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Herpes simplex virus type 1 deletion variants 1714 and 1716 pinpoint neurovirulence-related sequences in Glasgow strain 17⁺ between immediate early gene 1 and the ‘a’ sequence

MRC Virology Unit, Institute of Virology, Church Street, Glasgow G11 5JR, U.K.

Dideoxynucleotide sequence analysis of a spontaneously isolated deletion variant (1714) of Glasgow strain 17⁺ of herpes simplex virus type 1 (HSV-1) demonstrates that the deletion is 759 bp in length and is located within each copy of the BamHI s fragment (0 to 0.02 and 0.81 to 0.83 map units) of the long repeat region of the genome. The deletion removes one complete copy of the 18 bp DR₁ element of the ‘a’ sequence and terminates 1105 bp upstream of the 5' end of immediate early (IE) gene 1. The variant grows to high titre, is not temperature-sensitive and is not host cell type-restricted in vitro. In vivo studies demonstrate that 1714 is totally avirulent for BALB/c mice following intracerebral inoculation, with an LD₅₀ of 7 x 10⁶ p.f.u./mouse compared to < 10 p.f.u./mouse for the parental wild-type strain 17⁺. In vivo growth kinetics show that the non-neurovirulent phenotype is due to an inability to replicate in mouse brain. Because 1714 was in a genomic background in which the four XbaI sites had been removed and because the phenotype was thymidine kinase-negative, the 759 bp deletion was introduced into an otherwise totally wild-type background. The resulting variant (1716) is nonneurovirulent for mice, with an LD₅₀ of 7 x 10⁶ p.f.u./mouse. The deletion does not prevent the virus from establishing a latent infection or reactivating from it in vitro. The results demonstrate that sequences between IE-1 and the ‘a’ sequence produce neurovirulence in Glasgow strain 17⁺ and, in conjunction with the nonneurovirulence of the HSV-2 HG52 variant JH2604, identify a common function conserved in HSV-1 and -2.

Received 27 August 1990; accepted 29 November 1990.

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