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Requirement of Varicella-Zoster Virus Immediate-Early 4 Protein for Viral Replication

Bunji Sato, Marvin Sommer, Hideki Ito, and Ann M. Arvin^*

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

Received 2 April 2003/ Accepted 15 August 2003

Varicella-zoster virus (VZV) is an alphaherpesvirus that causes two diseases, chickenpox and zoster. VZV open reading frame 4 (ORF4) encodes the immediate-early 4 (IE4) protein, which is conserved among alphaherpesvirus and has transactivation activity in transient transfections. To determine whether the ORF4 gene product is essential for viral replication, we used VZV cosmids to remove ORF4 from the VZV genome. Deleting ORF4 was incompatible with recovery of infectious virus, whereas transfections done by using repaired cosmids with ORF4 inserted at a nonnative site yielded virus. To analyze the functional domain of IE4, we introduced a mutation altering the C-terminal amino acids, KYFKC (K443S), which was designed to disrupt the dimerization of IE4 protein. Transfections with these mutant cosmids yielded no virus, indicating that this KYFKC motif was essential for IE4 function.

Present address: Exploratory Research Laboratories, Fujisawa Pharmaceutical Co., Ltd., Tokodai, Tsukuba, Ibaraki 300-2698, Japan.

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