The role of IFN-γ in immune responses to viral infections of the central nervous system

Abstract Interferon (IFN)-γ, is not only a marker of T H 1 CD4, CD8 and natural killer (NK) cells, it is also a critical antiviral mediator which is central to the elimination of viruses from the CNS. In this review, we describe IFN-γ, its receptor, signal transduction from receptor engagement, and antiviral downstream mediators. We demonstrate that although neurons are post-mitotic and non-renewing, they respond to IFN-γ in a fashion similar to peripheral fibroblasts or lymphocytes. We have illustrated this review with details about studies on the role(s) of IFN-γ in the pathogenesis of measles virus (MV), herpes simplex virus (HSV) type 1, and vesicular stomatitis virus (VSV) infections of the CNS. For VSV infection, IFN-γ signals through Jaks 1 and 2 and STAT1 to activate (interferon regulatory factor) IRF-1; although viral protein synthesis is inhibited, PKR is not a critical mediator in the antiviral response to VSV in murine neurons. In contrast, induction of nitric oxide synthase (NOS) type 1 and its production of nitric oxide is essential in the elimination of viruses from neurons.

[1]  O. Haller,et al.  Interferon induces a unique protein in mouse cells bearing a gene for resistance to influenza virus. , 1983, Proceedings of the National Academy of Sciences of the United States of America.

[2]  K. Kristensson,et al.  Neuronal interferon‐γ immunoreactive molecule: Bioactivities and purification , 1994 .

[3]  J. Arndt,et al.  Nitric oxide as a chemical link in the generation of pain from veins in humans , 1996, Pain.

[4]  D. Chesler,et al.  Innate immune responses in viral encephalitis. , 2002, Current topics in microbiology and immunology.

[5]  P. Cresswell,et al.  Viperin (cig5), an IFN-inducible antiviral protein directly induced by human cytomegalovirus , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[6]  T. Werner,et al.  MatInd and MatInspector: new fast and versatile tools for detection of consensus matches in nucleotide sequence data. , 1995, Nucleic acids research.

[7]  R. Furchgott,et al.  Endothelial cells as mediators of vasodilation of arteries. , 1984, Journal of cardiovascular pharmacology.

[8]  T. Komatsu,et al.  Interferon-γ induced type I nitric oxide synthase activity inhibits viral replication in neurons , 1996, Journal of Neuroimmunology.

[9]  B. Carpick,et al.  Characterization of the Solution Complex between the Interferon-induced, Double-stranded RNA-activated Protein Kinase and HIV-I Trans-activating Region RNA* , 1997, The Journal of Biological Chemistry.

[10]  Chilakamarti V. Ramana,et al.  Biologic consequences of Stat1-independent IFN signaling , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[11]  J. Lancaster.  Nitric oxide :principles and actions , 1996 .

[12]  V. ter meulen,et al.  Cell type-specific MxA-mediated inhibition of measles virus transcription in human brain cells , 1994, Journal of virology.

[13]  J. Mannick.  The antiviral role of nitric oxide. , 1995, Research in immunology.

[14]  F. Krebs,et al.  HIV-1-associated central nervous system dysfunction. , 2000, Advances in pharmacology.

[15]  F. Bazer,et al.  Antiviral activity of the pregnancy recognition hormone ovine trophoblast protein-1. , 1988, Biochemical and biophysical research communications.

[16]  P. Vanhoutte,et al.  Endothelium‐derived relaxing and contracting factors , 1989, FASEB journal : official publication of the Federation of American Societies for Experimental Biology.

[17]  T. Taniguchi,et al.  IRF family of transcription factors as regulators of host defense. , 2001, Annual review of immunology.

[18]  R. Zinkernagel,et al.  Formalin inactivation of vesicular stomatitis virus impairs T-cell- but not T-help-independent B-cell responses , 1993, Journal of virology.

[19]  I. Schneider,et al.  Induction of nitric oxide synthase protects against malaria in mice exposed to irradiated Plasmodium berghei infected mosquitoes: involvement of interferon gamma and CD8+ T cells , 1994, The Journal of experimental medicine.

[20]  M. Nakahira,et al.  An Absolute Requirement for STAT4 and a Role for IFN-γ as an Amplifying Factor in IL-12 Induction of the Functional IL-18 Receptor Complex1 , 2001, The Journal of Immunology.

[21]  R. Silverman,et al.  Regulation of Human Immunodeficiency Virus Replication by 2′,5′-Oligoadenylate-Dependent RNase L , 1998, Journal of Virology.

[22]  P. Boudinot,et al.  Vesicular stomatitis virus and pseudorabies virus induce a vig1/cig5 homologue in mouse dendritic cells via different pathways. , 2000, The Journal of general virology.

[23]  I. Aránguez,et al.  Expression of interferon-gamma receptors on murine oligodendrocytes and its regulation by cytokines and mitogens. , 1995, Immunology.

[24]  B. Rouse,et al.  Viruses and autoimmunity: an affair but not a marriage contract , 2002, Reviews in medical virology.

[25]  C. de Felipe,et al.  Demonstration of the presence of a specific interferon-γ receptor on murine astrocyte cell surface , 1991, Journal of Neuroimmunology.

[26]  C. Aoki,et al.  Distribution of vesicular stomatitis virus proteins in the brain of BALB/c mice following intranasal inoculation: an immunohistochemical analysis , 1994, Brain Research.

[27]  Richard M. Ransohoff,et al.  Stat1-independent regulation of gene expression in response to IFN-γ , 2001, Proceedings of the National Academy of Sciences of the United States of America.

[28]  P. Ascenzi,et al.  S‐Nitrosylation of Viral Proteins: Molecular Bases for Antiviral Effect of Nitric Oxide , 1999, IUBMB life.

[29]  G. Karupiah,et al.  Inhibition of viral replication by nitric oxide and its reversal by ferrous sulfate and tricarboxylic acid cycle metabolites , 1995, The Journal of experimental medicine.

[30]  M J Clemens,et al.  The double-stranded RNA-dependent protein kinase PKR: structure and function. , 1997, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[31]  D. Ginty,et al.  Dynamic regulation of neuronal NO synthase transcription by calcium influx through a CREB family transcription factor-dependent mechanism. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[32]  K. Raddassi,et al.  Antiproliferative effects of NO synthase products. , 1991, Research in immunology.

[33]  A. Osterhaus,et al.  The predominance of CD8+ T cells after infection with measles virus suggests a role for CD8+ class I MHC-restricted cytotoxic T lymphocytes (CTL) in recovery from measles. Clonal analyses of human CD8+ class I MHC-restricted CTL. , 1990, Journal of immunology.

[34]  M. Clemens,et al.  Nuclear localization of the interferon-inducible protein kinase PKR in human cells and transfected mouse cells. , 1995, Experimental cell research.

[35]  D. Reis,et al.  Cloning and expression of inducible nitric oxide synthase from rat astrocytes , 1994, Journal of neuroscience research.

[36]  A. Huang,et al.  Cytolytic T lymphocytes from the BALB/c-H-2dm2 mouse recognize the vesicular stomatitis virus glycoprotein and are restricted by class II MHC antigens. , 1990, Journal of immunology.

[37]  P. Staeheli,et al.  Inhibition of vesicular stomatitis virus mRNA synthesis by human MxA protein , 1991, Journal of virology.

[38]  J. Stamler,et al.  Nitric oxide produced by human B lymphocytes inhibits apoptosis and Epstein-Barr virus reactivation , 1994, Cell.

[39]  H. Hartung,et al.  Production of nitrite by neonatal rat microglial cells/brain macrophages. , 1992, Cellular immunology.

[40]  Mikhail Chernov,et al.  Regulation of c‐myc expression by IFN‐γ through Stat1‐dependent and ‐independent pathways , 2000 .

[41]  A. Casadevall,et al.  Human astrocytes inhibit Cryptococcus neoformans growth by a nitric oxide-mediated mechanism , 1994, The Journal of experimental medicine.

[42]  M. Barna,et al.  Host immune response to vesicular stomatitis virus infection of the central nervous system in C57BL/6 mice. , 1996, Viral immunology.

[43]  J. Sever,et al.  Epidemiology of subacute sclerosing panencephalitis (SSPE). A report of the SSPE registry. , 1972, JAMA.

[44]  F. Bloom,et al.  Cytokine-mediated survival from lethal herpes simplex virus infection: role of programmed neuronal death. , 1995, Proceedings of the National Academy of Sciences of the United States of America.

[45]  M. Barna,et al.  Vesicular stomatitis virus infection of the central nervous system activates both innate and acquired immunity , 1995, Journal of virology.

[46]  Samuel Ce,et al.  Interferon-induced proteins and their mechanisms of action. , 1994 .

[47]  S. Fuller,et al.  Vesicular stomatitis virus infects and matures only through the basolateral surface of the polarized epithelial cell line, MDCK , 1984, Cell.

[48]  N. Sonenberg,et al.  The Murine Double-Stranded RNA-Dependent Protein Kinase PKR Is Required for Resistance to Vesicular Stomatitis Virus , 2000, Journal of Virology.

[49]  R. Roberts,et al.  Conceptus interferons and maternal recognition of pregnancy. , 1989, Biology of reproduction.

[50]  J. Lancaster,et al.  4 – The Intracellular Reactions of Nitric Oxide in the Immune System and Its Enzymatic Synthesis , 1996 .

[51]  N. Sarvetnick,et al.  Ectopic expression of gamma interferon in the eye protects transgenic mice from intraocular herpes simplex virus type 1 infections , 1994, Journal of virology.

[52]  P. Chapman,et al.  Nitric Oxide Facilitates Long-Term Potentiation, But Not Long-Term Depression , 1997, The Journal of Neuroscience.

[53]  S. Moyer,et al.  Assembly and transcription of synthetic vesicular stomatitis virus nucleocapsids , 1991, Journal of virology.

[54]  M. Marletta,et al.  Nitric oxide synthase structure and mechanism. , 1993, The Journal of biological chemistry.

[55]  Junbo Hu,et al.  CCAAT/Enhancer-binding Protein-β Regulates Interferon-induced Transcription through a Novel Element* , 2000, The Journal of Biological Chemistry.

[56]  M. Hirsch,et al.  Herpes simplex encephalitis: vidarabine therapy and diagnostic problems. , 1981, The New England journal of medicine.

[57]  C. Samuel,et al.  Antiviral Actions of Interferons , 2001, Clinical Microbiology Reviews.

[58]  S. L. Hart,et al.  7‐Nitro indazole, an inhibitor of nitric oxide synthase, exhibits anti‐nociceptive activity in the mouse without increasing blood pressure , 1993, British journal of pharmacology.

[59]  M. Farrar,et al.  The molecular cell biology of interferon-gamma and its receptor. , 1993, Annual review of immunology.

[60]  T. Uehara,et al.  Activation of Stat1 and subsequent transcription of inducible nitric oxide synthase gene in C6 glioma cells is independent of interferon‐γ‐induced MAPK activation that is mediated by p21 ras , 1997, FEBS letters.

[61]  S. Snyder,et al.  Targeted disruption of the neuronal nitric oxide synthase gene , 1993, Cell.

[62]  J. Coffin,et al.  Oligonucleotide fingerprints of RNA species obtained from rhabdoviruses belonging to the vesicular stomatitis virus subgroup , 1977, Journal of virology.

[63]  K. Melén,et al.  Survey Molecular pathogenesis of influenza A virus infection and virus-induced regulation of cytokine gene expression , 1998 .

[64]  J. Haley.  Gases as neurotransmitters. , 1998, Essays in biochemistry.

[65]  D. Chesler,et al.  Mechanisms of cytokine-mediated inhibition of viral replication. , 1999, Virology.

[66]  A. Osterhaus,et al.  Measles virus-specific human T cell clones. Characterization of specificity and function of CD4+ helper/cytotoxic and CD8+ cytotoxic T cell clones. , 1989, Journal of immunology.

[67]  C. Janeway.  Immunobiology: The Immune System in Health and Disease , 1996 .

[68]  R. Johnston,et al.  Effects of PKR/RNase L-dependent and alternative antiviral pathways on alphavirus replication and pathogenesis. , 2002, Viral immunology.

[69]  P. Ascenzi,et al.  Nitric oxide inhibits the HIV-1 reverse transcriptase activity. , 1999, Biochemical and biophysical research communications.

[70]  V. ter meulen,et al.  MxA-dependent inhibition of measles virus glycoprotein synthesis in a stably transfected human monocytic cell line , 1993, Journal of virology.

[71]  M. Marletta,et al.  Nitric oxide synthase: Aspects concerning structure and catalysis , 1994, Cell.

[72]  R. Anwyl,et al.  The selective neuronal NO synthase inhibitor 7-nitro-indazole blocks both long-term potentiation and depotentiation of field EPSPs in rat hippocampal CA1 in vivo , 1996, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[73]  J. Darnell,et al.  Stat3 and Stat4: members of the family of signal transducers and activators of transcription. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[74]  W. E. Josey,et al.  Antibodies to Herpesvirus hominis types 1 and 2 in humans. I. Patients with genital herpetic infections. , 1970, American journal of epidemiology.

[75]  R. Krug,et al.  Inhibition of influenza viral mRNA synthesis in cells expressing the interferon-induced Mx gene product , 1985, Journal of virology.

[76]  J. Christensen,et al.  Role of interferon-γ in the pathogenesis of LCMV-induced meningitis: unimpaired leucocyte recruitment, but deficient macrophage activation in interferon-γ knock-out mice , 1998, Journal of Neuroimmunology.

[77]  M. David,et al.  Interferonγ Activation of Raf-1 Is Jak1-dependent and p21ras-independent* , 1998, The Journal of Biological Chemistry.

[78]  G. Karupiah,et al.  Gamma interferon-induced, nitric oxide-mediated inhibition of vaccinia virus replication , 1995, Journal of virology.

[79]  O. Haller,et al.  Mx gene control of interferon action: different kinetics of the antiviral state against influenza virus and vesicular stomatitis virus , 1983, Journal of virology.

[80]  T. Komatsu,et al.  Does Nitric Oxide Play a Critical Role in Viral Infections? , 1998, Journal of Virology.

[81]  C. Aoki,et al.  The earliest events in vesicular stomatitis virus infection of the murine olfactory neuroepithelium and entry of the central nervous system. , 1995, Virology.

[82]  M. Katze,et al.  Biochemical and genetic evidence for complex formation between the influenza A virus NS1 protein and the interferon-induced PKR protein kinase. , 1998, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[83]  D. Ireland,et al.  IL-12 and Viral Infections , 1998, Cytokine & Growth Factor Reviews.

[84]  C. Brosnan,et al.  Expression of inducible nitric oxide synthase and nitrotyrosine in multiple sclerosis lesions. , 2001, The American journal of pathology.

[85]  M. Perkus,et al.  Reversal of the interferon-sensitive phenotype of a vaccinia virus lacking E3L by expression of the reovirus S4 gene , 1995, Journal of virology.

[86]  R. Roberts,et al.  Interferon-like sequence of ovine trophoblast protein secreted by embryonic trophectoderm , 1987, Nature.

[87]  D. Levy.  The house that Jak/Stat built. , 1997, Cytokine & growth factor reviews.

[88]  P. Roberts,et al.  Essential role for the dsRNA-dependent protein kinase PKR in innate immunity to viral infection. , 2000, Immunity.

[89]  K. Yoshida,et al.  Thymic aplasia with lymphopenia, plasma cells, and normal immunoglobulins. Relation to measles virus infection. , 1967, JAMA.

[90]  D. Griffin,et al.  Measles encephalomyelitis--clinical and immunologic studies. , 1984 .

[91]  D. Kalvakolanu,et al.  Interferon gamma-induced transcription of the murine ISGF3gamma (p48) gene is mediated by novel factors. , 1997, Proceedings of the National Academy of Sciences of the United States of America.

[92]  Eric R Kandel,et al.  Long-Term Potentiation Is Reduced in Mice That Are Doubly Mutant in Endothelial and Neuronal Nitric Oxide Synthase , 1996, Cell.

[93]  P. Ascenzi,et al.  Cysteine nitrosylation inactivates the HIV-1 protease. , 1998, Biochemical and biophysical research communications.

[94]  M. Dalakas,et al.  A Study of the Interferon Antiviral Mechanism: Apoptosis Activation by the 2–5A System , 1997, The Journal of experimental medicine.

[95]  A. Ellison,et al.  Establishment of latent herpes simplex virus type 1 infection in resistant, sensitive, and immunodeficient mouse strains. , 2000, Virology.

[96]  E. Cantin,et al.  Gamma interferon expression during acute and latent nervous system infection by herpes simplex virus type 1 , 1995, Journal of virology.

[97]  S. Roy,et al.  ERK1 and ERK2 Activate CCAAAT/Enhancer-binding Protein-β-dependent Gene Transcription in Response to Interferon-γ* , 2001, The Journal of Biological Chemistry.

[98]  H. Arnheiter,et al.  Mx proteins: antiviral proteins by chance or by necessity? , 1990, The New biologist.

[99]  S. Miller,et al.  Functional role of epitope spreading in the chronic pathogenesis of autoimmune and virus-induced demyelinating diseases. , 2001, Advances in experimental medicine and biology.

[100]  L. Ignarro,et al.  Microglial cell cytotoxicity of oligodendrocytes is mediated through nitric oxide. , 1993, Journal of immunology.

[101]  C. Lowenstein,et al.  Nitric oxide inhibition of coxsackievirus replication in vitro. , 1997, The Journal of clinical investigation.

[102]  R. Bronson,et al.  Murine infection by vesicular stomatitis virus: initial characterization of the H-2d system , 1991, Journal of virology.

[103]  M Aguet,et al.  The IFN gamma receptor: a paradigm for cytokine receptor signaling. , 1997, Annual review of immunology.

[104]  R. Sobel,et al.  Molecular mimicry between a viral peptide and a myelin oligodendrocyte glycoprotein peptide induces autoimmune demyelinating disease in mice , 1999, Journal of Neuroimmunology.

[105]  A. Cunningham,et al.  Alpha and Gamma Interferons Inhibit Herpes Simplex Virus Type 1 Infection and Spread in Epidermal Cells after Axonal Transmission , 2001, Journal of Virology.

[106]  M. Barna,et al.  Sex differences in susceptibility to viral infection of the central nervous system , 1996, Journal of Neuroimmunology.

[107]  E. Cantin,et al.  Role for Gamma Interferon in Control of Herpes Simplex Virus Type 1 Reactivation , 1999, Journal of Virology.

[108]  C. Rivas,et al.  Inducible expression of the 2-5A synthetase/RNase L system results in inhibition of vaccinia virus replication. , 1997, Virology.

[109]  O. Haller,et al.  Enhanced virus resistance of transgenic mice expressing the human MxA protein , 1995, Journal of virology.

[110]  V. ter meulen,et al.  Gamma interferon is a major mediator of antiviral defense in experimental measles virus-induced encephalitis , 1995, Journal of virology.

[111]  S H Snyder,et al.  Endothelial nitric oxide synthase localized to hippocampal pyramidal cells: implications for synaptic plasticity. , 1994, Proceedings of the National Academy of Sciences of the United States of America.

[112]  V. ter meulen,et al.  Pathogenic aspects of measles virus infections. , 1999, Archives of virology. Supplementum.

[113]  D. Griffin,et al.  Interferon-γ-Mediated Site-Specific Clearance of Alphavirus from CNS Neurons , 2001, Science.

[114]  C. Bogdan.  Nitric oxide and the regulation of gene expression. , 2001, Trends in cell biology.

[115]  L. Harbige,et al.  Characterization of the cellular and cytokine response in the central nervous system following Semliki Forest virus infection , 1997, Journal of Neuroimmunology.

[116]  M. Buchmeier,et al.  Interferon-γ Protects against Herpes Simplex Virus Type 1-Mediated Neuronal Death , 1997 .

[117]  M Aguet,et al.  Functional role of type I and type II interferons in antiviral defense. , 1994, Science.

[118]  M. Browning,et al.  Replication-defective viruses modulate immune responses. , 1991, Journal of immunology.

[119]  D. Rebouillat,et al.  The human 2',5'-oligoadenylate synthetase family: interferon-induced proteins with unique enzymatic properties. , 1999, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[120]  M. Rodriguez,et al.  Gamma interferon is critical for resistance to Theiler's virus-induced demyelination , 1995, Journal of virology.

[121]  S. Miller,et al.  Virus-induced autoimmunity: epitope spreading to myelin autoepitopes in Theiler's virus infection of the central nervous system. , 2001, Advances in virus research.

[122]  V. ter meulen,et al.  Susceptibility to measles virus-induced encephalitis in mice correlates with impaired antigen presentation to cytotoxic T lymphocytes , 1993, Journal of virology.

[123]  J. Lenard,et al.  Radiation inactivation analysis of fusion and hemolysis by vesicular stomatitis virus. , 1988, Virology.

[124]  K. Kristensson,et al.  Neuronal IFN-gamma in tuberomammillary neurones. , 1994, Neuroreport.

[125]  M. Chopp,et al.  Upregulation of neuronal nitric oxide synthase and mRNA, and selective sparing of nitric oxide synthase-containing neurons after local cerebral ischemia in rat , 1994, Brain Research.

[126]  A. Nahmias,et al.  Therapeutic challenges of neonatal herpes simplex virus infection. , 1985, Scandinavian Journal of Infectious Diseases. Supplementum.

[127]  M. Barna,et al.  Interleukin-12 promotes recovery from viral encephalitis. , 1997, Viral immunology.

[128]  N. Sarvetnick,et al.  Transgenic mice expressing IFN-gamma in the retina develop inflammation of the eye and photoreceptor loss. , 1994, Investigative ophthalmology & visual science.

[129]  R. Welsh,et al.  Apoptotic Regulation of T Cells and Absence of Immune Deficiency in Virus-Infected Gamma Interferon Receptor Knockout Mice , 1998, Journal of Virology.

[130]  M. Katze,et al.  Repression of the PKR protein kinase by the hepatitis C virus NS5A protein: a potential mechanism of interferon resistance. , 1998, Clinical and diagnostic virology.

[131]  Daniel L. Popkin,et al.  Novel Cell Type–Specific Antiviral Mechanism of Interferon γ Action in Macrophages , 2001, The Journal of experimental medicine.

[132]  D. Cave,et al.  Detection of vesicular stomatitis virus RNA and its defective-interfering particles in individual mouse brains , 1984, Journal of virology.

[133]  C. Nathan,et al.  Role of nitric oxide synthesis in macrophage antimicrobial activity. , 1991, Current opinion in immunology.

[134]  G. Borasio,et al.  Glial Cells of the Spinal Cord and Subcortical White Matter Up-regulate Neuronal Nitric Oxide Synthase in Sporadic Amyotrophic Lateral Sclerosis , 2001, Experimental Neurology.

[135]  M. Barna,et al.  IL-12 promotes enhanced recovery from vesicular stomatitis virus infection of the central nervous system. , 1995, Journal of immunology.

[136]  J. Glorioso,et al.  Herpes Simplex Virus Type 1 Glycoprotein B Requires a Cysteine Residue at Position 633 for Folding, Processing, and Incorporation into Mature Infectious Virus Particles , 1998, Journal of Virology.

[137]  M. Tardieu.  HIV-1-related central nervous system diseases. , 1999, Current opinion in neurology.

[138]  K. Khanna,et al.  Gamma Interferon Can Prevent Herpes Simplex Virus Type 1 Reactivation from Latency in Sensory Neurons , 2001, Journal of Virology.

[139]  Robert H. Silverman,et al.  Activation of p38 Mitogen-Activated Protein Kinase and c-Jun NH2-Terminal Kinase by Double-Stranded RNA and Encephalomyocarditis Virus: Involvement of RNase L, Protein Kinase R, and Alternative Pathways , 2000, Molecular and Cellular Biology.

[140]  A. Koromilas,et al.  PKR protection against intranasal vesicular stomatitis virus infection is mouse strain dependent. , 2002, Viral immunology.

[141]  Tyson V. Sharp,et al.  The vaccinia virus E3L gene product interacts with both the regulatory and the substrate binding regions of PKR: implications for PKR autoregulation. , 1998, Virology.

[142]  R. Wagner.  Rhabdovirus biology and infection an overview , 1987 .

[143]  A. Sabin,et al.  INFLUENCE OF HOST FACTORS ON NEUROINVASIVENESS OF VESICULAR STOMATITIS VIRUS , 1937, The Journal of experimental medicine.

[144]  C. Aoki,et al.  Central neuropathogenesis of vesicular stomatitis virus infection of immunodeficient mice , 1993, Journal of virology.

[145]  S. Abramson,et al.  Expression of nitric oxide synthase in human peripheral blood mononuclear cells and neutrophils. , 1995, Journal of inflammation.

[146]  S. B. Lee,et al.  Regulated expression of the interferon-induced protein kinase p68 (PKR) by vaccinia virus recombinants inhibits the replication of vesicular stomatitis virus but not that of poliovirus. , 1996, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[147]  G. Kreutzberg,et al.  Gamma interferon-like immunoreactive material in rat neurons: Evidence against a close relationship to gamma interferon , 1991, Neuroscience.

[148]  T. Olsson,et al.  Interferon‐gamma‐like immunoreactivity in certain neurons of the central and peripheral nervous system , 1989, Journal of neuroscience research.

[149]  Adolf Gr.  Human interferon omega--a review. , 1995 .

[150]  R. Detels,et al.  Further epidemiological studies of subacute sclerosing panencephalitis. , 1973, Lancet.

[151]  L. Rogge,et al.  Regulation of the IL‐12/IL‐12R axis: a critical step in T‐helper cell differentiation and effector function , 1999, Immunological reviews.

[152]  M. Barna,et al.  Activation of type III nitric oxide synthase in astrocytes following a neurotropic viral infection. , 1996, Virology.

[153]  F. Chisari,et al.  Noncytolytic control of viral infections by the innate and adaptive immune response. , 2001, Annual review of immunology.

[154]  D. Kolson,et al.  The effects of human immunodeficiency virus in the central nervous system. , 1998, Advances in virus research.

[155]  G. Trinchieri,et al.  Cutting Edge: Ectopic Expression of the IL-12 Receptor-β2 in Developing and Committed Th2 Cells Does Not Affect the Production of IL-4 or Induce the Production of IFN-γ1 , 2000, The Journal of Immunology.

[156]  U. Liebert,et al.  CD4+ T cells are essential in overcoming experimental murine measles encephalitis. , 1994, Immunology.

[157]  R. Roberts,et al.  A role for interferons in early pregnancy , 1991, BioEssays : news and reviews in molecular, cellular and developmental biology.

[158]  G. Karupiah,et al.  Inhibition of viral replication by interferon-gamma-induced nitric oxide synthase. , 1993, Science.

[159]  J. Richt,et al.  Protective and Pathological Immune Responses in the CNS , 2002, Current Topics in Microbiology and Immunology.

[160]  S. Landolfo,et al.  Interferons inhibit onset of murine cytomegalovirus immediate-early gene transcription. , 1993, Virology.

[161]  S. Dorman,et al.  Viral infections in interferon-γ receptor deficiency☆☆☆ , 1999, The Journal of Pediatrics.

[162]  G. Rall,et al.  Immune-Mediated Protection from Measles Virus-Induced Central Nervous System Disease Is Noncytolytic and Gamma Interferon Dependent , 2002, Journal of Virology.

[163]  D. Ireland,et al.  Neuronal expression of NOS-1 is required for host recovery from viral encephalitis. , 1999, Virology.

[164]  S. Ubol,et al.  Apoptosis induction in brain during the fixed strain of rabies virus infection correlates with onset and severity of illness. , 1998, Journal of neurovirology.

[165]  B. Williams,et al.  Effect of deficiency of the double-stranded RNA-dependent protein kinase, PKR, on antiviral resistance in the presence or absence of ribonuclease L: HSV-1 replication is particularly sensitive to deficiency of the major IFN-mediated enzymes. , 2000, Journal of interferon & cytokine research : the official journal of the International Society for Interferon and Cytokine Research.

[166]  Xiao-Ling Li,et al.  RNase L Mediates the Antiviral Effect of Interferon through a Selective Reduction in Viral RNA during Encephalomyocarditis Virus Infection , 1998, Journal of Virology.

[167]  D. Baltimore,et al.  Defective Viral Particles and Viral Disease Processes , 1970, Nature.

[168]  B. Robertson,et al.  Interferon-γ-responsive neuronal sites in the normal rat brain: receptor protein distribution and cell activation revealed by Fos induction , 2000, Brain Research Bulletin.

[169]  J. Mulder,et al.  Cortical cholinergic decline parallels the progression of Borna virus encephalitis , 2001, Neuroreport.

[170]  G. Koob,et al.  Prefrontal cortex dysfunction in borna disease virus (BDV)-infected rats , 1996, Biological Psychiatry.

[171]  K. Kristensson,et al.  SELECTIVE INFECTIONS OF OLFACTORY AND RESPIRATORY EPITHELIUM BY VESICULAR STOMATITIS AND SENDAI VIRUSES , 1987, Neuropathology and applied neurobiology.

[172]  D. R. Taylor,et al.  Inhibition of the interferon-inducible protein kinase PKR by HCV E2 protein. , 1999, Science.

[173]  O. Haller,et al.  Human and mouse Mx proteins inhibit different steps of the influenza virus multiplication cycle , 1992, Journal of virology.

[174]  L. Fiette,et al.  Theiler's virus infection of 129Sv mice that lack the interferon alpha/beta or interferon gamma receptors , 1995, The Journal of experimental medicine.

[175]  C. Lowenstein,et al.  Nitric oxide inhibits viral replication in murine myocarditis. , 1996, The Journal of clinical investigation.

[176]  J. Langland,et al.  When two strands are better than one: the mediators and modulators of the cellular responses to double-stranded RNA. , 1996, Virology.