Transcription factors of the NFAT (nuclear factor of activated T cells) family 
are expressed in most immune system cells and in a range of other cell types. 
Signaling through NFAT is implicated in the regulation of transcription for the 
immune response and other processes, including differentiation and apoptosis. 
NFAT normally resides in the cytoplasm, and a key aspect of the NFAT activation 
pathway is the regulation of its nuclear import by the 
Ca(2+)/calmodulin-dependent phosphatase calcineurin. In a cell line stably 
expressing green fluorescent protein (GFP)-NFAT, this import can be triggered by 
elevation of intracellular calcium and visualized in live cells. Here we show 
that the inducible nuclear import of GFP-NFAT is efficiently blocked at early 
stages of herpes simplex virus (HSV) infection. This is a specific effect, since 
we observed abundant nuclear accumulation of a test viral protein and no 
impediment to general nuclear localization signal-dependent nuclear import and 
retention in infected cells. We show that virus binding at the cell surface is 
not itself sufficient to inhibit the signaling that induces NFAT nuclear 
translocation. Since the block occurs following infection in the presence of 
phosphonoacetic acid but not cycloheximide, we infer that the entry of the 
virion and early gene transcription are required but the effect is independent 
of DNA replication or late virus gene expression. A consequence of the block to 
GFP-NFAT import is a reduction in NFAT-dependent transcriptional activation from 
the interleukin-2 promoter in infected cells. This HSV-mediated repression of 
the NFAT pathway may constitute an immune evasion strategy or subversion of 
other NFAT-dependent cellular processes to promote viral replication.