Varicella-zoster virus (VZV) causes chickenpox and shingles. Virus infection of cells is known to trigger several signaling pathways that are important for cell proliferation and prevention of programmed cell death (also known as apoptosis). We have used a virus genome wide approach to identify functions of VZV proteins. Nearly all of the 71 VZV genes were individually expressed in tissue culture cells along with a reporter system that responds to specific signaling proteins. Using this approach, last year we showed that VZV ORF12 protein activates two protein kinases (ERK1/2 and p38). ORF12 protein was shown to localize in the virus tegument (between the virus envelope and the protein structure surrounding the viral DNA). We also found that ORF12 inhibits programmed cell death (apoptosis) induced by chemical treatment of the cells. This year we extended our studies of VZV ORF12 and showed that the protein also activates the phosphatidylinositol 3-kinase (PI3K)/Akt pathway (a cell signaling pathway) to regulate cell cycle progression (important for cell division). Expression of ORF12 protein in cells induced phosphorylation of Akt to its active form. In addition infection of cells with wild-type VZV triggered phosphorylation of Akt, while infection with an VZV ORF12 deletion mutant induced less phosphorylation of Akt. Activation of Akt by ORF12 protein was associated with its binding to the p85 subunit of PI3K. Infection of cells with wild-type VZV resulted in increased levels of cyclin B1, cyclin D3, and phosphorylated glycogen synthase kinase 3-beta, while infection with the VZV ORF12 deletion mutant induced lower levels of these proteins. Wild-type VZV infection reduced the number of cells in the G1 phase of the cell cycle and increased the number of cells in the M phase of the cell cycle. Infection of cells with the VZV ORF12 deletion mutant had a reduced effect on the differences in the number of cells in the G1 and M phase of the cell cycle compared with infection with wild-type VZV. Inhibition of Akt activity in cells also reduced differences in the number of cells in the G1 and M phase of the cell cycle observed in cells infected with wild-type VZV. Thus, we have found that the VZV ORF12 protein activates the PI3K/Akt pathway to regulate progression through the cell cycle. Since VZV replicates in both dividing (keratinocytes) and non-dividing (neurons) cells, the ability of the VZV ORF12 protein to regulate the cell cycle is likely important for VZV replication in various cell types in the body. We have also been developing a more sensitive assay to detect antibody to VZV in recipients of the varicella vaccine. We are comparing our assay using sera from persons who received the vaccine, with results obtained from the fluorescent antibody to membrane antigen (FAMA) assay, to determine the sensitivity and specificity of our assay.

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Sadaoka, Tomohiko; Depledge, Daniel P; Rajbhandari, Labchan et al. (2016) In vitro system using human neurons demonstrates that varicella-zoster vaccine virus is impaired for reactivation, but not latency. Proc Natl Acad Sci U S A 113:E2403-12
Liu, XueQiao; Cohen, Jeffrey I (2015) The role of PI3K/Akt in human herpesvirus infection: From the bench to the bedside. Virology 479-480:568-77
Cohen, Jeffrey I (2015) A new vaccine to prevent herpes zoster. N Engl J Med 372:2149-50
Bayat, Ahmad; Burbelo, Peter D; Browne, Sarah K et al. (2015) Anti-cytokine autoantibodies in postherpetic neuralgia. J Transl Med 13:333
Gershon, Anne A; Breuer, Judith; Cohen, Jeffrey I et al. (2015) Varicella zoster virus infection. Nat Rev Dis Primers 1:15016
Liu, Xueqiao; Cohen, Jeffrey I (2014) Inhibition of Bim enhances replication of varicella-zoster virus and delays plaque formation in virus-infected cells. J Virol 88:1381-8
Cohen, Jeffrey I; Ali, Mir A; Bayat, Ahmad et al. (2014) Detection of antibodies to varicella-zoster virus in recipients of the varicella vaccine by using a luciferase immunoprecipitation system assay. Clin Vaccine Immunol 21:1288-91
Yamamoto, Takenobu; Ali, Mir A; Liu, XueQiao et al. (2014) Activation of H2AX and ATM in varicella-zoster virus (VZV)-infected cells is associated with expression of specific VZV genes. Virology 452-453:52-8
Cohen, Jeffrey I (2013) Clinical practice: Herpes zoster. N Engl J Med 369:255-63
Cohen, Jeffrey I (2013) Herpes zoster. N Engl J Med 369:1766-7

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