The bovine herpesvirus-1 LR ORF2 is critical for this gene's ability to restore the high wild-type reactivation phenotype to a herpes simplex virus-1 LAT null mutant

Kevin R. Mott, Nelson Osorio, Ling Jin, David J. Brick, Julie Naito, Jennifer Cooper, Gail Henderson, Melissa Inman, Clinton Jones, Steven L. Wechsler, Guey Chuen Perng

Research output: Contribution to journalArticle

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Abstract

During neuronal latency of herpes simplex virus (HSV)-1, the latency-associated transcript (LAT) is the only viral gene readily detectable. LAT is required for the high-level reactivation phenotype in animal models. LAT's anti-apoptotic activity was recently demonstrated by our group and it was proposed that LAT's anti-apoptotic function is involved in enhancing the reactivation phenotype. Recently, using chimeric virus CJLAT, it was shown that the reactivation phenotype of LAT- mutant dLAT2903 can be restored to wild-type levels by inserting the bovine herpes virus (BHV)-1 latency-related (LR) gene into the LAT locus of this HSV-1 LAT deletion mutant. Although transcription of the LR gene, like LAT, inhibits apoptosis, LR appears to be multifunctional. To investigate whether the LR gene's anti-apoptotic function was responsible for restoring the high-reactivation phenotype, a mutated BHV-1 LR gene was inserted into the LAT locus of HSV-1 generating the chimeric virus CJLATmut. This mutation consists of three stop codons inserted just after the ATG of the first LR open reading frame (ORF2). In plasmids and in a BHV-1 mutant, this mutation eliminated the LR gene's anti-apoptotic activity, strongly suggesting that ORF2 encodes a protein responsible for LR's anti-apoptotic activity. Reactivation of the CJLATmut virus, in both rabbits and mice, was significantly lower than in wild-type McKrae virus (P=0.0001 and P=0.0003, respectively) and CJLAT virus, containing wild-type LR in place of LAT (P<0.0001) and was similar to LAT- dLAT2903 (P=0.8 and P=0.7, respectively). Thus, disruption of BHV-1 LR ORF2 eliminated the high-reactivation phenotype.

Original languageEnglish (US)
Pages (from-to)2975-2985
Number of pages11
JournalJournal of General Virology
Volume84
Issue number11
DOIs
StatePublished - Nov 1 2003

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Bovine Herpesvirus 1
Virus Latency
Viruses
Phenotype
Genes
Mutation
Viral Genes
Terminator Codon
Open Reading Frames
herpes simplex virus-1 latency associated transcript
Plasmids
Animal Models
Apoptosis
Rabbits

ASJC Scopus subject areas

  • Virology

Cite this

The bovine herpesvirus-1 LR ORF2 is critical for this gene's ability to restore the high wild-type reactivation phenotype to a herpes simplex virus-1 LAT null mutant. / Mott, Kevin R.; Osorio, Nelson; Jin, Ling; Brick, David J.; Naito, Julie; Cooper, Jennifer; Henderson, Gail; Inman, Melissa; Jones, Clinton; Wechsler, Steven L.; Perng, Guey Chuen.

In: Journal of General Virology, Vol. 84, No. 11, 01.11.2003, p. 2975-2985.

Research output: Contribution to journalArticle

Mott, KR, Osorio, N, Jin, L, Brick, DJ, Naito, J, Cooper, J, Henderson, G, Inman, M, Jones, C, Wechsler, SL & Perng, GC 2003, 'The bovine herpesvirus-1 LR ORF2 is critical for this gene's ability to restore the high wild-type reactivation phenotype to a herpes simplex virus-1 LAT null mutant', Journal of General Virology, vol. 84, no. 11, pp. 2975-2985. https://doi.org/10.1099/vir.0.19421-0
Mott, Kevin R. ; Osorio, Nelson ; Jin, Ling ; Brick, David J. ; Naito, Julie ; Cooper, Jennifer ; Henderson, Gail ; Inman, Melissa ; Jones, Clinton ; Wechsler, Steven L. ; Perng, Guey Chuen. / The bovine herpesvirus-1 LR ORF2 is critical for this gene's ability to restore the high wild-type reactivation phenotype to a herpes simplex virus-1 LAT null mutant. In: Journal of General Virology. 2003 ; Vol. 84, No. 11. pp. 2975-2985.
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abstract = "During neuronal latency of herpes simplex virus (HSV)-1, the latency-associated transcript (LAT) is the only viral gene readily detectable. LAT is required for the high-level reactivation phenotype in animal models. LAT's anti-apoptotic activity was recently demonstrated by our group and it was proposed that LAT's anti-apoptotic function is involved in enhancing the reactivation phenotype. Recently, using chimeric virus CJLAT, it was shown that the reactivation phenotype of LAT- mutant dLAT2903 can be restored to wild-type levels by inserting the bovine herpes virus (BHV)-1 latency-related (LR) gene into the LAT locus of this HSV-1 LAT deletion mutant. Although transcription of the LR gene, like LAT, inhibits apoptosis, LR appears to be multifunctional. To investigate whether the LR gene's anti-apoptotic function was responsible for restoring the high-reactivation phenotype, a mutated BHV-1 LR gene was inserted into the LAT locus of HSV-1 generating the chimeric virus CJLATmut. This mutation consists of three stop codons inserted just after the ATG of the first LR open reading frame (ORF2). In plasmids and in a BHV-1 mutant, this mutation eliminated the LR gene's anti-apoptotic activity, strongly suggesting that ORF2 encodes a protein responsible for LR's anti-apoptotic activity. Reactivation of the CJLATmut virus, in both rabbits and mice, was significantly lower than in wild-type McKrae virus (P=0.0001 and P=0.0003, respectively) and CJLAT virus, containing wild-type LR in place of LAT (P<0.0001) and was similar to LAT- dLAT2903 (P=0.8 and P=0.7, respectively). Thus, disruption of BHV-1 LR ORF2 eliminated the high-reactivation phenotype.",
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AU - Jin, Ling

AU - Brick, David J.

AU - Naito, Julie

AU - Cooper, Jennifer

AU - Henderson, Gail

AU - Inman, Melissa

AU - Jones, Clinton

AU - Wechsler, Steven L.

AU - Perng, Guey Chuen

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