Inhibition of the NF-κB pathway by varicella-zoster virus in vitro and in human epidermal cells in vivo

Varicella-zoster virus (VZV) is an alphaherpesvirus that causes varicella and herpes zoster. Using human cellular DNA microarrays, we found that many nuclear factor kappa B (NF-kappa B) -responsive genes were down-regulated in VZV-infected fibroblasts, suggesting that VZV infection inhibited the NF-kappa B pathway. The activation of this pathway causes a cellular antiviral response, including the production of alpha/beta interferon, cytokines, and other proteins that restrict viral infection. In these experiments, we demonstrated that VZV interferes with NF-kappa B activation in cultured fibroblasts and in differentiated epidermal cells in skin xenografts of SCIDhu mice infected in vivo. VZV infection of fibroblasts caused a transient nuclear translocation of p50 and p65, the canonical NF-kappa B family members. In a process that was dependent upon the presence of infectious VZV, these proteins rapidly became sequestered in the cytoplasm of VZV-infected cells. Exclusion of NF-kappa B proteins from nuclei was associated with the continued presence of I kappa B alpha, which binds p50 and p65 and prevents their nuclear accumulation. I kappa B alpha levels did not diminish even though the protein became phosphorylated and ubiquitinated, as determined based on detection of the characteristic high-molecular-weight form of the protein, and the 26S proteasome remained functional in VZV-infected cells. VZV infection also inhibited the characteristic degradation of I kappa B alpha that is induced by exposure of fibroblasts to tumor necrosis factor alpha. As expected, herpes simplex virus 1 caused the persistent nuclear translocation of NF-kappa B proteins, which has been shown to facilitate its replication, whereas VZV infection progressed without persistent NF-kappa B nuclear localization. We suggest that VZV has evolved a mechanism to limit host cell antiviral defenses by sequestering NF-kappa B proteins in the cytoplasm, a strategy that appears to be unique among the herpesviruses.