (ET) domains of gE/gI might be important in cell-to-cell spread. First, gE/gI extensively accumulates at cell junctions, consistent with being tethered there. Second, expression of gE/gI in trans interfered with HSV spread between epithelial cells. To directly test whether the gE ET domain was necessary for gE/gI to promote virus spread, a panel of gE mutants with small insertions in the ET domain was constructed. Cell-to-cell spread was reduced when insertions were made within either of two regions, residues 256 to 291 or 348 to 380. There was a strong correlation between loss of cell-to-cell spread function and binding of immunoglobulin. gE ET domain mutants 277, 291, and 348 bound gI, produced mature forms of gE that reached the cell surface, and were incorporated into virions yet produced plaques similar to gE null mutants. Moreover, all three mutants were highly restricted in spread within the corneal epithelium, in the case of mutant 277 to only 4 to 6% of the number of cells compared with wild-type HSV. Therefore, the ET domain of gE is indispensable for efficient cell-to-cell spread. These observations are consistent with our working hypothesis that gE/gI can bind extracellular ligands, so-called gE/gI receptors that are concentrated at epithelial cell junctions. This fits with similarities in structure and function of gE/gI and gD, which is a receptor binding protein.

* Corresponding author. Mailing address: L-220, Room 6366/BSc, Dept. of Mol. Microbiology & Immunology, Oregon Health & Science University, 3181 SW Sam Jackson Park Rd., Portland, OR 97239. Phone: (503) 494-0834. Fax: (503) 494-6862. E-mail: johnsoda{at}ohsu.edu.

{dagger} Present address: Institute of Virology, Slovak Academy of Sciences, Bratislava, Slovak Republic.

{ddagger} Present address: UCL Centre for Infectious Disease Epidemiology, Royal Free Hospital, London, England.

Journal of Virology, September 2005, p. 11990-12001, Vol. 79, No. 18
0022-538X/05/$08.00+0     doi:10.1128/JVI.79.18.11990-12001.2005
Copyright © 2005, American Society for Microbiology. All Rights Reserved.



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