title: Reactivation of expression from quiescent herpes simplex virus type 1 genomes in the absence of immediate-early protein ICP0.
abstract: Model systems have previously been developed in which herpes simplex virus (HSV) is retained in human fibroblasts in a nonreplicating state known as quiescence. The HSV type 1 (HSV-1) immediate-early (IE) protein ICP0, an important activator of gene expression, reactivates the quiescent genome and promotes the resumption of virus replication. Previous studies reported that infection with ICP0-null HSV-1 mutants fails to reactivate quiescent HSV, even when the mutant itself undergoes productive replication, leading to the hypothesis that quiescent genomes exist in a silent configuration in which they are shielded from trans-acting factors. I reinvestigated these findings, using HSV-1 mutants with lesions in the transcription activators VP16, ICP0, and ICP4 to establish quiescent infection at high efficiency. Superinfection with ICP0-null HSV-1 mutants at a low multiplicity of infection (MOI), so that individual plaques were formed, reactivated expression from the quiescent genome, demonstrating that the requirement for ICP0 is not absolute. The previously reported failure to observe reactivation by ICP0-null mutants was shown to be a consequence of either a low initial MOI or a high superinfecting MOI. Competition between viral genomes at the level of gene expression and virus replication, especially when ICP0 was absent, was demonstrated during reactivation and also during normal infection of human fibroblasts. The results show that the multiplicity-dependent phenotype of ICP0-null mutants limits the efficiency of reactivation at low MOIs and that competition between genomes occurs at high MOIs. The conclusion that quiescent HSV genomes are extensively silenced and intrinsically insensitive to trans-acting factors must be reevaluated.
authors: Medical Research Council Virology Unit, Church Street, Glasgow, Scotland, United Kingdom. c.preston@mrcvu.gla.ac.uk
authors: Chris M
authors: CM
authors: Preston
mesh_terms: D004279:DNA, Viral / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism / Q000821:virology; D015967:Gene Expression Regulation, Viral; D005821:Genetic Techniques; D016679:Genome, Viral; D018259:Herpesvirus 1, Human / Q000235:genetics*; D006801:Humans; D017874:Immediate-Early Proteins / Q000378:metabolism*; D009154:Mutation; D010641:Phenotype; D010957:Plasmids / Q000378:metabolism; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D014764:Viral Proteins / Q000737:chemistry; D017735:Virus Latency; D014779:Virus Replication
chemical_list: D004279:DNA, Viral; D017874:Immediate-Early Proteins; D014764:Viral Proteins; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1
references: J Gen Virol. 1992 Feb;73 ( Pt 2):285-92
references: 1371540
references: J Virol. 2007 Oct;81(20):10991-1004
references: 17670833
references: J Virol. 1992 May;66(5):2916-27
references: 1313910
references: J Gen Virol. 1995 Jun;76 ( Pt 6):1417-31
references: 7782770
references: J Virol. 1995 Oct;69(10):6249-58
references: 7666525
references: Mol Cell Biol. 1996 Jun;16(6):3085-93
references: 8649420
references: J Virol. 1997 Aug;71(8):6191-3
references: 9223515
references: J Virol. 1999 Dec;73(12):9726-33
references: 10559282
references: J Virol. 2000 Jan;74(2):956-64
references: 10623758
references: J Virol. 2000 Feb;74(4):2052-6
references: 10644380
references: J Virol. 2001 Jan;75(2):750-8
references: 11134288
references: J Virol. 2001 Apr;75(7):3240-9
references: 11238850
references: J Virol. 2001 Apr;75(7):3391-403
references: 11238865
references: J Virol. 2001 Jul;75(13):6143-53
references: 11390616
references: J Virol. 2002 Jan;76(2):841-50
references: 11752173
references: J Virol. 2002 Mar;76(5):2180-91
references: 11836395
references: Clin Microbiol Rev. 2003 Jan;16(1):79-95
references: 12525426
references: Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7871-6
references: 12796511
references: J Virol. 2004 Feb;78(3):1139-49
references: 14722269
references: J Virol. 2004 Feb;78(4):1763-74
references: 14747541
references: J Virol. 2004 Mar;78(5):2169-78
references: 14963113
references: J Virol. 2004 Jun;78(12):6162-70
references: 15163709
references: J Virol. 2004 Nov;78(22):12508-18
references: 15507638
references: J Virol. 1979 Jan;29(1):275-84
references: 219222
references: Science. 1982 Sep 17;217(4565):1145-6
references: 6180477
references: J Gen Virol. 1984 May;65 ( Pt 5):859-63
references: 6327885
references: J Mol Biol. 1984 Nov 25;180(1):1-19
references: 6096556
references: J Gen Virol. 1986 Feb;67 ( Pt 2):397-403
references: 3003243
references: J Gen Virol. 1986 Dec;67 ( Pt 12):2571-85
references: 3025339
references: J Virol. 1987 Mar;61(3):829-39
references: 3027408
references: J Gen Virol. 1987 Dec;68 ( Pt 12):3009-18
references: 2826646
references: J Gen Virol. 1988 Oct;69 ( Pt 10):2595-605
references: 2844968
references: J Virol. 1989 May;63(5):2260-9
references: 2539517
references: J Gen Virol. 1989 Mar;70 ( Pt 3):695-704
references: 2543754
references: J Gen Virol. 1989 May;70 ( Pt 5):1185-202
references: 2543774
references: J Virol. 1989 Aug;63(8):3513-5
references: 2545921
references: J Virol. 1990 Sep;64(9):4489-98
references: 2166826
references: J Gen Virol. 1991 Apr;72 ( Pt 4):907-13
references: 1849973
references: Clin Microbiol Rev. 1997 Jul;10(3):419-43
references: 9227860
references: J Virol. 1997 Oct;71(10):7807-13
references: 9311867
references: J Gen Virol. 1998 Jan;79 ( Pt 1):117-24
references: 9460932
references: J Virol. 1998 Apr;72(4):3307-20
references: 9525658
references: J Virol. 1999 Oct;73(10):8512-8
references: 10482604
references: J Virol. 2005 Jan;79(1):525-35
references: 15596845
references: Virus Res. 2005 Aug;111(2):108-19
references: 15951043
references: Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16055-9
references: 16247011
references: Virol J. 2005;2:85
references: 16300675
references: J Virol. 2006 Feb;80(4):2063-8
references: 16439563
references: J Virol. 2006 Apr;80(7):3360-8
references: 16537603
references: Virology. 2006 Aug 15;352(1):237-52
references: 16750236
references: J Virol. 2006 Nov;80(22):10919-30
references: 16943285
references: J Virol. 1992 May;66(5):2904-15
references: 1313909