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Journal of Virology, December 2004, p. 13293-13305, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.13293-13305.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.

Differential Requirement for Cell Fusion and Virion Formation in the Pathogenesis of Varicella-Zoster Virus Infection in Skin and T Cells

Jaya Besser,1 Minako Ikoma,2 Konstanze Fabel,3 Marvin H. Sommer,1 Leigh Zerboni,1 Charles Grose,2 and Ann M. Arvin1*

Departments of Pediatrics and Microbiology,1 Department of Neurosurgery, Stanford University, School of Medicine, Stanford, California,3 Departments of Pediatrics and Central Microscopy Research Facility, University of Iowa, Iowa City, Iowa2

Received 7 May 2004/ Accepted 25 June 2004

The protein product of varicella-zoster virus (VZV) ORF47 is a serine/threonine protein kinase and tegument component. Evaluation of two recombinants of the Oka strain, rOka47{Delta}C, with a C-terminal truncation of ORF47, and rOka47D-N, with a point mutation in the conserved kinase motif, showed that ORF47 kinase function was necessary for optimal VZV replication in human skin xenografts in SCID mice but not in cultured cells. We now demonstrate that rOka47{Delta}C and rOka47D-N mutants do not infect human T-cell xenografts. Differences in the growth of kinase-defective ORF47 mutants allowed an examination of requirements for VZV pathogenesis in skin and T cells in vivo. Although virion assembly was reduced and no virion transport to cell surfaces was observed, epidermal cell fusion persisted, and VZV polykaryocytes were generated by rOka47{Delta}C and rOka47D-N in skin. Virion assembly was also impaired in vitro, but VZV-induced cell fusion continued to cause syncytia in cultured cells infected with rOka47{Delta}C or rOka47D-N. Intracellular trafficking of envelope glycoprotein E and the ORF47 and IE62 proteins, components of the tegument, was aberrant without ORF47 kinase activity. In summary, normal VZV virion assembly appears to require ORF47 kinase function. Cell fusion was induced by ORF47 mutants in skin, and cell-cell spread occurred even though virion formation was deficient. VZV-infected T cells do not undergo cell fusion, and impaired virion assembly by ORF47 mutants was associated with a complete elimination of T-cell infectivity. These observations suggest a differential requirement for cell fusion and virion formation in the pathogenesis of VZV infection in skin and T cells.

* Corresponding author. Mailing address: Stanford University, Department of Pediatrics, 300 Pasteur Dr., G-311, Stanford, CA 94305-5208. Phone: (650) 723-6353. Fax: (650) 725-8040. E-mail: aarvin{at}stanford.edu.

Journal of Virology, December 2004, p. 13293-13305, Vol. 78, No. 23
0022-538X/04/$08.00+0     DOI: 10.1128/JVI.78.23.13293-13305.2004
Copyright © 2004, American Society for Microbiology. All Rights Reserved.



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