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Journal of Virology, August 2009, p. 7560-7572, Vol. 83, No. 15
0022-538X/09/$08.00+0     doi:10.1128/JVI.00118-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Regulation of the ORF61 Promoter and ORF61 Functions in Varicella-Zoster Virus Replication and Pathogenesis{triangledown}

Li Wang,* Marvin Sommer, Jaya Rajamani, and Ann M. Arvin

Departments of Pediatrics and Microbiology & Immunology, Stanford University School of Medicine, Stanford, California 94305

Received 18 January 2009/ Accepted 13 May 2009

Varicella-zoster virus (VZV) open reading frame 61 (ORF61) encodes a protein that transactivates viral and cellular promoters in transient-transfection assays and is the ortholog of herpes simplex virus ICP0. In this report, we mapped the ORF61 promoter and investigated its regulation by viral and cellular proteins in transient-expression experiments and by mutagenesis of the VZV genome (parent Oka strain). The 5' boundary of the minimal ORF61 promoter required for IE62 transactivation was mapped to position –95 relative to the mRNA start site, and three noncanonical GT-rich Sp1-binding sites were documented to occur within the region comprising positions –95 to –45. Contributions of the three Sp1-binding-site motifs, designated Sp1a, Sp1b, and Sp1c, to ORF61 expression and viral replication were varied despite their similar sequences. Two sites, Sp1a and Sp1c, functioned synergistically. When both sites were mutated in the pOka genome to produce pOka-61pro{Delta}Sp1ac, the mutant virus expressed significantly less ORF61 protein. Using this mutant to investigate ORF61 functions resulted in reductions in the expression levels of IE proteins, viral kinases ORF47 and ORF66, and the major glycoprotein gE, with the most impact on gE. Virion morphogenesis appeared to be intact despite minimal ORF61 expression. Pretreating melanoma cells with sodium butyrate enhanced titers of pOka-61pro{Delta}Sp1ac but not pOka, suggesting that ORF61 has a role in histone deacetylase inhibition. Growth of pOka-61pro{Delta}Sp1ac was impaired in SCIDhu skin xenografts, indicating that the regulation of the ORF61 promoter by Sp1 family proteins is important for ORF61 expression in vivo and that ORF61 contributes to VZV virulence at skin sites of replication.

* Corresponding author. Mailing address: Stanford University School of Medicine, 300 Pasteur Drive, S356, Stanford, CA 94305-5208. Phone: (650) 723-6353. Fax: (650) 725-9828. E-mail: vlwang{at}stanford.edu

{triangledown} Published ahead of print on 20 May 2009.

Journal of Virology, August 2009, p. 7560-7572, Vol. 83, No. 15
0022-538X/09/$08.00+0     doi:10.1128/JVI.00118-09
Copyright © 2009, American Society for Microbiology. All Rights Reserved.



This article has been cited by other articles:

  • Walters, M. S., Erazo, A., Kinchington, P. R., Silverstein, S. (2009). Histone Deacetylases 1 and 2 Are Phosphorylated at Novel Sites during Varicella-Zoster Virus Infection. J. Virol. 83: 11502-11513 [Abstract] [Full Text]  


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