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-kappaB)-responsive genes were down-regulated in VZV-infected fibroblasts, suggesting that VZV
infection inhibited the
NF-kappaB 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-kappaB 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-kappaB 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-kappaB proteins from nuclei was associated with the continued presence of
IkappaBalpha, which binds p50 and p65 and prevents their nuclear accumulation.
IkappaBalpha 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
IkappaBalpha 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-kappaB proteins, which has been shown to facilitate its replication, whereas VZV
infection progressed without persistent
NF-kappaB nuclear localization. We suggest that VZV has evolved a mechanism to limit host cell
antiviral defenses by sequestering
NF-kappaB proteins in the cytoplasm, a strategy that appears to be unique among the herpesviruses.