Evidence that the herpes simplex virus type 1 uracil DNA glycosylase is required for efficient viral replication and latency in the murine nervous system

Richard Pyles, Richard L. Thompson

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89 Citations (Scopus)

Abstract

Herpes simplex virus (HSV) encodes a uracil DNA glycosylase (UNG; UL2), which has been shown to be dispensable for normal replication of HSV-1 in cultured cells (J. Mullaney, H. W. Moss, and D. J. McGeoch, J. Gen. Virol. 70:449-454, 1989). In adult neurons, UNG activity is undetectable (F. Focher, P. Mazzarello, A. Verri, U. Hubscher, and S. Spadari, Mutat. Res. 237:65-73, 1990), suggesting that the HSV-1 UNG may play an important role in viral replication in neurons acutely and/or following reactivation. To examine the contribution of the HSV-1 UNG in vivo, two independent strain 17 Syn+ Ung- mutants, designated uB1 and uB2, were examined in a mouse model of herpetic disease. Following direct intracranial inoculation, both mutants exhibited a 10-fold reduction in neurovirulence compared with the parental strain 17 Syn+. Inoculations by a peripheral route demonstrated that the Ung- mutants were at least 100,000-fold less neuroinvasive than 17 Syn+. Replication kinetics in vivo demonstrated that uB1 and uB2 replicated less well in both the mouse peripheral and central nervous systems. Latency was established by both of the mutants in 100% of the animals examined. Following transient hyperthermia, however, the frequency of reactivation of the mutants in vivo was dramatically reduced. Restoration of the UNG locus resulted in full neurovirulence, neuroinvasiveness, and the ability to reactivate in vivo. These findings suggest that the HSV-1 UNG plays an important role during acute viral replication in vivo and possibly in the reactivation process.

Original languageEnglish (US)
Pages (from-to)4963-4972
Number of pages10
JournalJournal of Virology
Volume68
Issue number8
StatePublished - Aug 1994
Externally publishedYes

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Uracil-DNA Glycosidase
Virus Latency
Human herpesvirus 1
Human Herpesvirus 1
virus replication
nervous system
Nervous System
mutants
mice
Neurons
neurons
Peripheral Nervous System
Simplexvirus
herpes simplex
peripheral nervous system
Cultured Cells
Fever
Central Nervous System
cultured cells
fever

ASJC Scopus subject areas

  • Immunology

Cite this

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title = "Evidence that the herpes simplex virus type 1 uracil DNA glycosylase is required for efficient viral replication and latency in the murine nervous system",
abstract = "Herpes simplex virus (HSV) encodes a uracil DNA glycosylase (UNG; UL2), which has been shown to be dispensable for normal replication of HSV-1 in cultured cells (J. Mullaney, H. W. Moss, and D. J. McGeoch, J. Gen. Virol. 70:449-454, 1989). In adult neurons, UNG activity is undetectable (F. Focher, P. Mazzarello, A. Verri, U. Hubscher, and S. Spadari, Mutat. Res. 237:65-73, 1990), suggesting that the HSV-1 UNG may play an important role in viral replication in neurons acutely and/or following reactivation. To examine the contribution of the HSV-1 UNG in vivo, two independent strain 17 Syn+ Ung- mutants, designated uB1 and uB2, were examined in a mouse model of herpetic disease. Following direct intracranial inoculation, both mutants exhibited a 10-fold reduction in neurovirulence compared with the parental strain 17 Syn+. Inoculations by a peripheral route demonstrated that the Ung- mutants were at least 100,000-fold less neuroinvasive than 17 Syn+. Replication kinetics in vivo demonstrated that uB1 and uB2 replicated less well in both the mouse peripheral and central nervous systems. Latency was established by both of the mutants in 100{\%} of the animals examined. Following transient hyperthermia, however, the frequency of reactivation of the mutants in vivo was dramatically reduced. Restoration of the UNG locus resulted in full neurovirulence, neuroinvasiveness, and the ability to reactivate in vivo. These findings suggest that the HSV-1 UNG plays an important role during acute viral replication in vivo and possibly in the reactivation process.",
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