Replication of thymidine kinase deficient herpes simplex virus type 1 in neuronal cell culture: infection of the PC 12 cell.

Replication of a thymidine kinase deficient (TK-) mutant of herpes simplex virus type 1 (HSV-1) was compared to replication of its parental TK+ strain in the PC 12 cell. This is a cell which ceases cell division and undergoes neuron-like morphological and physiological differentiation in the presence of nerve growth factor (NGF). No difference between mutant and parental strain replication was detected either when these cells were infected in the proliferative state or while maintained under the influence of NGF. Neither viral TK nor enhanced cellular TK activity was detected during TK- HSV-1 replication, which proceeded in the presence of selective antiviral drugs that inhibited TK+ HSV-1 viral replication. Moreover, thymidylate synthetase was inhibited early in TK- infection, and reutilization of thymine nucleotides derived from degraded cellular DNA was not detected. Under the conditions of these in vitro studies, increased production of dTTP as a result of enhanced TK activity did not appear to be rate-limiting, despite the non-dividing "differentiated" state of the PC 12 cell.