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Journal of Virology, January 2000, p. 956-964, Vol. 74, No. 2
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.

Long-Term Transgene Expression in Mice Infected with a Herpes Simplex Virus Type 1 Mutant Severely Impaired for Immediate-Early Gene Expression

Ker R. Marshall,1 Robin H. Lachmann,2 Stacey Efstathiou,2 Angela Rinaldi,1 and Chris M. Preston1,*

Medical Research Council Virology Unit, Glasgow G11 5JR, Scotland,1 and Division of Virology, Department of Pathology, University of Cambridge, Cambridge CB2 1QP, England2

Received 27 August 1999/Accepted 14 October 1999

The role of viral immediate-early (IE) gene expression in herpes simplex virus type 1 (HSV-1) latency was investigated. The HSV-1 multiple mutant in1312, defective for the expression of the virion transactivator VP16 and the IE proteins ICP0 and ICP4, was used as the parent for these studies. The coding sequences of the Escherichia coli lacZ gene, preceded by the encephalomyocarditis virus internal ribosome entry site, were inserted into the region of in1312 that encodes the latency-associated transcripts (LATs) such that transcription of the transgene was controlled by the LAT promoter. This insert has previously been shown to direct long-term latent-phase expression of beta -galactosidase in a wild-type HSV-1 genome (R. H. Lachmann and S. Efstathiou, J. Virol. 71, 3197-3207, 1997). The resulting recombinant, in1388, was apathogenic after inoculation into mice via the footpad and did not detectably replicate in dorsal root ganglia (DRG) or footpads. Mutant in1388 established latency in DRG, and beta -galactosidase was expressed in increasing numbers of neurons over the first 25 days of infection. During latency, more than 1% of neurons in ganglia that innervate the footpad expressed beta -galactosidase, with the number of positive cells remaining constant for at least 5 months. Rescue of the VP16, ICP0, or ICP4 mutations of in1388 did not affect the number of beta -galactosidase-expressing neurons detected during latency. The results demonstrate that HSV-1 mutants severely impaired for IE gene expression are capable of establishing latency and efficiently expressing a foreign gene product under control of the LAT promoter.

* Corresponding author. Mailing address: Medical Research Council Virology Unit, Church St., Glasgow G11 5JR, Scotland. Phone: 44 141 330 3921. Fax: 44 141 337 2236. E-mail: c.preston{at}vir.gla.ac.uk.

Journal of Virology, January 2000, p. 956-964, Vol. 74, No. 2
0022-538X/00/$04.00+0
Copyright © 2000, American Society for Microbiology. All rights reserved.


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