MOLECULAR BIOLOGY OF VARICELLA ZOSTER VIRUS INFECTIONS

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1) Primary infection with varicella-zoster virus (VZV) causes chickenpox, and reactivation of the virus from latency results in zoster. The goals of this project are to identify and determine the function of VZV genes that are expressed during active infection and during latency in the body. 2) VZV genes that are expressed during active infection and regulate viral gene expression in vitro are being studied. Analysis of VZV gene products during acute infection indicate that five VZV genes, ORF4, ORF10, ORF61, ORF62, and ORF63, regulate the expression of other VZV genes in vitro. Two cellular proteins (Oct1, HCF) have been shown to interact with a VZV protein (ORF10) to activate the ORF62 gene. These cellular proteins have been shown to bind to a specific sequence on the VZV ORF62 promoter. A different cellular protein (USF) has been found to interact with another VZV protein (ORF62) to activate expression of two VZV genes (ORF28, ORF29). The USF protein binds to a specific sequence located between the ORF 28 and 29 genes. 3) Critical domains required for the activity of two VZV genes (VZV ORF4 and ORF61) have been identified. A domain near the amino terminus of ORF4 is required to activate expression of other VZV genes. This domain can functionally substitute for its corresponding homolog in a herpes simplex virus protein. A domain in ORF61 is found in the RING finger family of proteins and is required for functional activity of ORF61 protein. The transcription activation domain of ORF10 has been identified at the amino terminus of the protein. This activation domain has been found to share structural features with its herpes simplex virus VP16 homolog. 4) Central nervous system tissues obtained from individuals who have recovered from chicken pox infection in the distant past are being studied to determine which VZV genes are expressed while the virus in dormant in the human body. Analysis of trigeminal ganglia from human cadavers without active evidence of VZV infection indicates that two VZV genes, ORF29 and ORF62, are expressed during latency in non-neuronal (satellite) cells, while other viral genes (ORF10, ORF61) are not expressed.