A herpes simplex virus type 1 recombinant with both copies of the Vmw175 coding sequences replaced by the homologous varicella-zoster virus open reading frame

Disney, Graham H.; Everett, Roger D.

doi:10.1099/0022-1317-71-11-2681

Cited by 46 publications

(30 citation statements)

References 38 publications

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“…Vmw175 is an essential protein with a central role in regulation of the HSV-1 transcriptional programme, and has been the subject of intense study (reviewed by Everett, 1987). The VZV gene 62 protein is highly similar (Davison & Scott, 1985;McGeoch et al, 1986) and functionally analogous to Vmw175 (Felser et al, 1988;Disney & Everett, 1990), and has been identified immunologically in infected cells (Felser et al, 1988;Forghani et al, 1990). Vmw63 is an essential protein which regulates later phases of HSV-1 transcription (reviewed by Sandri-Goldin, 1991).…”

Section: Introductionmentioning

confidence: 99%

Characterization of the varicella-zoster virus gene 61 protein

Stevenson

Colman²,

Davison³

1992

Journal of General Virology

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Section: Introductionmentioning

confidence: 99%

Characterization of the varicella-zoster virus gene 61 protein

Stevenson

Colman²,

Davison³

1992

Journal of General Virology

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“…The IE62 protein exhibits functional characteristics resembling those of HSV ICP4, which it complements, and has some similarities to HSV VP16 (19,27,28,40,44,49,59). IE62 protein substitutes for ICP4 function in transient-expression assays (14,15) and in HSV mutants from which ICP4 has been deleted (10). IE62 protein differs from ICP4 in being a relatively abundant tegument protein, whereas much less ICP4 is associated with HSV-1 virions (63).…”

mentioning

confidence: 99%

Mutational Analysis of Open Reading Frames 62 and 71, Encoding the Varicella-Zoster Virus Immediate-Early Transactivating Protein, IE62, and Effects on Replication In Vitro and in Skin Xenografts in the SCID-hu Mouse In Vivo

Sato

Ito

Hinchliffe

et al. 2003

J Virol

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The varicella-zoster virus (VZV) genome has unique long (U L ) and unique short (U S ) segments which are flanked by internal repeat (IR) and terminal repeat (TR) sequences. The immediate-early 62 (IE62) protein, encoded by open reading frame 62 (ORF62) and ORF71 in these repeats, is the major VZV transactivating protein. Mutational analyses were done with VZV cosmids generated from parent Oka (pOka), a low-passage clinical isolate, and repair experiments were done with ORF62 from pOka and vaccine Oka (vOka), which is derived from pOka. Transfections using VZV cosmids from which ORF62, ORF71, or the ORF62/71 gene pair was deleted showed that VZV replication required at least one copy of ORF62. The insertion of ORF62 from pOka or vOka into a nonnative site in U S allowed VZV replication in cell culture in vitro, although the plaque size and yields of infectious virus were decreased. Targeted mutations in binding sites reported to affect interaction with IE4 protein and a putative ORF9 protein binding site were not lethal. Single deletions of ORF62 or ORF71 from cosmids permitted recovery of infectious virus, but recombination events repaired the defective repeat region in some progeny viruses, as verified by PCR and Southern hybridization. VZV infectivity in skin xenografts in the SCID-hu model required ORF62 expression; mixtures of single-copy recombinant Oka⌬62 (rOka⌬62) or rOka⌬71 and repaired rOka generated by recombination of the single-copy deletion mutants were detected in some skin implants. Although insertion of ORF62 into the nonnative site permitted replication in cell culture, ORF62 expression from its native site was necessary for cell-cell spread in differentiated human skin tissues in vivo.Varicella-zoster virus (VZV) belongs to the alphaherpesvirus subfamily of the Herpesviridae. VZV is the causative agent of varicella, which is characterized by cell-associated viremia and a cutaneous vesicular rash (4). VZV establishes latency in cells within sensory ganglia during primary infection. VZV reactivation from latency results in herpes zoster, a localized skin rash in the distribution of nerves from the affected ganglion. VZV is the first human herpesvirus for which a vaccine has been developed to prevent primary infection (58). This live attenuated varicella vaccine was created by serial passage of a wild-type clinical isolate, the parent Oka (pOka) strain, in guinea pig embryo cells and human fibroblasts to generate the varicella vaccine virus (vOka).The VZV genome consists of approximately 125 kb and has at least 70 unique open reading frames (ORFs) (52). As is characteristic of herpesviruses, the double-stranded DNA genome has unique long (U L ) and unique short (U S ) segments which are flanked by internal repeat (IR) and terminal repeat (TR) sequences. Three duplicated genes, ORF62/71, ORF63/ 70, and ORF64/69, are located in repeats at each end of the U S segment. The two VZV origins of replication, designated OriS, are also located in these repeat regions. The immediate-early 62 (IE62) protein,...

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“…IE62 is expressed from an IE gene (14) and is a powerful transcriptional activator (4,21,39,44,52,53). IE62 has considerable structural and functional conservation to the major HSV-1 regulatory protein ICP4, sharing many of the properties attributed to HSV-1 ICP4 and likely acting through similar mechanisms (10,13). In VZV-infected cells, IE62 localizes to the nucleus, using a typical arginine/ lysine-rich nuclear localization signal that includes amino acids 676 to 685 (2,14,31).…”

mentioning

confidence: 99%

Nuclear Accumulation of IE62, the Varicella-Zoster Virus (VZV) Major Transcriptional Regulatory Protein, Is Inhibited by Phosphorylation Mediated by the VZV Open Reading Frame 66 Protein Kinase

Kinchington

Fite

Turse

2000

J Virol

109

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IE62, the major transcriptional activator protein encoded by varicella-zoster virus (VZV), locates to the nucleus when expressed in transfected cells. We show here that cytoplasmic forms of IE62 accumulate in transfected and VZV-infected cells as the result of the protein kinase activity associated with VZV open reading frame 66 (ORF66). Expression of the ORF66 protein kinase but not the VZV ORF47 protein kinase impaired the ability of coexpressed IE62 to transactivate promoter-reporter constructs. IE62 that was coexpressed with the ORF66 protein accumulated predominantly in the cytoplasm, whereas the normal nuclear localization of other proteins was not affected by the ORF66 protein. In cells infected with VZV, IE62 accumulated in the cytoplasm at late times of infection, whereas in cells infected with a VZV recombinant unable to express ORF66 protein (ROka66S), IE62 was completely nuclear. Point mutations introduced into the predicted serine/ threonine catalytic domain and ATP binding domain of ORF66 abrogated its ability to influence IE62 nuclear localization, indicating that the protein kinase activity was required. The region of IE62 that was targeted by ORF66 was mapped to amino acids 602 to 733. IE62 peptides containing this region were specifically phosphorylated in cells coexpressing the ORF66 protein kinase and in cells infected with wild-type VZV but were not phosphorylated in cells infected with ROka66S. We conclude that the ORF66 protein kinase phosphorylates IE62 to induce its cytoplasmic accumulation, most likely by inhibiting IE62 nuclear import.

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A herpes simplex virus type 1 recombinant with both copies of the Vmw175 coding sequences replaced by the homologous varicella-zoster virus open reading frame

Cited by 46 publications

References 38 publications

Characterization of the varicella-zoster virus gene 61 protein

Characterization of the varicella-zoster virus gene 61 protein

Mutational Analysis of Open Reading Frames 62 and 71, Encoding the Varicella-Zoster Virus Immediate-Early Transactivating Protein, IE62, and Effects on Replication In Vitro and in Skin Xenografts in the SCID-hu Mouse In Vivo

Nuclear Accumulation of IE62, the Varicella-Zoster Virus (VZV) Major Transcriptional Regulatory Protein, Is Inhibited by Phosphorylation Mediated by the VZV Open Reading Frame 66 Protein Kinase

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