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G Haase - One of the best experts on this subject based on the ideXlab platform.
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Adenoviral vectors for in vivo gene delivery to oligodendrocytes: transgene expression and Cytopathic consequences.
Gene therapy, 1999Co-Authors: R J M Franklin, M M Quick, G HaaseAbstract:Replication defective viral vectors provide a potentially useful means of gene transfer to oligodendrocytes and thus for studying the pathogenesis of white matter disease. In this study we have examined the expression pattern of E1/E3 deleted adenoviral vectors expressing the reporter gene LacZ (AdlacZ) as a means of establishing the value of these vectors for gene delivery to oligodendrocytes in adult rat white matter. Our results indicate that although such an approach can be used to induce transgene expression in oligodendrocytes, it is complicated by both immunogenic and Cytopathic effects. Thus, in normal animals, injection of DeltaE1/E3 adenoviral vectors was associated with a robust immune response that led to a lack of expression by 40 days after injection. In order to overcome this complication, virus was injected into the white matter of immuno-deficient athymic rats. These experiments indi- cated that even in the absence of a T cell response high viral titres of DeltaE1/E3 adenoviral vectors had a profound Cytopathic effect leading to death of oligodendrocytes and hence demyelination. A similar Cytopathic effect was demonstrated using an adenoviral vector expressing the neurocytokine ciliary neurotrophic factor (AdCNTF). As the titre of injected virus was decreased there was a significant decrease in the number of transgene expressing cells. These experiments therefore indicated that in immunodeficient recipients there is a narrow window of virus titre that results in a high rate of infectivity and expression without significant Cytopathic consequences. At higher viral titres the Cytopathic effects include oligodendrocyte death and demyelination, while at lower titres there is a significant decrease in the efficiency of the number of cells expressing the transgene.
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Adenoviral vectors for in vivo gene delivery to oligodendrocytes: transgene expression and Cytopathic consequences
Gene Therapy, 1999Co-Authors: R J M Franklin, M M Quick, G HaaseAbstract:Replication defective viral vectors provide a potentially useful means of gene transfer to oligodendrocytes and thus for studying the pathogenesis of white matter disease. In this study we have examined the expression pattern of E1/E3 deleted adenoviral vectors expressing the reporter gene LacZ (AdlacZ) as a means of establishing the value of these vectors for gene delivery to oligodendrocytes in adult rat white matter. Our results indicate that although such an approach can be used to induce transgene expression in oligodendrocytes, it is complicated by both immunogenic and Cytopathic effects. Thus, in normal animals, injection of ΔE1/E3 adenoviral vectors was associated with a robust immune response that led to a lack of expression by 40 days after injection. In order to overcome this complication, virus was injected into the white matter of immuno-deficient athymic rats. These experiments indi- cated that even in the absence of a T cell response high viral titres of ΔE1/E3 adenoviral vectors had a profound Cytopathic effect leading to death of oligodendrocytes and hence demyelination. A similar Cytopathic effect was demonstrated using an adenoviral vector expressing the neurocytokine ciliary neurotrophic factor (AdCNTF). As the titre of injected virus was decreased there was a significant decrease in the number of transgene expressing cells. These experiments therefore indicated that in immunodeficient recipients there is a narrow window of virus titre that results in a high rate of infectivity and expression without significant Cytopathic consequences. At higher viral titres the Cytopathic effects include oligodendrocyte death and demyelination, while at lower titres there is a significant decrease in the efficiency of the number of cells expressing the transgene.
R J M Franklin - One of the best experts on this subject based on the ideXlab platform.
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Adenoviral vectors for in vivo gene delivery to oligodendrocytes: transgene expression and Cytopathic consequences.
Gene therapy, 1999Co-Authors: R J M Franklin, M M Quick, G HaaseAbstract:Replication defective viral vectors provide a potentially useful means of gene transfer to oligodendrocytes and thus for studying the pathogenesis of white matter disease. In this study we have examined the expression pattern of E1/E3 deleted adenoviral vectors expressing the reporter gene LacZ (AdlacZ) as a means of establishing the value of these vectors for gene delivery to oligodendrocytes in adult rat white matter. Our results indicate that although such an approach can be used to induce transgene expression in oligodendrocytes, it is complicated by both immunogenic and Cytopathic effects. Thus, in normal animals, injection of DeltaE1/E3 adenoviral vectors was associated with a robust immune response that led to a lack of expression by 40 days after injection. In order to overcome this complication, virus was injected into the white matter of immuno-deficient athymic rats. These experiments indi- cated that even in the absence of a T cell response high viral titres of DeltaE1/E3 adenoviral vectors had a profound Cytopathic effect leading to death of oligodendrocytes and hence demyelination. A similar Cytopathic effect was demonstrated using an adenoviral vector expressing the neurocytokine ciliary neurotrophic factor (AdCNTF). As the titre of injected virus was decreased there was a significant decrease in the number of transgene expressing cells. These experiments therefore indicated that in immunodeficient recipients there is a narrow window of virus titre that results in a high rate of infectivity and expression without significant Cytopathic consequences. At higher viral titres the Cytopathic effects include oligodendrocyte death and demyelination, while at lower titres there is a significant decrease in the efficiency of the number of cells expressing the transgene.
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Adenoviral vectors for in vivo gene delivery to oligodendrocytes: transgene expression and Cytopathic consequences
Gene Therapy, 1999Co-Authors: R J M Franklin, M M Quick, G HaaseAbstract:Replication defective viral vectors provide a potentially useful means of gene transfer to oligodendrocytes and thus for studying the pathogenesis of white matter disease. In this study we have examined the expression pattern of E1/E3 deleted adenoviral vectors expressing the reporter gene LacZ (AdlacZ) as a means of establishing the value of these vectors for gene delivery to oligodendrocytes in adult rat white matter. Our results indicate that although such an approach can be used to induce transgene expression in oligodendrocytes, it is complicated by both immunogenic and Cytopathic effects. Thus, in normal animals, injection of ΔE1/E3 adenoviral vectors was associated with a robust immune response that led to a lack of expression by 40 days after injection. In order to overcome this complication, virus was injected into the white matter of immuno-deficient athymic rats. These experiments indi- cated that even in the absence of a T cell response high viral titres of ΔE1/E3 adenoviral vectors had a profound Cytopathic effect leading to death of oligodendrocytes and hence demyelination. A similar Cytopathic effect was demonstrated using an adenoviral vector expressing the neurocytokine ciliary neurotrophic factor (AdCNTF). As the titre of injected virus was decreased there was a significant decrease in the number of transgene expressing cells. These experiments therefore indicated that in immunodeficient recipients there is a narrow window of virus titre that results in a high rate of infectivity and expression without significant Cytopathic consequences. At higher viral titres the Cytopathic effects include oligodendrocyte death and demyelination, while at lower titres there is a significant decrease in the efficiency of the number of cells expressing the transgene.
Hans Hengartner - One of the best experts on this subject based on the ideXlab platform.
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Antiviral antibody responses: the two extremes of a wide spectrum
Nature Reviews Immunology, 2006Co-Authors: Lars Hangartner, Rolf M. Zinkernagel, Hans HengartnerAbstract:Viruses elicit a diverse spectrum of antiviral antibody responses. In this review, we discuss two widely used experimental model systems for viral infections — non-Cytopathic lymphocytic choriomeningitis virus (LCMV) and acutely Cytopathic vesicular stomatitis virus (VSV) — to analyse two fundamentally different types of antiviral antibody response. The basic principles found in these model infections are discussed in the context of other viral infections, and with regard to protective neutralizing versus non-protective enzyme-linked immunosorbent assay (ELISA)-detected antibody responses. Issues of antibody specificity, affinity and avidity, maturation and escape are discussed in the context of co-evolution of the host and viruses. Control of virus infection usually requires both cellular and humoral immune responses. This Review outlines the role of virus-specific antibodies in combating viral infections, using lymphocytic choriomeningitis virus as a model non-Cytopathic virus and vesicular stomatitis virus as a model acutely Cytopathic virus. Viruses elicit a broad spectrum of antibody responses. By focusing on two experimental virus infections — the non-Cytopathic, persistency-prone lymphocytic choriomeningitis virus (LCMV) and the acutely Cytopathic, rabies-like vesicular stomatitis virus (VSV) in mice — we outline two fundamentally different types of antiviral antibody response. These results are discussed in the context of other viral infections, such as influenza virus and HIV. The immunogenicity of viral surface proteins is influenced by various factors, including accessibility, glycosylation, repetitiveness and organization. The availability of B cells that encode immunoglobulin that is specific for these different viral epitopes also has a great impact on their immunogenicity. Acutely Cytopathic virus infections, such as VSV, must be controlled rapidly before the virus can spread to vital organs and kill the host. Therefore, most Cytopathic viruses support the rapid generation of neutralizing antibodies. Poorly or non-Cytopathic viruses, such as LCMV, tend to persist and actively interfere with the generation of neutralizing antibodies. These viruses are frequently transmitted vertically from a virus-carrier mother to her immuno-incompetent offspring. Spleen and bone marrow have a limited capacity to accommodate antibody-producing plasma cells. However, IgM has a short serum half-life, and protective IgM titres require many plasma cells to be maintained. The longer serum half-life of IgG isotype class-switched antibodies allows protective titres to be maintained by fewer plasma cells. In addition, IgG antibodies can be transferred to the infant for protection during the early period of immunoincompentence. There is evidence that germline-encoded antibodies can provide early and sufficient protection against Cytopathic viruses, without undergoing somatic hypermutation (SHM). By contrast, extensive SHM and affinity maturation are required for the formation of protective humoral responses against poorly Cytopathic viruses that have a tendency to persist. In these cases, the germline repertoire does not normally provide antibodies with sufficient affinity to be immediately protective. Viruses tend to escape neutralizing antibody responses. In general, rapidly transmitting, acutely Cytopathic, and therefore lethal, viruses have to evade herd immunity and therefore frequently exist in closely related but immunologically distinct varieties (serotypes). By contrast, poorly Cytopathic viruses evade the immune response of the individual host by diversifying into numerous quasi-species, with individual neutralizing specificities within a single infected individual.
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Lactate dehydrogenase-elevating virus (LDV): lifelong coexistence of virus and LDV-specific immunity.
Journal of Immunology, 1997Co-Authors: M. F. Van Den Broek, Chen Even, Roman Spörri, E. Hanseler, Hans Hengartner, Rolf M. ZinkernagelAbstract:Viruses have developed various strategies to coexist with vertebrate hosts. Lactate dehydrogenase-elevating virus (LDV) is a highly Cytopathic virus exhibiting an extraordinary rate of replication; LDV nevertheless establishes a persistent infection without harming the host. The cytotoxic and helper T cell responses to LDV were monitored in mice with different genetic backgrounds. LDV-specific cytotoxic and helper T cells were found in all strains tested. These responses persisted for at least up to 250 days despite high levels of LDV in the blood. Thus, the Cytopathic LDV induces and maintains an inefficient immune response that is not exhausted. LDV infection in mice reveals a special type of host-virus equilibrium where LDV quickly establishes persistence despite continuously induced LDV-specific helper and cytotoxic T cell responses, which apparently are too slow to control the highly Cytopathic and extremely fast replicating virus.
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The roles of perforin- and Fas-dependent cytotoxicity in protection against Cytopathic and nonCytopathic viruses.
European journal of immunology, 1995Co-Authors: David Kägi, Rolf M. Zinkernagel, Peter Seiler, Jovan Pavlovic, Birgit Ledermann, Kurt Bürki, Hans HengartnerAbstract:In vitro, T cell-dependent cytotoxicity is mediated by two distinct mechanisms, one being perforin-, the other Fas-dependent. The contribution of both of these mechanisms to clearance of viral infections was investigated in mice for the non-Cytopathic lymphocytic choriomeningitis virus (LCMV) and the Cytopathic vaccinia, vesicular stomatitis (VSV) and Semliki forest (SFV) viruses. Clearance of an acute LCMV infection was mediated by the perforin-dependent mechanism without measurable involvement of the Fas-dependent pathway. For the resolution of vaccinia virus infection and for resistance against VSV and SFV, however, neither of the two pathways was required. These data suggest that perforin-dependent cytotoxicity mediated by T cells is crucial for protection against non-Cytopathic viruses, whereas infections with Cytopathic viruses are controlled by nonlytic T cell-dependent soluble mediators such as cytokines (IFN-gamma against vaccinia virus) and neutralizing antibodies (against VSV and SFV).
Joseph Sodroski - One of the best experts on this subject based on the ideXlab platform.
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Role of the human immunodeficiency virus type I envelope glycoprotein in Cytopathic effect.
Advances in experimental medicine and biology, 1991Co-Authors: Joseph Sodroski, William A. Haseltine, Mark KowalskiAbstract:The pathogenesis of acquired immune deficiency syndrome (AIDS) is characterized by a depletion of CD4-positive lymphocytes (for review, see Fauci, 1988). HIV-1 infection of CD4-positive lymphocytes and, to a lesser extent, monocyte/macrophages in tissue culture is accompanied by Cytopathic effects (Popovic et al., 1984). The Cytopathic effects follow a temporal course with the initial phase consisting of a period of formation of multinucleated giant cells or syncytia. This is followed by a phase of single cell lysis, which in turn is followed by a period of host cell resistance to Cytopathic effect. In the latter phase, cells often continue to produce high titers of viruses that are Cytopathic for fresh target cells, without undergoing obvious Cytopathic effects.
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attenuation of human immunodeficiency virus type 1 Cytopathic effect by a mutation affecting the transmembrane envelope glycoprotein
Journal of Virology, 1991Co-Authors: Mark Kowalski, William A. Haseltine, L Bergeron, Tatyana Dorfman, Joseph SodroskiAbstract:The Cytopathic effects of human immunodeficiency virus type 1 (HIV-1) infection are specific for cells that express the CD4 viral receptor and consist of syncytium formation and single-cell lysis. Here we report that a mutation (517A) affecting the amino terminus of the HIV-1 gp41 transmembrane envelope glycoprotein resulted in a virus that was markedly less Cytopathic than was wild-type HIV-1. In systems in which cell-to-cell transmission of HIV-1 occurred, the replication ability of the 517A virus was comparable with that of the wild-type virus. Even though the levels of viral protein expression, virion production, and interaction of the envelope glycoproteins with CD4 were similar for the 517A and wild-type viruses, both syncytium formation and single-cell lysis were attenuated for the 517A mutant virus. These results demonstrate that an envelope glycoprotein region important for mediating post-receptor binding events in cell membrane fusion is important for the induction of Cytopathic effects by HIV-1. These results also indicate that levels of HIV-1 viral proteins or viral particles produced in infected cells are in themselves not sufficient to induce Cytopathic effects.
Georg A Funk - One of the best experts on this subject based on the ideXlab platform.
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hiv replication elicits little Cytopathic effects in vivo analysis of surrogate markers for virus production cytotoxic t cell response and infected cell death
Journal of Medical Virology, 2006Co-Authors: Georg A Funk, Annette Oxenius, Marek Fischer, Milos Opravil, Beda Joos, Markus Flepp, Rainer Weber, Huldrych F GunthardAbstract:Several potential mechanisms for viral destruction of HIV-infected cells have been described. The hypothesis was examined that if HIV were Cytopathic, a positive relation between the in vivo virus production or CTL activity and infected cell death should be observed. In a regression analysis no significant relation was found between surrogate markers for in vivo virus production or the virus-specific CTL response and death rates of productively infected cells. In a subgroup of patients the hypothesis is rejected that HIV replication elicits a large (R2 > 0.25) Cytopathic effect (P < 0.05, N = 36). It is concluded that HIV replication elicits little Cytopathic effect in productively infected cells and that CD4+ T lymphocytes are eroded by other mechanisms. J. Med. Virol. 78:1141–1146, 2006. © 2006 Wiley-Liss, Inc.
