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Replication, establishment of latent infection, expression of the latency-associated transcripts and explant reactivation of herpes simplex virus type 1 34.5 mutants in a mouse eye model

¹ The Wistar Institute, 36th Street at Spruce, Philadelphia, PA 19104
² MRC Virology Unit, Institute of Virology, University of Glasgow, Glasgow, Scotland G11 5JR
³ Department of Neuropharmacology, The Scripps Research Institute, 10666 North Torrey Pines Road, La Jolla, CA 92037
and⁴ Ag Research Ltd., Wallaceville Animal Research Centre, P.O. Box 40063, Upper Hutt, New Zealand

The herpes simplex virus type 1 (HSV-1) 34·5 gene is located within a region that is transcriptionally active during latent HSV-1 infection. To determine whether the 34·5 gene deletion affects latency-associated transcript (LAT) gene expression or latent HSV-1 infection, a 34·5 gene deletion mutant, 1716, and a stop codon insertion mutant, 1771, were studied in the mouse eye model. Although the 34·5 gene is not essential, 1716 and 1771 replicated poorly in mouse eyes and trigeminal ganglia (TG). When mice were inoculated with 1716, infectious virus was detected in eyes only on the first day post-infection (p.i.), and was not detected at any time point in TG. Following inoculation with 1771, a small amount of virus was detected in the eyes on days 2 and 4 p.i., and in the TG of one animal on day 2 p.i. Reactivation of virus from mice latently infected with 1716 (0/30 TG) and 1771 (1/20 TG) was extremely low compared with the parental strain, 17⁺, and appropriate rescuants (80 to 100% reactivation), even though latent 1716 DNA was detected by PCR in 50% of TG. These results differ from those obtained following footpad inoculation; in the footpad there was limited 1716 replication and reactivatable latent infection was established in some dorsal root ganglia. The data support the hypothesis that the role of 34·5 may be tissue and/or cell type specific. The synthesis, processing, and stability of the 2.0 kb LAT during 1716 and 1771 replication was not affected by these mutations in the 34·5 gene. However, during latent infection of 1716 in mice the LATs were not detectable in TG by Northern blot, and were present in reduced amounts ( 10-fold less) during 1771 latency. The LATs from 1716 were barely detectable in a few neurons by in situ hybridization. Therefore, the 34·5 gene might (i) affect replication in the eye, and reduce the amount of virus available to establish latent infection, be directly involved in (ii) establishment of latency, and/or (iii) the reactivation process.

^* Author for correspondence. Fax + 1 215 898 3849. e-mail FRASER@WISTA.WISTAR.UPENN.EDU

Received 14 June 1994; accepted 17 October 1994.

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