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Volume 16, Number 18, Issue of September 15, 1996 pp. 5644-5653
Copyright ©1996 Society for Neuroscience

Selective Vulnerability of Mouse CNS Neurons to Latent Infection with a Neuroattenuated Herpes Simplex Virus-1

Received June 7, 1996; revised June 28, 1996; accepted July 2, 1996.

Santosh Kesari^{1, 2}, Virginia M.-Y. Lee², S. Moira Brown³, John Q. Trojanowski², and Nigel W. Fraser¹

¹ The Wistar Institute and ² Department of Pathology and Laboratory Medicine, University of Pennsylvania School of Medicine, Philadelphia, Pennsylvania 19104, and ³ Medical Research Council Virology Institute, Glasgow, Scotland G115JR

Herpes simplex viruses that lack ICP34.5 are neuroattenuated and are presently being considered for cancer and gene therapy in the nervous system. Previously, we documented the focal presence of the latency-associated transcripts (LATs) in the hippocampi of immunocompromised mice after intracranial (IC) inoculation of an ICP34.5-deficient virus called strain 1716. To characterize further the biological properties of strain 1716 in the CNS of immunocompetent mice, we determined the extent of viral gene expression in different cell types and regions of the CNS after stereotactic IC inoculation of this virus. At survival times of >30 d after inoculation, we found that (1) infectious virus was not detectable by titration and immunohistochemical studies; (2) neurons harbored virus as demonstrated by the detection of the LATs by in situ hybridization (ISH); (3) transcripts expressed during the lytic cycle of infection were not detected by ISH; and (4) subsets of neurons were selectively vulnerable to latent infection, depending on the site of inoculation. These results suggest that the absence of ICP34.5 does not abrogate latent infection of the CNS by strain 1716. Additional studies of strain 1716 in the model system described here will facilitate the elucidation of the mechanisms that regulate the selective vulnerability of CNS cells to latent viral infection and lead to the development of ICP34.5 mutant viruses as therapeutic vectors for CNS diseases.

Key words: herpes simplex virus; ICP34.5; latency; neuron-specific gene expression; gene transfer; viral vectors

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