title: JC virus promoter/enhancers contain TATA box-associated Spi-B-binding sites that support early viral gene expression in primary astrocytes.
abstract: JC virus (JCV) is the aetiological agent of the demyelinating disease progressive multifocal leukoencephalopathy, an AIDS defining illness and serious complication of mAb therapies. Initial infection probably occurs in childhood. In the working model of dissemination, virus persists in the kidney and lymphoid tissues until immune suppression/modulation causes reactivation and trafficking to the brain where JCV replicates in oligodendrocytes. JCV infection is regulated through binding of host factors such as Spi-B to, and sequence variation in the non-coding control region (NCCR). Although NCCR sequences differ between sites of persistence and pathogenesis, evidence suggests that the virus that initiates infection in the brain disseminates via B-cells derived from latently infected haematopoietic precursors in the bone marrow. Spi-B binds adjacent to TATA boxes in the promoter/enhancer of the PML-associated JCV Mad-1 and Mad-4 viruses but not the non-pathogenic, kidney-associated archetype. The Spi-B-binding site of Mad-1/Mad-4 differs from that of archetype by a single nucleotide, AAAAGGGAAGGGA to AAAAGGGAAGGTA. Point mutation of the Mad-1 Spi-B site reduced early viral protein large T-antigen expression by up to fourfold. Strikingly, the reverse mutation in the archetype NCCR increased large T-antigen expression by 10-fold. Interestingly, Spi-B protein binds the NCCR sequence flanking the viral promoter/enhancer, but these sites are not essential for early viral gene expression. The effect of mutating Spi-B-binding sites within the JCV promoter/enhancer on early viral gene expression strongly suggests a role for Spi-B binding to the viral promoter/enhancer in the activation of early viral gene expression.
authors.affiliation: Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892-1296, USA.
authors.forename: Leslie J
authors.initials: LJ
authors.lastname: Marshall
authors.affiliation: Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892-1296, USA.
authors.forename: Lisa D
authors.initials: LD
authors.lastname: Moore
authors.affiliation: Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892-1296, USA.
authors.forename: Matthew M
authors.initials: MM
authors.lastname: Mirsky
authors.affiliation: Laboratory of Molecular Medicine and Neuroscience, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD, 20892-1296, USA.
authors.forename: Eugene O
authors.initials: EO
authors.lastname: Major
mesh_terms: D001253:Astrocytes / Q000821:virology*; D001665:Binding Sites; D002478:Cells, Cultured; D004268:DNA-Binding Proteins / Q000378:metabolism*; D004742:Enhancer Elements, Genetic; D015967:Gene Expression Regulation, Viral; D006801:Humans; D007577:JC Virus / Q000235:genetics / Q000254:growth & development*; D011401:Promoter Regions, Genetic; D011485:Protein Binding; D016385:TATA Box; D014157:Transcription Factors / Q000378:metabolism*
chemical_list: D004268:DNA-Binding Proteins; D014157:Transcription Factors; C076877:SPIB protein, human
references.citation: J Clin Virol. 2010 Apr;47(4):306-12
references.pmid: 20060360
references.citation: J Virol. 1987 May;61(5):1435-41
references.pmid: 3033272
references.citation: Genes Dev. 2003 Jun 1;17(11):1309-20
references.pmid: 12782648
references.citation: J Virol. 1990 Apr;64(4):1657-66
references.pmid: 2319649
references.citation: Proc Natl Acad Sci U S A. 1993 Feb 15;90(4):1580-4
references.pmid: 8434021
references.citation: Nucleic Acids Res. 1993 Apr 25;21(8):1959-64
references.pmid: 8388103
references.citation: J Virol. 2001 Oct;75(20):9687-95
references.pmid: 11559801
references.citation: J Virol. 2010 Oct;84(20):10448-56
references.pmid: 20686041
references.citation: J Neurovirol. 2000 Oct;6(5):398-409
references.pmid: 11031693
references.citation: Mol Cell Biol. 1992 Jan;12(1):368-78
references.pmid: 1729611
references.citation: J Virol. 1985 Jan;53(1):306-11
references.pmid: 2981353
references.citation: J Clin Microbiol. 2011 Jun;49(6):2196-9
references.pmid: 21430099
references.citation: J Virol. 1998 Jul;72(7):5335-42
references.pmid: 9620986
references.citation: Genes Dev. 1987 Nov;1(9):962-72
references.pmid: 2828177
references.citation: Ann Neurol. 2003 May;53(5):636-46
references.pmid: 12730998
references.citation: Arch Immunol Ther Exp (Warsz). 2006 May-Jun;54(3):149-63
references.pmid: 16652219
references.citation: Oncogene. 1996 Feb 15;12(4):863-73
references.pmid: 8632909
references.citation: Oncogene. 2003 May 15;22(19):2882-96
references.pmid: 12771939
references.citation: J Virol. 1984 Aug;51(2):458-69
references.pmid: 6086957
references.citation: J Neurovirol. 2011 Aug;17(4):303-13
references.pmid: 21547609
references.citation: Arch Virol. 1991;120(3-4):305-11
references.pmid: 1659802
references.citation: J Virol. 1999 Dec;73(12):10146-57
references.pmid: 10559330
references.citation: Genes Dev. 1997 Jun 15;11(12):1605-17
references.pmid: 9203586
references.citation: Mult Scler. 2005 Oct;11(5):568-72
references.pmid: 16193895
references.citation: Nat Rev Neurol. 2010 Dec;6(12):667-79
references.pmid: 21131916
references.citation: J Neurovirol. 2003 Oct;9(5):559-66
references.pmid: 13129770
references.citation: Genes Dev. 1996 Jun 1;10(11):1369-81
references.pmid: 8647434
references.citation: J Virol. 1996 Apr;70(4):2387-93
references.pmid: 8642666
references.citation: Prog Clin Biol Res. 1983;105:41-59
references.pmid: 6304771
references.citation: J Neurochem. 1996 Aug;67(2):473-81
references.pmid: 8764570
references.citation: J Virol. 1990 Jun;64(6):3139-43
references.pmid: 2159570
references.citation: J Neuroimmunol. 2008 Feb;194(1-2):153-64
references.pmid: 18178259
references.citation: Res Virol. 1998 May-Jun;149(3):163-70
references.pmid: 9711540
references.citation: Virus Res. 2009 Dec;146(1-2):97-106
references.pmid: 19747512
references.citation: J Gen Virol. 2010 Dec;91(Pt 12):3042-52
references.pmid: 20826618
references.citation: Nucleic Acids Res. 1991 May 11;19(9):2499
references.pmid: 2041787
references.citation: J Virol. 1995 Sep;69(9):5843-8
references.pmid: 7637031
references.citation: J Exp Med. 1996 Jul 1;184(1):203-14
references.pmid: 8691135
references.citation: J Gen Virol. 1998 Apr;79 ( Pt 4):789-99
references.pmid: 9568974
references.citation: J Virol. 1994 Nov;68(11):6947-58
references.pmid: 7933076
references.citation: Biochem Biophys Res Commun. 1996 Jun 14;223(2):257-63
references.pmid: 8670269
references.citation: Eur J Biochem. 1993 Jan 15;211(1-2):7-18
references.pmid: 8425553
references.citation: J Neurovirol. 2005 Feb;11(1):51-7
references.pmid: 15804959
references.citation: J Gen Virol. 1993 Aug;74 ( Pt 8):1499-507
references.pmid: 8393910
references.citation: Mol Cell Biol. 1992 Oct;12(10):4297-304
references.pmid: 1406622
references.citation: J Virol. 1993 Jul;67(7):3885-90
references.pmid: 8389910
references.citation: Oncogene. 2000 Dec 18;19(55):6443-54
references.pmid: 11175360
references.citation: Mol Cell Biol. 1999 Apr;19(4):2455-64
references.pmid: 10082511
references.citation: J Biol Chem. 1989 Apr 25;264(12):7025-32
references.pmid: 2540170
references.citation: Drug Saf. 2010 Nov 1;33(11):969-83
references.pmid: 20925435
references.citation: J Infect Dis. 2009 Mar 15;199(6):881-8
references.pmid: 19434914
references.citation: J Neurovirol. 2008 Oct;14(5):455-8
references.pmid: 18989816
references.citation: J Neurovirol. 2001 Aug;7(4):280-7
references.pmid: 11517403
references.citation: J Virol. 2006 Dec;80(24):12079-85
references.pmid: 17035332
references.citation: J Infect Dis. 2011 Jul 15;204(2):237-44
references.pmid: 21673034
references.citation: J Virol. 1995 Apr;69(4):2434-42
references.pmid: 7884891
references.citation: Lupus. 1997;6(3):325-6
references.pmid: 9296778
references.citation: J Virol. 2010 Sep;84(18):9200-9
references.pmid: 20610709
references.citation: J Biol Chem. 1992 Jul 15;267(20):14204-11
references.pmid: 1321139
references.citation: Annu Rev Med. 2010;61:35-47
references.pmid: 19719397
references.citation: J Biol Chem. 1999 Apr 16;274(16):11115-24
references.pmid: 10196196
references.citation: J Neuroimmune Pharmacol. 2010 Sep;5(3):404-17
references.pmid: 20401541
references.citation: J Virol. 1994 Nov;68(11):7637-43
references.pmid: 7933155
references.citation: Virology. 1996 Feb 1;216(1):90-101
references.pmid: 8615010
references.citation: Nature. 1995 Jun 29;375(6534):812-5
references.pmid: 7596417