A neuroattenuated ICP34.5-deficient herpes simplex virus type 1 replicates in ependymal cells of the murine central nervous system

Herpes simplex virus type 1 (HSV-1) variant 1716 is deleted in the gene encoding ICP34.5 and is neuroattenuated after intracranial inoculation of mice. Although the mechanism of attenuation is unclear, this property has been exploited to eliminate experimental brain tumours. Previously, it was shown that infectious 1716 was recoverable for up to 3 days after intracranial inoculation suggesting that there may be limited replication in the central nervous system (CNS). Here it is demonstrated that 1716 replicates in specific cell types (predominantly CNS ependymal cells) of BALB/c mice, using immunohistochemical, immunofluorescence, in situ hybridization and virus titration studies. While 1716-infected mice exhibited no overt signs of encephalitis, histological analysis showed a persistent loss of the ependymal lining. Thus, although ICP34.5-deficient viruses are neuroattenuated, they do retain the ability to replicate in and destroy the ependyma of the murine CNS. A detailed understanding of the mechanism(s) of neuroattenuation and limited replication could lead to the rational design of safe HSV vectors for cancer and gene therapy in the CNS.