title: Disruption of HDAC/CoREST/REST repressor by dnREST reduces genome silencing and increases virulence of herpes simplex virus.
abstract: In nonneuronal cells, herpes simplex virus 1 overcomes host defenses, replicates, and ultimately kills the infected cell. Among the host defenses suppressed by the virus is a repressor complex whose key components are histone deacetylase (HDAC) 1 or 2, RE-1 silencing transcription factor (REST), corepressor of REST (CoREST), and lysine-specific demethylase (LSD) 1. In neurons innervating cells at the portal of entry into the body, the virus establishes a "latent" infection in which viral DNA is silenced with the exception of a family of genes. The question posed here is whether the virus hijacks this repressor complex to silence itself in neurons during the latent state. To test this hypothesis, we inserted into the wild-type virus genome a wild-type REST [recombinant (R) 111], a dominant-negative REST (dnREST) lacking the N- and C-terminal repressor domains (R112), or an insertion control consisting of tandem repeats of stop codons (R113). The recombinant virus R112 carrying the dnREST replicated better and was more virulent than the wild-type parent or the other recombinant viruses when administered by the corneal or i.p. routes. Moreover, in contrast to other recombinants, corneal route inoculation by R112 recombinant virus resulted in higher DNA copy numbers, higher levels of infectious virus in eye, trigeminal ganglion, or brain, and virtually complete destruction of trigeminal ganglia in mice that may ultimately succumb to infection. These results support an earlier conclusion that the HDAC/CoREST/REST/LSD1 repressor complex is a significant component of the host innate immunity and are consistent with the hypothesis that HSV-1 hijacks the repressor to silence itself during latent infection.
authors.affiliation: The University of Chicago, IL 60637, USA.
authors.forename: Te
authors.initials: T
authors.lastname: Du
authors.forename: Guoying
authors.initials: G
authors.lastname: Zhou
authors.forename: Shaniya
authors.initials: S
authors.lastname: Khan
authors.forename: Haidong
authors.initials: H
authors.lastname: Gu
authors.forename: Bernard
authors.initials: B
authors.lastname: Roizman
mesh_terms: D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology*; D034622:RNA Interference; D012097:Repressor Proteins / Q000037:antagonists & inhibitors*; D018139:Simplexvirus / Q000472:pathogenicity*; D014774:Virulence; D000099229:RE1-Silencing Transcription Factor
chemical_list: D056572:Histone Deacetylase Inhibitors; D012097:Repressor Proteins; D000099229:RE1-Silencing Transcription Factor
references.citation: Nat Med. 2009 Nov;15(11):1312-7
references.pmid: 19855399
references.citation: Neuromolecular Med. 2009;11(3):183-99
references.pmid: 19458943
references.citation: Curr Opin Neurobiol. 2005 Oct;15(5):500-6
references.pmid: 16150588
references.citation: J Virol. 1992 Sep;66(9):5598-602
references.pmid: 1323713
references.citation: J Virol. 1989 Nov;63(11):4756-61
references.pmid: 2552151
references.citation: Ann Neurol. 1979 Jan;5(1):2-5
references.pmid: 426465
references.citation: Nature. 2008 Mar 20;452(7185):370-4
references.pmid: 18354483
references.citation: Cell. 2005 May 20;121(4):645-657
references.pmid: 15907476
references.citation: J Neurosci. 2003 Mar 15;23(6):2112-21
references.pmid: 12657670
references.citation: Proc Natl Acad Sci U S A. 1997 Feb 18;94(4):1177-82
references.pmid: 9037026
references.citation: J Virol. 1996 Mar;70(3):1810-7
references.pmid: 8627705
references.citation: Proc Natl Acad Sci U S A. 2007 Oct 23;104(43):17134-9
references.pmid: 17939992
references.citation: J Gen Virol. 1982 Dec;63(2):315-23
references.pmid: 6185625
references.citation: J Neurovirol. 2005 Jul;11(3):306-17
references.pmid: 16036811
references.citation: J Virol. 2004 Feb;78(4):1763-74
references.pmid: 14747541
references.citation: J Virol. 2007 Dec;81(23):13248-53
references.pmid: 17881451
references.citation: Future Neurol. 2009;4(3):317-329
references.pmid: 19885378
references.citation: Nucleic Acids Res. 2008 Sep;36(16):5221-31
references.pmid: 18684996
references.citation: Science. 2007 Jun 8;316(5830):1497-502
references.pmid: 17540862
references.citation: Nature. 2008 Mar 20;452(7185):365-9
references.pmid: 18354482
references.citation: J Neurosci. 1998 Feb 15;18(4):1280-96
references.pmid: 9454838
references.citation: J Neurol Sci. 1984 May;64(2):213-7
references.pmid: 6379105
references.citation: Proc Natl Acad Sci U S A. 2006 Jun 27;103(26):9993-8
references.pmid: 16785443
references.citation: Nature. 2008 Aug 7;454(7205):780-3
references.pmid: 18596690
references.citation: Proc Natl Acad Sci U S A. 2005 May 24;102(21):7571-6
references.pmid: 15897453
references.citation: J Virol. 2006 Feb;80(4):2063-8
references.pmid: 16439563