Mutational Analysis of the Repeated Open Reading Frames, ORFs 63 and 70 and ORFs 64 and 69, of Varicella-Zoster Virus

doi:10.1128/JVI.75.17.8224-8239.2001

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Journal of Virology, September 2001, p. 8224-8239, Vol. 75, No. 17
0022-538X/01/$04.00+0 DOI: 10.1128/JVI.75.17.8224-8239.2001
Copyright © 2001, American Society for Microbiology. All rights reserved.

Mutational Analysis of the Repeated Open Reading Frames, ORFs 63 and 70 and ORFs 64 and 69, of Varicella-Zoster Virus

Marvin H. Sommer,¹^,^* Edward Zagha,¹ Oscar K. Serrano,¹ Chia Chi Ku,¹ Leigh Zerboni,¹ Armin Baiker,¹ Richard Santos,² Mary Spengler,³ Jennifer Lynch,³ Charles Grose,² William Ruyechan,³ John Hay,³ and Ann M. Arvin¹

Department of Pediatrics, Stanford University School of Medicine, Stanford, California¹; Department of Pediatrics, University of Iowa, Iowa City, Iowa²; and Department of Microbiology, State University of New York at Buffalo, Buffalo, New York³

Received 15 February 2001/Accepted 4 June 2001

Varicella-zoster virus (VZV) open reading frame 63 (ORF63), located between nucleotides 110581 and 111417 in the internalrepeat region, encodes a nuclear phosphoprotein which is homologousto herpes simplex virus type 1 (HSV-1) ICP22 and is duplicatedin the terminal repeat region as ORF70 (nucleotides 118480 to119316). We evaluated the role of ORFs 63 and 70 in VZV replication,using recombinant VZV cosmids and PCR-based mutagenesis to makesingle and dual deletions of these ORFs. VZV was recovered within8 to 10 days when cosmids with single deletions were transfectedinto melanoma cells along with the three intact VZV cosmids. Incontrast, VZV was not detected in transfections carried out witha dual deletion cosmid. Infectious virus was recovered when ORF63was cloned into a nonnative AvrII site in this cosmid, confirmingthat failure to generate virus was due to the dual ORF63/70 deletionand that replication required at least one gene copy. This requirementmay be related to our observation that ORF63 interacts directlywith ORF62, the major immediate-early transactivating proteinof VZV. ORF64 is located within the inverted repeat region betweennucleotides 111565 and 112107; it has some homology to the HSV-1Us10 gene and is duplicated as ORF69 (nucleotides 117790 to 118332).ORF64 and ORF69 were deleted individually or simultaneously usingthe VZV cosmid system. Single deletions of ORF64 or ORF69 yieldedviral plaques with the same kinetics and morphology as virusesgenerated with the parental cosmids. The dual deletion of ORF64and ORF69 was associated with an abnormal plaque phenotype characterizedby very large, multinucleated syncytia. Finally, all of the deletionmutants that yielded recombinants retained infectivity for humanT cells in vitro and replicated efficiently in human skin in theSCIDhu mouse model of VZVpathogenesis.

^* Corresponding author. Mailing address: 300 Pasteur Dr., Rm. G312, Stanford University School of Medicine, Stanford, CA 94305-5208.Phone: (650) 723-5682. Fax: (650) 725-8040. E-mail: marvman{at}stanford.edu.

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