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Peter G W Plagemann - One of the best experts on this subject based on the ideXlab platform.
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2016Co-Authors: Raymond R. R. Rowl, Chen Even, Zongyu Chen, Grant W Anderson, Peter G W PlagemannAbstract:Neonatal infection of mice with Lactate Dehydrogenase-Elevating Virus results in suppression of humoral antiviral immune response but does not alter the course of viraemia or the polyclonal activation of B cells and immune complex formatio
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Lactate Dehydrogenase-Elevating Virus, equine arteritis Virus, and simian hemorrhagic fever Virus: a new group of positive-strand RNA Viruses.
Advances in Virus Research, 2008Co-Authors: Peter G W Plagemann, Volker MoennigAbstract:Publisher Summary The last comprehensive reviews of nonarbotogaViruses included discussions on pestiViruses, rubella Virus, Lactate Dehydrogenase-Elevating Virus (LDV), equine arteritis Virus (EAV), simian hemorrhagic fever Virus (SHFV), cell fusion agent, and nonarboflaviViruses. The inclusion of all these Viruses in the family Togaviridae was largely based on the similarities in morphological and physical–chemical properties of these Viruses, and in the sizes and polarities of their genomes. In the intervening years, considerable new information on the replication strategies of these Viruses and the structure and organization of their genomes has become available that has led to the reclassification or suggestions for reclassification of some of them. The replication strategy of EAV resembles that of the coronaViruses, involving a 3'-coterminal nested set of mRNAs. Therefore, EAV has been suggested to be included in a Virus superfamily, along with coronaViruses and toroViruses. Recent evidence indicates that LDV not only resembles EAV in morphology, virion and genome size, and number and size of their structural proteins, but also in genome organization and replication via a 3'-coterminal set of mRNAs. SHFV, although not fully characterized, exhibits properties resembling those of LDV and EAV, and the recent evidence suggest that it may possess the same genome organization as these Viruses. The three Viruses may, therefore, represent a new family of positive-strand RNA Viruses and are reviewed together in this chapter. In this chapter, emphasis is on the recent information concerning their molecular properties and pathogenesis in vitro and in vivo and on the host immune responses to infections by these Viruses.
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Glucocorticoid regulation of Lactate Dehydrogenase-Elevating Virus replication in macrophages
Virus Research, 2003Co-Authors: William A Cafruny, Quentin A Jones, Peter G W Plagemann, Nicole L. Zitterkopf, Thomas R Haven, Raymond R R RowlandAbstract:Lactate Dehydrogenase-Elevating Virus (LDV) is a macrophage-tropic arteriVirus which generally causes a persistent viremic infection in mice. LDV replication in vivo seems to be primarily regulated by the extent and dynamics of a Virus-permissive macrophage population. Previous studies have shown that glucocorticoid treatment of chronically LDV-infected mice transiently increases viremia 10-100-fold, apparently by increasing the productive infection of macrophages. We have further investigated this phenomenon by comparing the effect of dexamethasone on the in vivo and in vitro replication of two LDV quasispecies that differ in sensitivity to immune control by the host. The single neutralizing epitope of LDV-P is flanked by two N-glycans that impair its immunogenicity and render LDV-P resistant to antibody neutralization. In contrast, replication of the neuropathogenic mutant LDV-C is suppressed by antibody neutralization because its epitope lacks the two protective N-glycans. Dexamethasone treatment of mice 16 h prior to LDV-P infection, or of chronically LDV-P infected mice, stimulated viremia 10-100-fold, which correlated with an increase of LDV permissive macrophages in the peritoneum and increased LDV infected cells in the spleen, respectively. The increase in viremia occurred in the absence of changes in total anti-LDV and neutralizing antibodies. The results indicate that increased viremia was due to increased availability of LDV permissive macrophages, and that during a chronic LDV-P infection Virus replication is strictly limited by the rate of regeneration of permissive macrophages. In contrast, dexamethasone treatment had no significant effect on the level of viremia in chronically LDV-C infected mice, consistent with the view that LDV-C replication is primarily restricted by antibody neutralization and not by a lack of permissive macrophages. beta-Glucan, the receptor of which is induced on macrophages by dexamethasone treatment, had no effect on the LDV permissiveness of macrophages.
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Hydrophobic IgG-Containing Immune Complexes in the Plasma of Autoimmune MRL/lpr Mice, Lactate Dehydrogenase-Elevating Virus-Infected Mice, and Pigs: Association with Transforming Growth Factor-β and pH-Dependent Amplification
Viral Immunology, 2003Co-Authors: Nicole L. Zitterkopf, Quentin A Jones, Raymond R R Rowland, Peter G W Plagemann, David S. Bradley, Kelly A Durick, William A CafrunyAbstract:Persistent infection of mice with Lactate Dehydrogenase-Elevating Virus (LDV) is associated with polyclonal B cell activation, autoimmunity, and circulating hydrophobic IgG-containing immune comple...
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Complexity of the single linear neutralization epitope of the mouse arteriVirus Lactate Dehydrogenase-Elevating Virus.
Virology, 2001Co-Authors: Peter G W PlagemannAbstract:Abstract Results from indirect ELISAs using synthetic peptides of various length that represent segments of the ectodomain of the envelope glycoprotein, VP-3P, of Lactate Dehydrogenase-Elevating Virus (LDV) showed that the primary neutralization epitope of LDV is located in a short linear hydrophilic segment in the center of the ectodomain. The epitope becomes slightly altered by amino acid substitutions in the ectodomain and inactivation of virions by various treatments. Neutralizing anti-VP-3P antibodies (Abs) to the epitope interact with the synthetic peptides only if they possess a certain conformation. When the peptides were immobilized on ELISA plates, neutralizing mAbs elicited to inactivated LDV and neutralizing Abs from infected mice bound best to the peptides that consisted of the full-length, 30-amino-acid-long ectodomain. The Abs bound poorly, if at all, to most of the shorter peptides when immobilized, whether truncated at the N- or C-end, but when in solution the same peptides strongly inhibited the binding of the Abs to immobilized full-length peptides. Thus, a conformation of the epitope required for Ab binding and (or) its steric accessibility were lost upon immobilization of the shorter peptides on ELISA plates. Abs raised in mice to peptide–bovine serum albumin conjugates reacted only with immobilized peptides in the indirect ELISA and failed to neutralize LDV. The neutralization epitope of the common LDV quasispecies, LDV-P and LDV-vx, is flanked by N-glycans that block the immunogenicity of the epitope and the neutralization of these LDVs. Abs to a second weakly immunogenic and probably discontinuous epitope appear in LDV infected mice about 1 month postinfection.
Jean-paul Coutelier - One of the best experts on this subject based on the ideXlab platform.
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the tlr7 ligand r848 prevents mouse graft versus host disease and cooperates with anti interleukin 27 antibody for maximal protection and regulatory t cell upregulation
Haematologica, 2019Co-Authors: Melanie Gaignage, Reece Gerrad Marillier, Perrine M Cochez, Laure Dumoutier, Catherine Uyttenhove, Jean-paul Coutelier, Jacques Van SnickAbstract:In spite of considerable therapeutic progress, acute graft-versus-host disease still limits allogeneic hematopoietic cell transplantation. We recently reported that mouse infection with nidoVirus Lactate dehydrogenase elevating Virus impairs disease in non-conditioned B6D2F1 recipients of parental B6 spleen cells. As this Virus activates TLR7, we tested a pharmacological TLR7 ligand, R848, in this model and observed complete survival if donor and recipients were treated before transplantation. Mixed lymphocyte culture performed 48 h after R848-treatment of normal mice demonstrated that both T-cell allo-responsiveness and antigen presentation by CD11b+ and CD8α+ dendritic cells were inhibited. These inhibitions were dependent on IFNAR-1 signaling. In the B6 to B6D2F1 transplantation model, R848 decelerated, but did not abrogate, donor T-cell implantation and activation. However, it decreased interferon-gamma, tumor necrosis factor-alpha and interleukin-27 while upregulating active transforming growth factor-beta 1 plasma levels. In addition, donor and recipient Foxp3+ regulatory T-cell numbers were increased in recipient mice and their elimination compromised disease prevention. R848 also strongly improved survival of lethally irradiated BALB/c recipients of B6 hematopoietic cells and this also correlated with an upregulation of CD4 and CD8 Foxp3+ regulatory T cells that could be further increased by inhibition of interleukin-27. The combination of anti-interleukin-27p28 mono -clonal antibody and R848 showed strong synergy in preventing disease in the B6 to B6D2F1 transplantation model when recipients were sublethally irradiated and this also correlated with upregulation of regulatory T cells. We conclude that R848 modulates multiple aspects of graft-versus-host disease and offers potential for safe allogeneic bone marrow transplantation that can be further optimized by inhibition of interleukin-27.
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IMMUNOBIOLOGY Exacerbation of autoantibody-mediated thrombocytopenic purpura by infection with mouse Viruses
2016Co-Authors: Andrei Musaji, César L. Cambiaso, Jean-paul CoutelierAbstract:Antigenic mimicry has been proposed as a major mechanism by which Viruses could trigger the development of immune thrombocytopenic purpura (ITP). How-ever, because antigenic mimicry implies epitope similarities between viral and self antigens, it is difficult to understand how widely different Viruses can be involved by this sole mechanism in the pathogene-sis of ITP. Here, we report that in mice treated with antiplatelet antibodies at a dose insufficient to induce clinical dis-ease by themselves, infection with Lactate Dehydrogenase-Elevating Virus (LDV) was followed by severe thrombocytopenia and by the appearance of petechiae similar to those observed in patients with ITP. A similar exacerbation of antiplatelet-mediated thrombocytopenia was induced by mouse hepatitis Virus. This enhance-ment of antiplatelet antibody pathogenic-ity by LDV was not observed with F(ab)2 fragments, suggesting that phagocytosis was involved in platelet destruction. Treat-ment of mice with clodronate-containing liposomes and with total immunoglobulin G (IgG) indicated that platelets were cleared by macrophages. The increase of thrombocytopenia triggered by LDV after administration of antiplatelet antibodies was largely suppressed in animals deficient for -interferon receptor. Together, these re-sults suggest that Viruses may exacer-bate autoantibody-mediated ITP by acti-vating macrophages through -interferon production, a mechanism that may ac-count for the pathogenic similarities of multiple infectious agents. (Blood. 2004
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modulation of the host microenvironment by a common non oncolytic mouse Virus leads to inhibition of plasmacytoma development through nk cell activation
Journal of General Virology, 2014Co-Authors: Gaëtan Thirion, Jacques Van Snick, Xavier Hulhoven, Anubha Saxena, Dominique Markinegoriaynoff, Jean-paul CoutelierAbstract:Although many cells undergo transformation, few actually develop into tumours, due to successful mechanisms of immunosurveillance. To investigate whether an infectious agent may play a role in this process, the growth of a plasmacytoma was investigated in mice infected by Lactate Dehydrogenase-Elevating Virus. Acutely infected animals were significantly protected against tumour development. The mechanisms responsible for this protection were analysed in mice deficient for relevant immune cells or molecules and after in vivo cell depletion. This protection by viral infection correlated with NK cell activation and with IFN-γ production. It might also be related to activation of NK/T-cells, although this remains to be proven formally. Therefore, our results indicated that infections with benign micro-organisms may protect the host against cancer development, through non-specific stimulation of the host's innate immune system and especially of NK cells.
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L’infection par le « Lactate Dehydrogenase-Elevating Virus » : un modèle expérimental de modulation du microenvironnement immunitaire
Virologie, 2014Co-Authors: Jean-paul CoutelierAbstract:Lactate Dehydrogenase-Elevating Virus (LDV), a mouse arteriVirus, is characterized by a lifelong viremia, despite antiviral innate and adaptative immune response. It induces strong modifications of the host immune microenvironment, including macrophage and natural killer cell activation, secretion of pro-inflammatory cytokines, modulation of T helper cell differentiation and polyclonal activation of B-lymphocytes. This modification of the immune microenvironment results in the protection against some diseases such as allergies, graft-versus-host reaction, experimental autoimmune encephalitis, and growth of some tumors. In contrast, it exacerbates other pathologies such as endotoxin shock and autoantibody-mediated autoimmune diseases. Thus, LDV infection provides an interesting model to understand the consequences of viral infections on pathogenic mechanisms and to define new therapeutic approaches.
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Changes in antibody specificities and cytokine release after infection with Lactate Dehydrogenase-Elevating Virus
International Immunopharmacology, 2013Co-Authors: Jose Luis Aparicio, Jean-paul Coutelier, Jacques Van Snick, Anubha Saxena, Lilia A. ReteguiAbstract:Lactate Dehydrogenase-Elevating Virus (LDV) is an apparently innocuous and persistent Virus that can modify mouse immune reactions. We have shown that LDV-infected mice immunized with human growth hormone (hGH) showed a deep modification of the specificity of the anti-hGH antibodies (Ab) in CBA/Ht mice but not BALB/c animals. The aim of this work was to extend the previous observations to another mouse strain, C57BL/6, as well as to an antigen unrelated to hGH, ovalbumin (OVA), and to explore at the same time the production of various cytokines at serum and cellular levels. The amount of Ab directed to hGH or OVA native antigenic determinants versus the concentration of Ab to cryptic epitopes was evaluated by ELISA competition experiments. Results indicated that LDV infection affected Ab specificity solely in CBA/Ht mice. In CBA/Ht the Virus infection was associated with a reduction of the Ab titers to hGH native epitopes and with a decrease of IL-13 and IL-17 serum levels, but Ab to native OVA epitopes were increased with a simultaneous increase of IL-17. Accordingly, only lymph node cells from infected CBA/Ht mice immunized with OVA were found to produce INF-γ, IL-13 and IL-17. Thus, a correlation of cytokine production with a change in Ab specificity after a viral infection was found, although this phenomenon was restricted to a given antigen and to the genetic background of immunized animals. These observations suggest that an apparent harmless Virus can affect some immunological mechanisms, which could lead, for example, to inflammatory or autoimmune disorders.
William A Cafruny - One of the best experts on this subject based on the ideXlab platform.
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Suppression of Acute Anti-Friend Virus CD8+ T-Cell Responses by Coinfection with Lactate Dehydrogenase-Elevating Virus
Journal of Virology, 2007Co-Authors: Shelly J. Robertson, Christoph G. Ammann, Ronald J. Messer, Aaron B. Carmody, Lara Myers, Ulf Dittmer, Savita Nair, Nicole Gerlach, Leonard H. Evans, William A CafrunyAbstract:Friend Virus (FV) and Lactate Dehydrogenase-Elevating Virus (LDV) are endemic mouse Viruses that can cause long-term chronic infections in mice. We found that numerous mouse-passaged FV isolates also contained LDV and that coinfection with LDV delayed FV-specific CD8+ T-cell responses during acute infection. While LDV did not alter the type of acute pathology induced by FV, which was severe splenomegaly caused by erythroproliferation, the immunosuppression mediated by LDV increased both the severity and the duration of FV infection. Compared to mice infected with FV alone, those coinfected with both FV and LDV had delayed CD8+ T-cell responses, as measured by FV-specific tetramers. This delayed response accounted for the prolonged and exacerbated acute phase of FV infection. Suppression of FV-specific CD8+ T-cell responses occurred not only in mice infected concomitantly with LDV but also in mice chronically infected with LDV 8 weeks prior to infection with FV. The LDV-induced suppression was not mediated by T regulatory cells, and no inhibition of the CD4+ T-cell or antibody responses was observed. Considering that most human adults are carriers of chronically infectious Viruses at the time of new Virus insults and that coinfections with Viruses such as human immunodeficiency Virus and hepatitis C Virus are currently epidemic, it is of great interest to determine how infection with one Virus may impact host responses to a second infection. Coinfection of mice with LDV and FV provides a well-defined, natural host model for such studies.
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Lactate Dehydrogenase-Elevating Virus induces apoptosis in cultured macrophages and in spinal cords of C58 mice coincident with onset of murine amyotrophic lateral sclerosis.
Virus Research, 2004Co-Authors: Nicole L. Zitterkopf, David S. Bradley, David W. Mcneal, Kathleen M. Eyster, William A CafrunyAbstract:Abstract Age-dependent poliomyelitis (ADPM) or murine amyotrophic lateral sclerosis (ALS) is a murine paralytic disease triggered in immunosuppressed genetically-susceptible mice by infection with the arteriVirus Lactate Dehydrogenase-Elevating Virus (LDV). This disease provides an animal model for ALS, affecting anterior horn neurons and resulting in neuroparalysis 2–3 weeks after LDV infection. We have tested the hypothesis that spinal cord apoptosis is a feature of the LDV-induced murine ALS, since apoptosis is postulated to be a causal factor in human ALS. Gene microarray analyses of spinal cords from paralyzed animals revealed upregulation of several genes associated with apoptosis. Spinal cord apoptosis was investigated further by TUNEL and activated caspase-3 assays, and was observed to emerge concurrent with paralytic symptoms in both neuronal and non-neuronal cells. Caspase-3-dependent apoptosis was also triggered in cultured macrophages by neurovirulent LDV infection. Thus, Virus-induced spinal cord apoptosis is a pre-mortem feature of ADPM, which affects both neuronal and support cells, and may contribute to the pathogenesis of this ALS-like disease.
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Glucocorticoid regulation of Lactate Dehydrogenase-Elevating Virus replication in macrophages
Virus Research, 2003Co-Authors: William A Cafruny, Quentin A Jones, Peter G W Plagemann, Nicole L. Zitterkopf, Thomas R Haven, Raymond R R RowlandAbstract:Lactate Dehydrogenase-Elevating Virus (LDV) is a macrophage-tropic arteriVirus which generally causes a persistent viremic infection in mice. LDV replication in vivo seems to be primarily regulated by the extent and dynamics of a Virus-permissive macrophage population. Previous studies have shown that glucocorticoid treatment of chronically LDV-infected mice transiently increases viremia 10-100-fold, apparently by increasing the productive infection of macrophages. We have further investigated this phenomenon by comparing the effect of dexamethasone on the in vivo and in vitro replication of two LDV quasispecies that differ in sensitivity to immune control by the host. The single neutralizing epitope of LDV-P is flanked by two N-glycans that impair its immunogenicity and render LDV-P resistant to antibody neutralization. In contrast, replication of the neuropathogenic mutant LDV-C is suppressed by antibody neutralization because its epitope lacks the two protective N-glycans. Dexamethasone treatment of mice 16 h prior to LDV-P infection, or of chronically LDV-P infected mice, stimulated viremia 10-100-fold, which correlated with an increase of LDV permissive macrophages in the peritoneum and increased LDV infected cells in the spleen, respectively. The increase in viremia occurred in the absence of changes in total anti-LDV and neutralizing antibodies. The results indicate that increased viremia was due to increased availability of LDV permissive macrophages, and that during a chronic LDV-P infection Virus replication is strictly limited by the rate of regeneration of permissive macrophages. In contrast, dexamethasone treatment had no significant effect on the level of viremia in chronically LDV-C infected mice, consistent with the view that LDV-C replication is primarily restricted by antibody neutralization and not by a lack of permissive macrophages. beta-Glucan, the receptor of which is induced on macrophages by dexamethasone treatment, had no effect on the LDV permissiveness of macrophages.
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Hydrophobic IgG-Containing Immune Complexes in the Plasma of Autoimmune MRL/lpr Mice, Lactate Dehydrogenase-Elevating Virus-Infected Mice, and Pigs: Association with Transforming Growth Factor-β and pH-Dependent Amplification
Viral Immunology, 2003Co-Authors: Nicole L. Zitterkopf, Quentin A Jones, Raymond R R Rowland, Peter G W Plagemann, David S. Bradley, Kelly A Durick, William A CafrunyAbstract:Persistent infection of mice with Lactate Dehydrogenase-Elevating Virus (LDV) is associated with polyclonal B cell activation, autoimmunity, and circulating hydrophobic IgG-containing immune comple...
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Enhancement of murine susceptibility to oral Lactate Dehydrogenase-Elevating Virus infection by non-steroidal anti-inflammatory agents, and antagonism by misoprostol
Antiviral Research, 2002Co-Authors: William A Cafruny, James J. Broen, Scott E. Desjarlais, Matthew L. Hecht, Richard A. JaquaAbstract:The murine Lactate Dehydrogenase-Elevating Virus (LDV) was used to study the effects of prostaglandin-acting agents on mucosal resistance to Virus infection. Mice treated with non-steroidal anti-inflammatory drugs (NSAIDs) prior to oral exposure to LDV demonstrated a reduction in the mucosal barrier to LDV infection. Histological studies indicated that these NSAID effects were not a result of gross or microscopic tissue damage. The effects of two NSAIDs, indomethacin and diclofenac, were inhibited by co-treatment of mice with misoprostol, a synthetic PGE1 analog. The ability of misoprostol to modulate NSAID effects was not due to direct antiviral activity or to actions on LDV-permissive macrophages. These results show that the mammalian mucosal barrier to Virus infection is prostaglandin-sensitive, and provide a model for the study of resistance to viral infection.
Chen Even - One of the best experts on this subject based on the ideXlab platform.
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2016Co-Authors: Raymond R. R. Rowl, Chen Even, Zongyu Chen, Grant W Anderson, Peter G W PlagemannAbstract:Neonatal infection of mice with Lactate Dehydrogenase-Elevating Virus results in suppression of humoral antiviral immune response but does not alter the course of viraemia or the polyclonal activation of B cells and immune complex formatio
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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, Peter G W Plagemann, 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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Differential glycosylation of the ectodomain of the primary envelope glycoprotein of two strains of Lactate Dehydrogenase-Elevating Virus that differ in neuropathogenicity.
Virus Research, 1995Co-Authors: Kay S. Faaberg, Chen Even, Gene A Palmer, Grant W Anderson, Peter G W PlagemannAbstract:Abstract ORF 5 encoding the primary envelope glycoprotein, VP-3P, of a highly neuropathogenic isolate of Lactate Dehydrogenase-Elevating Virus (LDV-v) has been sequenced. It exhibits 92% nucleotide identify with the ORF 5 of an LDV isolate that lacks neuropathogenicity, LDV-P, and the amino acid identifies of the predicted VP-3Ps of the two strains is 90%. Most striking, however, is the absence in the ectodomain of VP-3P of LDV-P. The ectodomain of VP-3P has been implicated to play an important role in host receptor interaction. VP-3P of another neuropathogenic LDV strain, LDV-C, lacks the same two N-glycosylation sites (Godeny et al., 1993). In vitro transcription/translation of the ORFs 5 of LDV-P and LDV-v indicated that all three N-glycosylation sites in the ectodomain of LDV-P VP-3P became glycosylated when synthesized in the presence of microsomal membranes, whereas the glycosylation of the ORF 5 proteins of LDV-v and LDV-C was consistent with glycosylation at a single site. No other biological differences between the neuropathogenic and non-neuropathogenic strains have been detected. They replicate with equal efficiency in mice and in primary macrophage cultures.
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Lactate Dehydrogenase-Elevating Virus: an ideal persistent Virus?
Springer Seminars in Immunopathology, 1995Co-Authors: Peter G W Plagemann, Raymond R R Rowland, Chen Even, Kay S. FaabergAbstract:LDV contradicts all commonly held views about mechanisms of Virus persistence, namely that persistence is primarily associated with noncytopathic Viruses, or the selection of immune escape variants or other mutants, or a decrease in expression of certain viral proteins by infected cells, or replication in “immune-privileged sites”, or a general suppression of the host immune system, etc. [1, 2, 5, 54, 77, 78]. LDV is a highly cytocidal Virus that invariably establishes a life-long, viremic, persistence in mice, in spite of normal anti-viral immune responses. One secret of LDV's success in persistence is its specificity for a renewable, nonessential population of cells that is continuously regenerated, namely a subpopulation of macrophages. Since the continuous destruction of these cells is not associated with any obvious health effects, this macrophage population seems nonessential to the well-being of its host. The only function identified for this subpopulation of macrophages is clearance of the muscle type of LDH and some other enzymes [59, 67, 68]. Furthermore, the effects of LDV infection on the host immune system, namely the polyclonal activation of B cells and its associated production of autoantibodies, and the slight impairment of primary and secondary antibody responses also do not seem to be severe enough to cause any clinical consequences. But how does LDV replication in macrophages escape all host defenses? Persistence is not dependent on the seletion of immune escape variants or other mutants ([58] and Palmer, Even and Plagemann, unpublished results). Also, LDV replication is not restricted to immune-privileged sites [5]. LDV replication persists in the liver, lymphoidal tissues and testis [66]. Only the latter could be considered a site not readily accessible to immune surveillance. Most likely, resistance of LDV replication to antiviral immune responses is related to the unique structure of its envelope proteins and the production of large quantities of viral antigens. High titers of anti-LDV antibodies are generated in infected mice but they neutralize LDV infectivity only very inefficiently and, even though the antiviral antibodies are mainly of the IgG2a and IgG2b isotypes, they do not mediate complement lyses of virions [31]. Interaction of the antibodies and complement with the VP-3/VP-2 heterodimers in the viral envelope may be impeded by the exposure of only very short peptide segments of these proteins at the envelope surface and the presence of large oligosaccharide side chains. Furthermore, since LDV maturation is restricted to intracytoplasmic cisternae [59, 71], the question arises of whether any of the viral proteins are available on the surface of infected cells for ADCC. CTLs also fail to control LDV replication. Altough CTLs specific for N/VP-1 are rapidly generated, these have disappeared by 30 days p.i. [26]. The reasons for this loss are unknown, but high-dose clonal exhaustion [41, 51, 77, 78] is a reasonable possibility since, regardless of the infectious dose, large amounts of LDV proteins are present in all the lymphoidal tissues at the time of the induction of the CTL response. Furthermore, after exhaustion of CTLs in the periphery, continuous replication of LDV in the thymus [65] assures that the mice become permanently immunologically tolerant with respect to LDV antigen-specific CTLs as a result of negative selection in the thymus. LDV might be a primary example for the effectiveness of a permanent clonal CTL deletion in adult animals under natural conditions of infection. The presumed modes of transmission of LDV in nature and the events associated with its infection of mice are strikingly similar to those observed during the acute and asymptomatic phases of infection with human immunodeficiency Virus (HIV) [24, 29, 74, 78]. These include: (1) primary inefficient transmission via sexual and transplacental routes but effective transmission via blood; (2) primary replication in renewable populations of lymphoidal cells with production of large amounts of Virus after the initial infection of the host followed by persistent low level of viremia in spite of antiviral immune responses; (3) persistence, reflecting continuous rounds of productive, cytocidal infection of permissive cells [59, 74] and the rate of generation of permissive cells which may be the main factor in determining the level of Virus production (in the case of HIV, the rate of activation of CD4^+ T cells to support a productive HIV replication might be the factor determining the rate of Virus production and the progression of the disease); (4) rapid antibody formation but delayed production of neutralizing antibodies with limited neutralizing capacity; (5) rapid but transient generation of Virus-specific CTLs; and (6) accumulation of large amounts of Virus in newly formed germinal centers in the spleen and lymph nodes concomitant with an initiation of a permanent polyclonal activation of B cells resulting in an elevation of plasma IgG2a. The events described under points 2–6 might be generally associated with natural viremic persistent Virus infections. Such persistent Viruses, by necessity, have evolved properties that allow them to escape all host defenses and control of their infection by immunological processes is, therefore, difficult, if not impossible. Prevention of infection and chemotherapy may be the only approaches available to combat such Virus infections.
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Lactate dehydrogenase elevating Virus replication persists in liver spleen lymph node and testis tissues and results in accumulation of viral rna in germinal centers concomitant with polyclonal activation of b cells
Journal of Virology, 1995Co-Authors: Grant W Anderson, Raymond R R Rowland, Chen Even, Gene A Palmer, Peter G W PlagemannAbstract:Lactate Dehydrogenase-Elevating Virus (LDV) replicates primarily and most likely solely in a subpopulation of macrophages in extraneuronal tissues. Infection of mice, regardless of age, with LDV leads to the rapid cytocidal replication of the Virus in these cells, resulting in the release of large amounts of LDV into the circulation. The infection then progresses into life-long, asymptomatic, low-level viremic persistence, which is maintained by LDV replication in newly generated LDV-permissive cells which escapes all antiviral immune responses. In situ hybridization studies of tissue sections of adult FVB mice revealed that by 1 day postinfection (p.i.), LDV-infected cells were present in practically all tissues but were present in the highest numbers in the lymph nodes, spleen, and skin. In the central nervous system, LDV-infected cells were restricted to the leptomeninges. Most of the infected cells had disappeared at 3 days p.i., consistent with the cytocidal nature of the LDV infection, except for small numbers in lymph node, spleen, liver, and testis tissues. These tissues harbored infected cells until at least 90 days p.i. The results suggest that the generation of LDV-permissive cells during the persistent phase is restricted to these tissues. The continued presence of LDV-infected cells in testis tissue suggests the possibility of LDV release in semen and sexual transmission. Most striking was the accumulation of large amounts of LDV RNA in newly generated germinal centers of lymph nodes and the spleen. The LDV RNA was not associated with infected cells but was probably associated with virions or debris of infected, lysed cells. The appearance of LDV RNA in germinal centers in these mice coincided in time with the polyclonal activation of B cells, which leads to the accumulation of polyclonal immunoglobulin G2a and low-molecular-weight immune complexes in the circulation.
Kay S. Faaberg - One of the best experts on this subject based on the ideXlab platform.
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the primary neutralization epitope of porcine respiratory and reproductive syndrome Virus strain vr 2332 is located in the middle of the gp5 ectodomain
Archives of Virology, 2002Co-Authors: P. G. W. Plagemann, Raymond R R Rowland, Kay S. FaabergAbstract:Pigs infected with porcine respiratory and reproductive syndrome Virus (PRRSV) strain VR-2332 were found to generate high levels of antibodies (Abs) that bound in an indirect ELISA to synthetic peptides representing segments of the primary envelope glycoprotein (GP5) ectodomain of this Virus. Use of overlapping GP5 ectodomain peptides of various length indicated that the epitope recognized by the Abs was located in the middle of the ectodomain (amino acids 36-52), in the same relative segment that contains the single linear neutralization epitope of the closely related mouse arteriVirus, Lactate Dehydrogenase-Elevating Virus (LDV). The VR-2332 GP5 segment exhibits 77% amino acid homology with the corresponding GP5 ectodomain segments of both the European PRRSV strain Lelystad Virus (LV) and LDV. This explains some observed crossreaction between the pig Abs and neutralizing anti-LDV monoclonal Abs with peptides representing the GP5 ectodomains of VR-2332, LV and LDV. The GP5 binding Abs of pigs seem to be the primary PRRSV neutralizing Abs, since the well timed appearance in sera of all VR-2332 infected pigs of GP5 peptide binding Abs correlated 100% with the appearance of neutralizing Abs and earlier studies indicated that GP5 of PRRSV, like that of other arteriViruses, contains the main neutralization epitope of PRRSV. In addition, one neutralizing anti-LDV monoclonal Ab that is specific for the GP5 ectodomain epitope of LDV also strongly neutralized both PRRSV strains, VR-2332 and LV. The PRRSV GP5 epitope is associated with an N-glycan that is conserved in both PRRSV genotypes and all LDV isolates. This N-glycan may impede the humoral immune control of PRRSV in infected pigs and might be responsible for the low immunogenicity of PRRSV when injected into mice.
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orf 3 of Lactate dehydrogenase elevating Virus encodes a soluble nonstructural highly glycosylated and antigenic protein
Virology, 1997Co-Authors: Kay S. Faaberg, Peter G W PlagemannAbstract:Abstract Open reading frame (ORF) 3 of the genome of Lactate Dehydrogenase-Elevating Virus (LDV), strain P, was cloned into the plasmid pcDNAI/Amp and in vitro transcribed and translated. Translation of ORF 3 yielded a soluble protein of the expected size (about 21 kDa). When synthesized in the presence of endoplasmic reticulum (ER) membranes the resulting glycoprotein of about 36 kDa became associated with the membranes. However, disruption of the ER vesicles by incubation in carbonate buffer, pH 11.5, resulted in the release of the protein from the membranes. Hydrophobic moment analysis of the ORF 3 protein indicated the absence of any potential transmembrane segments, except for a N-terminal signal peptide, but no cleavage of the signal peptide was observed during membrane-associated in vitro synthesis. The ORF 3 protein elicited a strong antibody response in infected mice. The antibodies from infected mice as well as a monoclonal antibody specifically precipitated the in vitro -synthesized ORF 3 protein, but no protein from LDV virions. The overall results suggest that the ORF 3 protein is a nonstructural, highly glycosylated, and antigenic glycoprotein that is probably soluble and secreted or at most only weakly associated with membranes via the signal peptide.
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Differential glycosylation of the ectodomain of the primary envelope glycoprotein of two strains of Lactate Dehydrogenase-Elevating Virus that differ in neuropathogenicity.
Virus Research, 1995Co-Authors: Kay S. Faaberg, Chen Even, Gene A Palmer, Grant W Anderson, Peter G W PlagemannAbstract:Abstract ORF 5 encoding the primary envelope glycoprotein, VP-3P, of a highly neuropathogenic isolate of Lactate Dehydrogenase-Elevating Virus (LDV-v) has been sequenced. It exhibits 92% nucleotide identify with the ORF 5 of an LDV isolate that lacks neuropathogenicity, LDV-P, and the amino acid identifies of the predicted VP-3Ps of the two strains is 90%. Most striking, however, is the absence in the ectodomain of VP-3P of LDV-P. The ectodomain of VP-3P has been implicated to play an important role in host receptor interaction. VP-3P of another neuropathogenic LDV strain, LDV-C, lacks the same two N-glycosylation sites (Godeny et al., 1993). In vitro transcription/translation of the ORFs 5 of LDV-P and LDV-v indicated that all three N-glycosylation sites in the ectodomain of LDV-P VP-3P became glycosylated when synthesized in the presence of microsomal membranes, whereas the glycosylation of the ORF 5 proteins of LDV-v and LDV-C was consistent with glycosylation at a single site. No other biological differences between the neuropathogenic and non-neuropathogenic strains have been detected. They replicate with equal efficiency in mice and in primary macrophage cultures.
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The Envelope Proteins of Lactate Dehydrogenase-Elevating Virus and Their Membrane Topography
Virology, 1995Co-Authors: Kay S. Faaberg, Peter G W PlagemannAbstract:Abstract We have studied the membrane topography and N-glycosylation of the envelope proteins of Lactate Dehydrogenase-Elevating Virus (LDV, strain P). Transcripts of open reading frames (ORFs) 2, 5, and 6 were in vitro translated in the absence and presence of microsomal membranes, and the products analyzed for molecular weight, sensitivity to endoglycosidase F/N-glycosidase F and proteinases, and reaction with anti-LDV antibodies. The ORF 6 mRNA translation was enhanced in the presence of microsomal membranes. ORF 6 encodes a polytopic class III membrane protein identified as the nonglycosylated virion envelope protein (M/VP-2; ∼ 18 kDa). The protein has a very short (about 11 amino acids) ectodomain, a longer (about 79 amino acids) C-terminal endodomain, and crosses the membrane three times between these domains. ORF 5 encodes the primary virion envelope glycoprotein (VP-3P) (25 - 42 kDa). Our results suggest that it is a polytopic class I glycoprotein. After removal of a signal peptide, the processed protein of about 171 amino acids consists of a short (approximately 30 amino acids) N-terminal ectodomain with three asparagine residues that appear to be N-glycosylated, a segment that crosses the membrane three times, and an about 74 amino acid long C-terminal endodomain. Neutralizing anti-LDV antibodies are probably directed to an epitope(s) in the N-terminal ectodomain. The ORF 2 protein is a standard crass I glycoprotein with a single C-terminal membrane anchor segment and its signal peptide is removed during membrane-associated synthesis. The remaining ectodomain (about 165 amino acids) contains three asparagine residues which appear to be N-glycosylated. Our results suggest that the ORF 2 protein may be present in a low concentration in LDV virions (VP3M).
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Lactate Dehydrogenase-Elevating Virus: an ideal persistent Virus?
Springer Seminars in Immunopathology, 1995Co-Authors: Peter G W Plagemann, Raymond R R Rowland, Chen Even, Kay S. FaabergAbstract:LDV contradicts all commonly held views about mechanisms of Virus persistence, namely that persistence is primarily associated with noncytopathic Viruses, or the selection of immune escape variants or other mutants, or a decrease in expression of certain viral proteins by infected cells, or replication in “immune-privileged sites”, or a general suppression of the host immune system, etc. [1, 2, 5, 54, 77, 78]. LDV is a highly cytocidal Virus that invariably establishes a life-long, viremic, persistence in mice, in spite of normal anti-viral immune responses. One secret of LDV's success in persistence is its specificity for a renewable, nonessential population of cells that is continuously regenerated, namely a subpopulation of macrophages. Since the continuous destruction of these cells is not associated with any obvious health effects, this macrophage population seems nonessential to the well-being of its host. The only function identified for this subpopulation of macrophages is clearance of the muscle type of LDH and some other enzymes [59, 67, 68]. Furthermore, the effects of LDV infection on the host immune system, namely the polyclonal activation of B cells and its associated production of autoantibodies, and the slight impairment of primary and secondary antibody responses also do not seem to be severe enough to cause any clinical consequences. But how does LDV replication in macrophages escape all host defenses? Persistence is not dependent on the seletion of immune escape variants or other mutants ([58] and Palmer, Even and Plagemann, unpublished results). Also, LDV replication is not restricted to immune-privileged sites [5]. LDV replication persists in the liver, lymphoidal tissues and testis [66]. Only the latter could be considered a site not readily accessible to immune surveillance. Most likely, resistance of LDV replication to antiviral immune responses is related to the unique structure of its envelope proteins and the production of large quantities of viral antigens. High titers of anti-LDV antibodies are generated in infected mice but they neutralize LDV infectivity only very inefficiently and, even though the antiviral antibodies are mainly of the IgG2a and IgG2b isotypes, they do not mediate complement lyses of virions [31]. Interaction of the antibodies and complement with the VP-3/VP-2 heterodimers in the viral envelope may be impeded by the exposure of only very short peptide segments of these proteins at the envelope surface and the presence of large oligosaccharide side chains. Furthermore, since LDV maturation is restricted to intracytoplasmic cisternae [59, 71], the question arises of whether any of the viral proteins are available on the surface of infected cells for ADCC. CTLs also fail to control LDV replication. Altough CTLs specific for N/VP-1 are rapidly generated, these have disappeared by 30 days p.i. [26]. The reasons for this loss are unknown, but high-dose clonal exhaustion [41, 51, 77, 78] is a reasonable possibility since, regardless of the infectious dose, large amounts of LDV proteins are present in all the lymphoidal tissues at the time of the induction of the CTL response. Furthermore, after exhaustion of CTLs in the periphery, continuous replication of LDV in the thymus [65] assures that the mice become permanently immunologically tolerant with respect to LDV antigen-specific CTLs as a result of negative selection in the thymus. LDV might be a primary example for the effectiveness of a permanent clonal CTL deletion in adult animals under natural conditions of infection. The presumed modes of transmission of LDV in nature and the events associated with its infection of mice are strikingly similar to those observed during the acute and asymptomatic phases of infection with human immunodeficiency Virus (HIV) [24, 29, 74, 78]. These include: (1) primary inefficient transmission via sexual and transplacental routes but effective transmission via blood; (2) primary replication in renewable populations of lymphoidal cells with production of large amounts of Virus after the initial infection of the host followed by persistent low level of viremia in spite of antiviral immune responses; (3) persistence, reflecting continuous rounds of productive, cytocidal infection of permissive cells [59, 74] and the rate of generation of permissive cells which may be the main factor in determining the level of Virus production (in the case of HIV, the rate of activation of CD4^+ T cells to support a productive HIV replication might be the factor determining the rate of Virus production and the progression of the disease); (4) rapid antibody formation but delayed production of neutralizing antibodies with limited neutralizing capacity; (5) rapid but transient generation of Virus-specific CTLs; and (6) accumulation of large amounts of Virus in newly formed germinal centers in the spleen and lymph nodes concomitant with an initiation of a permanent polyclonal activation of B cells resulting in an elevation of plasma IgG2a. The events described under points 2–6 might be generally associated with natural viremic persistent Virus infections. Such persistent Viruses, by necessity, have evolved properties that allow them to escape all host defenses and control of their infection by immunological processes is, therefore, difficult, if not impossible. Prevention of infection and chemotherapy may be the only approaches available to combat such Virus infections.
