Reactivation of expression from quiescent herpes simplex virus type 1 genomes in the absence of immediate-early protein ICP0.
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.
Preston
Chris M
CM
Medical Research Council Virology Unit, Church Street, Glasgow, Scotland, United Kingdom. c.preston@mrcvu.gla.ac.uk
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
D004279:DNA, Viral; D017874:Immediate-Early Proteins; D014764:Viral Proteins; D044767:Ubiquitin-Protein Ligases; C051804:Vmw110 protein, Human herpesvirus 1
J Gen Virol. 1992 Feb;73 ( Pt 2):285-92
1371540
J Virol. 2007 Oct;81(20):10991-1004
17670833
J Virol. 1992 May;66(5):2916-27
1313910
J Gen Virol. 1995 Jun;76 ( Pt 6):1417-31
7782770
J Virol. 1995 Oct;69(10):6249-58
7666525
Mol Cell Biol. 1996 Jun;16(6):3085-93
8649420
J Virol. 1997 Aug;71(8):6191-3
9223515
J Virol. 1999 Dec;73(12):9726-33
10559282
J Virol. 2000 Jan;74(2):956-64
10623758
J Virol. 2000 Feb;74(4):2052-6
10644380
J Virol. 2001 Jan;75(2):750-8
11134288
J Virol. 2001 Apr;75(7):3240-9
11238850
J Virol. 2001 Apr;75(7):3391-403
11238865
J Virol. 2001 Jul;75(13):6143-53
11390616
J Virol. 2002 Jan;76(2):841-50
11752173
J Virol. 2002 Mar;76(5):2180-91
11836395
Clin Microbiol Rev. 2003 Jan;16(1):79-95
12525426
Proc Natl Acad Sci U S A. 2003 Jun 24;100(13):7871-6
12796511
J Virol. 2004 Feb;78(3):1139-49
14722269
J Virol. 2004 Feb;78(4):1763-74
14747541
J Virol. 2004 Mar;78(5):2169-78
14963113
J Virol. 2004 Jun;78(12):6162-70
15163709
J Virol. 2004 Nov;78(22):12508-18
15507638
J Virol. 1979 Jan;29(1):275-84
219222
Science. 1982 Sep 17;217(4565):1145-6
6180477
J Gen Virol. 1984 May;65 ( Pt 5):859-63
6327885
J Mol Biol. 1984 Nov 25;180(1):1-19
6096556
J Gen Virol. 1986 Feb;67 ( Pt 2):397-403
3003243
J Gen Virol. 1986 Dec;67 ( Pt 12):2571-85
3025339
J Virol. 1987 Mar;61(3):829-39
3027408
J Gen Virol. 1987 Dec;68 ( Pt 12):3009-18
2826646
J Gen Virol. 1988 Oct;69 ( Pt 10):2595-605
2844968
J Virol. 1989 May;63(5):2260-9
2539517
J Gen Virol. 1989 Mar;70 ( Pt 3):695-704
2543754
J Gen Virol. 1989 May;70 ( Pt 5):1185-202
2543774
J Virol. 1989 Aug;63(8):3513-5
2545921
J Virol. 1990 Sep;64(9):4489-98
2166826
J Gen Virol. 1991 Apr;72 ( Pt 4):907-13
1849973
Clin Microbiol Rev. 1997 Jul;10(3):419-43
9227860
J Virol. 1997 Oct;71(10):7807-13
9311867
J Gen Virol. 1998 Jan;79 ( Pt 1):117-24
9460932
J Virol. 1998 Apr;72(4):3307-20
9525658
J Virol. 1999 Oct;73(10):8512-8
10482604
J Virol. 2005 Jan;79(1):525-35
15596845
Virus Res. 2005 Aug;111(2):108-19
15951043
Proc Natl Acad Sci U S A. 2005 Nov 1;102(44):16055-9
16247011
Virol J. 2005;2:85
16300675
J Virol. 2006 Feb;80(4):2063-8
16439563
J Virol. 2006 Apr;80(7):3360-8
16537603
Virology. 2006 Aug 15;352(1):237-52
16750236
J Virol. 2006 Nov;80(22):10919-30
16943285
J Virol. 1992 May;66(5):2904-15
1313909