The gamma 1(34.5) gene of herpes simplex virus 1 was previously shown to play a role in viral virulence since deletion of the gene reduced by a factor of approximately 100,000 the capacity of the virus to replicate in the central nervous system and cause mortality in the mouse. Here we show that in the human neuroblastoma cell line SK-N-SH of neuronal origin gamma 1(34.5) null mutants expressed early proteins, viral DNA, and mRNA of late genes. However, the onset of viral DNA synthesis triggered complete cessation of incorporation of radioactive precursors into proteins. The mutant and wild-type viruses replicated and could not be differentiated in cell lines or cell strains of nonneuronal origin. The results indicate that in the absence of the gamma 1(34.5) gene the SK-N-SH neuroblastoma cells triggered a response similar to the programed cell death of neuronal cells induced by metabolic stress. The gamma 1(34.5) protein precludes this cell response possibly in order to enable the protein synthesis necessary for viral replication.