scholarly journals Varicella-Zoster Virus Immediate-Early Protein 62 Blocks Interferon Regulatory Factor 3 (IRF3) Phosphorylation at Key Serine Residues: a Novel Mechanism of IRF3 Inhibition among Herpesviruses

2010 ◽  
Vol 84 (18) ◽  
pp. 9240-9253 ◽  
Author(s):  
Nandini Sen ◽  
Marvin Sommer ◽  
Xibing Che ◽  
Kris White ◽  
William T. Ruyechan ◽  
...  
Keyword(s):  
Varicella Zoster Virus ◽  
Immediate Early ◽  
Lung Fibroblasts ◽  
Poly I:C ◽  
Interferon Response ◽  
Luciferase Reporter ◽  
Type I ◽  
Human Embryonic Lung ◽  
Varicella Zoster ◽  
Early Protein

ABSTRACT Varicella-zoster virus (VZV) is an alphaherpesvirus that is restricted to humans. VZV infection of differentiated cells within the host and establishment of latency likely require evasion of innate immunity and limited secretion of antiviral cytokines. Since interferons (IFNs) severely limit VZV replication, we examined the ability of VZV to modulate the induction of the type I IFN response in primary human embryonic lung fibroblasts (HELF). IFN-β production was not detected, and transcription of two interferon response factor 3 (IRF3)-dependent interferon-stimulated genes (ISGs), ISG54 and ISG56, in response to poly(I:C) stimulation was downregulated in VZV-infected HELF. Inhibition of IRF3 function did not require VZV replication; the viral immediate-early protein 62 (IE62) alone was sufficient to produce this effect. IE62 blocked TBK1-mediated IFN-β secretion and IRF3 function, as shown in an IFN-stimulated response element (ISRE)-luciferase reporter assay. However, IRF3 function was preserved if constitutively active IRF3 (IRF3-5D) was expressed in VZV-infected or IE62-transfected cells, indicating that VZV interferes with IRF3 phosphorylation. IE62-mediated inhibition was mapped to blocking phosphorylation of at least three serine residues on IRF3. However, IE62 binding to TBK1 or IRF3 was not detected and IE62 did not perturb TBK1-IRF3 complex formation. IE62-mediated inhibition of IRF3 function was maintained even if IE62 transactivator activity was disrupted. Thus, IE62 has two critical but discrete roles following VZV entry: to induce expression of VZV genes and to disarm the IFN-dependent antiviral defense through a novel mechanism that prevents IRF3 phosphorylation.

The cellular transcription factor USF cooperates with varicella-zoster virus immediate-early protein 62 to symmetrically activate a bidirectional viral promoter

1994 ◽  
Vol 14 (10) ◽  
pp. 6896-6906 ◽  
Author(s):  
J L Meier ◽  
X Luo ◽  
M Sawadogo ◽  
S E Straus
Keyword(s):  
Dna Binding ◽  
Varicella Zoster Virus ◽  
Dominant Negative ◽  
Immediate Early ◽  
Activation Process ◽  
Viral Promoter ◽  
Varicella Zoster ◽  
Cellular Transcription Factor ◽  
Early Protein ◽  
Target Promoters

The mechanisms governing the function of cellular USF and herpesvirus immediate-early transcription factors are subjects of considerable interest. In this regard, we identified a novel form of coordinate gene regulation involving a cooperative interplay between cellular USF and the varicella-zoster virus immediate-early protein 62 (IE 62). A single USF-binding site defines the potential level of IE 62-dependent activation of a bidirectional viral early promoter of the DNA polymerase and major DNA-binding protein genes. We also report a dominant negative USF-2 mutant lacking the DNA-binding domain that permits the delineation of the biological role of both USF-1 and USF-2 in this activation process. The symmetrical stimulation of the bidirectional viral promoter by IE 62 is achieved at concentrations of USF-1 (43 kDa) or USF-2 (44 kDa) already existing in cells. Our observations support the notion that cellular USF can intervene in and possibly target promoters for activation by a herpesvirus immediate-early protein.

scholarly journals Identification of phosphorylated residues on varicella-zoster virus immediate-early protein ORF63

2010 ◽  
Vol 91 (5) ◽  
pp. 1133-1137 ◽  
Author(s):  
N. H. Mueller ◽  
M. S. Walters ◽  
R. A. Marcus ◽  
L. L. Graf ◽  
J. Prenni ◽  
...  
Keyword(s):  
Varicella Zoster Virus ◽  
Immediate Early ◽  
Varicella Zoster ◽  
Early Protein

scholarly journals Mutational analysis of varicella-zoster virus (VZV) immediate early protein (IE62) subdomains and their importance in viral replication

Virology ◽  
2016 ◽  
Vol 492 ◽  
pp. 82-91 ◽  
Author(s):  
Mohamed I. Khalil ◽  
Xibing Che ◽  
Phillip Sung ◽  
Marvin H. Sommer ◽  
John Hay ◽  
...  
Keyword(s):  
Viral Replication ◽  
Varicella Zoster Virus ◽  
Mutational Analysis ◽  
Immediate Early ◽  
Varicella Zoster ◽  
Early Protein

scholarly journals Inhibition of Varicella-Zoster Virus by Penciclovir in Cell Culture and Mechanism of Action

1996 ◽  
Vol 7 (2) ◽  
pp. 71-78 ◽  
Author(s):  
T. H. Bacon ◽  
J. Gilbart ◽  
B. A. Howard ◽  
R. Standring-Cox
Keyword(s):  
Dna Synthesis ◽  
Varicella Zoster Virus ◽  
Clinical Isolates ◽  
Continuous Treatment ◽  
Lung Fibroblasts ◽  
Human Embryonic Lung ◽  
Viral Dna ◽  
Plaque Reduction Assay ◽  
Varicella Zoster ◽  
Infected Cells

The effect of penciclovir (BRL 39123) on the replication of varicella-zoster virus (VZV) in human embryonic lung fibroblasts (MRC-5 cells) was similar to aciclovir when the compounds were present continuously. However, when the compounds were withdrawn the antiviral activity of penciclovir was maintained more effectively than that of aciclovir. In the plaque reduction assay, median 50% effective concentrations (EC50s) were 3.8 μg ml−1 for penciclovir and 4.2 μg ml−1 for aciclovir ( n = 29 clinical isolates). Similarly, penciclovir and aciclovir were equally effective in reducing the numbers of VZV-infected MRC-5 cells and in reducing VZV DNA synthesis within infected cells following continuous treatment. Within VZV-infected cells (S)-penciclovir-triphosphate was formed from penciclovir with >95% enantiomeric purity, and the concentration of penciclovir-triphosphate was 360-fold greater than aciclovir-triphosphate immediately after treatment. This phosphorylation ratio compensates for the lower affinity of VZV DNA polymerase for penciclovir-triphosphate compared with aciclovir-triphosphate (Kis = 7.5 μM and 0.2 μM, respectively). When VZV-infected cultures were treated for 3 days, followed by withdrawal of the compound, inhibition of viral DNA synthesis by penciclovir was maintained for 24 h, whereas viral DNA synthesis resumed more readily after removal of aciclovir. Furthermore, following 8 h daily pulse treatment for 5 days, penciclovir was significantly more active than aciclovir in reducing VZV DNA synthesis ( p = 0.006, n = 10 clinical isolates). The long intracellular half-life of penciclovir-triphosphate (9.1 h) compared with that of aciclovir-triphosphate (0.8 h) accounts for the sustained inhibition of virus replication by penciclovir. This property may contribute to the clinical efficacy of famciclovir, the oral form of penciclovir.

scholarly journals Antibody to Varicella-Zoster Virus Immediate-Early Protein 62 Augments Allodynia in Zoster via Brain-Derived Neurotrophic Factor

2009 ◽  
Vol 84 (3) ◽  
pp. 1616-1624 ◽  
Author(s):  
Yuka Hama ◽  
Kimiyasu Shiraki ◽  
Yoshihiro Yoshida ◽  
Atsushi Maruyama ◽  
Makoto Yasuda ◽  
...  
Keyword(s):  
Varicella Zoster Virus ◽  
Nerve Injury ◽  
Neurotrophic Factor ◽  
Mechanical Allodynia ◽  
Brain Derived Neurotrophic Factor ◽  
Cross Reactivity ◽  
Immediate Early ◽  
Morphological Development ◽  
Varicella Zoster ◽  
Early Protein

ABSTRACT Varicella-zoster virus (VZV) expresses immediate-early protein 62 (IE62), and zoster is associated with neuropathic pain. Brain-derived neurotrophic factor (BDNF) is involved in the neuronal mechanism underlying pain hypersensitivity. Zoster is associated with prodrome and the robust production of booster antibody to VZV. We hypothesized that the intrathecal production of antibody to IE62 cross-reacting with BDNF and the nerve injury by skin lesions may augment allodynia in zoster by enhancing BDNF activity. One of three monoclonal antibodies against the 268-556 peptide of IE62 recognized BDNF. Immunological cross-reactivity between IE62 and BDNF and the effects of anti-IE62 monoclonal antibody (anti-IE62 MAb) cross-reactivity with BDNF on BDNF activity in cultured neurons were examined. Anti-IE62 MAb and anti-BDNF MAbs recognized the 414-429 peptide of IE62 and the BDNF dimer. Anti-IE62 MAb significantly augmented BDNF-related transcription in neurons and the morphological development of spinal dorsal horn neurons. Sera from patients recognized IE62 and BDNF and enhanced BDNF activity in neurons. The effect of anti-IE62 antibody on mechanical allodynia was characterized by the threshold of allodynia using von Frey filaments in a spinal nerve injury (SNI) in mice. The administration of anti-IE62 MAb to or immunization with cross-reacting IE62 protein to mice significantly enhanced mechanical allodynia on the side with SNI but not on the uninjured side. Anti-IE62 antibody augmented BDNF activity in neurons and allodynia in mice with SNI. The intrathecal production of anti-IE62 antibody augmenting BDNF activity and peripheral nerve injury by zoster may participate in the pathogenesis of allodynia in zoster.

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