title: The case for immunomodulatory approaches in treating HSV encephalitis.
abstract: HSV encephalitis (HSE) is the most prevalent sporadic viral encephalitis. Although safe and effective antiviral therapies and greatly improved noninvasive diagnostic procedures have significantly improved outcomes, mortality (~20%) and debilitating neurological sequelae in survivors remain unacceptably high. An encouraging new development is that the focus is now shifting away from the virus exclusively, to include consideration of the host immune response to infection in the pathology underlying development of HSE. In this article, the authors discuss results from recent studies in experimental mouse models, as well as clinical reports that demonstrate a role for exaggerated host inflammatory responses in the brain in the development of HSE that is motivating researchers and clinicians to consider new therapeutic approaches for treating HSE. The authors also discuss results from a few studies that have shown that immunomodulatory drugs can be highly protective against HSE, which supports a role for deleterious host inflammatory responses in HSE. The impressive outcomes of some immunomodulatory approaches in mouse models of HSE emphasize the urgent need for clinical trials to rigorously evaluate combination antiviral and immunomodulatory therapy in comparison with standard antiviral therapy for treatment of HSE, and support for such an initiative is gaining momentum.
authors: Department of Virology, Beckman Research Institute of City of Hope; Duarte, CA 91010-3000, USA.
authors: Chandran
authors: C
authors: Ramakrishna
authors: Harry
authors: H
authors: Openshaw
authors: Edouard M
authors: EM
authors: Cantin
keywords: acyclovir; encephalitis; herpesvirus; immune pathology; immunomodulation; inflammation; innate immunity; intravenous immunoglobulin; reactive oxygen species
references: Virology. 2012 Nov 10;433(1):116-23
references: 22884293
references: Virol J. 2005 Aug 03;2:59
references: 16076403
references: Eur J Neurol. 1999 Sep;6(5):531-8
references: 10457385
references: Lancet. 1984 Sep 29;2(8405):707-11
references: 6148470
references: J Virol. 2004 Sep;78(18):10086-95
references: 15331741
references: J Exp Med. 1999 Feb 15;189(4):663-72
references: 9989981
references: PLoS Pathog. 2011 Sep;7(9):e1002250
references: 21949653
references: J Interferon Cytokine Res. 2009 Sep;29(9):599-607
references: 19694546
references: J Neurol Neurosurg Psychiatry. 1985 Apr;48(4):297-301
references: 3998736
references: J Infect Dis. 2007 Mar 15;195(6):817-25
references: 17299711
references: Clin Infect Dis. 2007 Oct 1;45(7):875-80
references: 17806053
references: J Neuroinflammation. 2011 Sep 26;8:123
references: 21943001
references: J Virol. 1995 Aug;69(8):4898-905
references: 7609058
references: J Infect Dis. 1995 Apr;171(4):857-63
references: 7706811
references: Clin Infect Dis. 1999 Jan;28(1):148-9
references: 10028092
references: Nat Rev Immunol. 2011 Oct 10;11(11):762-74
references: 21984070
references: Ann Neurol. 2001 Nov;50(5):612-9
references: 11706967
references: Virus Res. 2006 Oct;121(1):1-10
references: 16621100
references: Invest Ophthalmol Vis Sci. 2000 May;41(6):1402-9
references: 10798656
references: Nat Rev Immunol. 2011 Sep 09;11(10):685-92
references: 21904387
references: J Neurol. 2006 Feb;253(2):163-70
references: 16222428
references: Brain Pathol. 2010 Jul;20(4):738-50
references: 20002440
references: Cytokine. 2012 Jan;57(1):1-8
references: 22079335
references: Cell Host Microbe. 2010 May 20;7(5):343-53
references: 20478536
references: Nat Immunol. 2012 Jun 17;13(8):737-43
references: 22706339
references: J Neurol. 2010 May;257(5):843-5
references: 20099066
references: J Child Neurol. 2010 Jul;25(7):901-8
references: 20179002
references: Cell. 2010 Mar 19;140(6):805-20
references: 20303872
references: Science. 2006 Oct 13;314(5797):308-12
references: 16973841
references: Neuropathology. 2011 Aug;31(4):392-400
references: 21175863
references: BMC Neurol. 2008 Oct 29;8:40
references: 18959773
references: Viruses. 2009 Dec;1(3):979-1002
references: 21994578
references: J Virol. 2006 Dec;80(24):12387-92
references: 17005636
references: PLoS One. 2012;7(4):e36216
references: 22558388
references: J Neurovirol. 2003 Feb;9(1):118-25
references: 12587075
references: N Engl J Med. 2011 Oct 6;365(14):1284-92
references: 21991950
references: J Infect Dis. 2005 Mar 1;191(5):746-8
references: 15688290
references: J Neurovirol. 2002 Aug;8(4):295-305
references: 12161814
references: Biochem Biophys Res Commun. 2012 Feb 24;418(4):806-10
references: 22310710
references: Cytokine. 2009 May;46(2):187-93
references: 19261488
references: J Gen Virol. 1986 Jun;67 ( Pt 6):1025-33
references: 3011968
references: Exp Cell Res. 2012 Aug 1;318(13):1461-6
references: 22507273
references: Immunol Rev. 2010 Jul;236:265-75
references: 20636822
references: Proc Natl Acad Sci U S A. 2004 Aug 3;101(31):11416-21
references: 15272082
references: J Neuroimmunol. 2011 Feb;231(1-2):61-9
references: 21056913
references: PLoS Pathog. 2011 Jun;7(6):e1002071
references: 21655109
references: J Gen Virol. 1986 Sep;67 ( Pt 9):1859-66
references: 3018128
references: Curr Opin Immunol. 2007 Dec;19(6):646-51
references: 18032008
references: J Exp Med. 2011 Sep 26;208(10):2083-98
references: 21911422
references: J Virol. 1999 Jun;73(6):5196-200
references: 10233988
references: J Virol. 2012 Feb;86(4):2273-81
references: 22171256
references: Blood. 2004 Feb 15;103(4):1433-7
references: 14563635
references: Proc Natl Acad Sci U S A. 2004 Feb 3;101(5):1315-20
references: 14739339
references: J Neurol Neurosurg Psychiatry. 2003 Feb;74(2):262-4
references: 12531966
references: J Virol. 2000 Jul;74(14):6680-3
references: 10864685
references: J Virol. 2008 Jul;82(14):7078-88
references: 18480436
references: Immunity. 2008 Mar;28(3):315-23
references: 18342006
references: J Virol. 2007 Oct;81(20):11128-38
references: 17686871
references: Nature. 1980 Nov 20;288(5788):288-90
references: 6253827
references: Ann Neurol. 1979 Jan;5(1):2-5
references: 426465
references: J Virol. 2003 Oct;77(20):11082-93
references: 14512556
references: J Virol. 1996 Jan;70(1):264-71
references: 8523535
references: J Immunol. 2005 Oct 1;175(7):4189-93
references: 16177057
references: Am J Pathol. 2010 Nov;177(5):2433-45
references: 20864677
references: Clin Exp Immunol. 2009 Dec;158 Suppl 1:2-13
references: 19883419
references: J Immunol. 2008 Nov 1;181(9):6417-26
references: 18941232
references: Nature. 2011 Jun 19;475(7354):110-3
references: 21685887
references: PLoS Pathog. 2011 Feb 03;7(2):e1001271
references: 21304882
references: Clin Infect Dis. 2002 Aug 1;35(3):254-60
references: 12115090
references: J Neurol Neurosurg Psychiatry. 2005 Nov;76(11):1544-9
references: 16227548
references: J Neurol. 2010 Sep;257(9):1432-7
references: 20495814
references: J Neurol. 2009 Aug;256(8):1243-51
references: 19353228
references: J Gen Virol. 1986 Apr;67 ( Pt 4):613-21
references: 3007658
references: J Virol. 2004 Apr;78(8):3846-50
references: 15047800
references: Clin Rev Allergy Immunol. 2012 Apr;42(2):247-55
references: 21732045
references: N Engl J Med. 1991 Feb 14;324(7):450-4
references: 1988830
references: J Neuroimmunol. 2010 Mar 30;220(1-2):1-9
references: 19819030
references: Nat Rev Immunol. 2011 Feb;11(2):143-54
references: 21267015
references: Science. 2006 Aug 4;313(5787):670-3
references: 16888140
references: Proc Natl Acad Sci U S A. 2006 Nov 14;103(46):17343-8
references: 17085599
references: J Virol. 2007 Dec;81(24):13315-24
references: 17913820
references: J Neurol Neurosurg Psychiatry. 1997 Sep;63(3):321-6
references: 9328248
references: J Virol. 2003 Nov;77(21):11661-73
references: 14557652
references: J Gen Virol. 1989 Aug;70 ( Pt 8):2139-47
references: 2769233
references: Blood. 2012 Mar 29;119(13):2991-3002
references: 22246037
references: J Infect Dis. 1993 Nov;168(5):1248-52
references: 8228358
references: Best Pract Res Clin Haematol. 2006;19(1):3-25
references: 16377538
references: J Immunol. 2008 Dec 15;181(12):8604-12
references: 19050280
references: J Exp Med. 2008 Sep 29;205(10):2319-37
references: 18779347
references: J Neurovirol. 2002 Feb;8(1):35-44
references: 11847590
references: Curr Top Microbiol Immunol. 1981;92:15-24
references: 6171384
references: J Virol. 2003 Oct;77(20):11158-69
references: 14512563
references: Neurologist. 2007 Sep;13(5):261-71
references: 17848866
references: Proc Natl Acad Sci U S A. 2012 Nov 20;109(47):19386-91
references: 23132945
references: Virus Res. 1989 Jul;13(3):263-70
references: 2549748
references: J Pediatr Hematol Oncol. 2011 Dec;33(8):e350-1
references: 21127434
references: Nat Immunol. 2009 Oct;10(10):1065-72
references: 19609254
references: Clin Sci (Lond). 1998 Jun;94(6):557-72
references: 9854452
references: J Virol. 1988 Mar;62(3):749-56
references: 2828670
references: Virology. 2011 Mar 15;411(2):153-62
references: 21334037
references: Antimicrob Agents Chemother. 1987 Jul;31(7):1006-9
references: 2821882
references: Immunotherapy. 2009 Nov;1(6):995-1015
references: 20635915
references: J Exp Med. 1989 Apr 1;169(4):1503-7
references: 2538554
references: J Neurol Neurosurg Psychiatry. 2005 Nov;76(11):1469
references: 16227530
references: Infect Immun. 1983 Nov;42(2):740-6
references: 6196293
references: Curr Opin Immunol. 2011 Aug;23(4):495-9
references: 21752617
references: Invest Ophthalmol Vis Sci. 2007 Sep;48(9):4162-70
references: 17724202
references: J Neuroinflammation. 2010 Jun 28;7:35
references: 20584314
references: Annu Rev Med. 1981;32:335-40
references: 7013672
references: J Neurovirol. 2000 Feb;6(1):25-32
references: 10786994
references: Viral Immunol. 2005;18(3):466-73
references: 16212525
references: Science. 2007 Sep 14;317(5844):1522-7
references: 17872438
references: Cell. 2009 Aug 7;138(3):576-91
references: 19631370
references: Rev Med Virol. 2012 Mar;22(2):106-21
references: 22020814
references: PLoS Pathog. 2011 Feb;7(2):e1001304
references: 21383977
references: Virology. 2000 Dec 20;278(2):309-21
references: 11118355
references: Trends Immunol. 2008 Dec;29(12):608-15
references: 18926775