Identification of a Hydrophobic Domain in Varicella-Zoster Virus ORF61 Necessary for ORF61 Self-Interaction, Viral Replication, and Skin Pathogenesis

The varicella-zoster virus (VZV) ORF61 protein is necessary for normal replication in vitro and virulence in human skin xeno-grafts in the severe combined immunodeficiency mouse model in vivo. These experiments identify a hydrophobic domain that mediates ORF61 self-interaction. While not needed to inhibit host cell defenses, disruption of this domain (residues 250 to 320) severely impairs VZV growth, transactivation of the immediate early 63 and glycoprotein E genes, and the pathogenesis of VZV skin infection in vivo. Varicella-zoster virus (VZV) is a human alphaherpesvirus thatcauses varicella (chicken pox) during primary infection, es-tablishes lifelong latency in the host, and reactivates to cause zoster (shingles) (1). VZV has a double-stranded DNA genome of ap-proximately 125 kbp which encodes at least 70 unique viral pro-teins. Although not present in the virion tegument, ORF61 is a 467-amino-acid protein expressed along with IE62 shortly after virus entry (2). ORF61 truncation and promoter mutations that severely limit ORF61 synthesis are associatedwith little or noVZV replication in cultured cells (3, 4). Our investigations of the ORF61 promotermutant virus revealed that this protein is critica