770 THE HCV NS3/4A-MEDIATED IMPAIRMENT OF THE HEPATIC ANTIVIRAL IMMUNE RESPONSE IS REVERSED BY PROTEASE INHIBITION OR RIBAVIRIN IN VIVO

2012 ◽  
Vol 56 ◽  
pp. S302
Author(s):  
E.D. Brenndörfer ◽  
A. Brass ◽  
J. Söderholm ◽  
L. Frelin ◽  
J.G. Bode ◽  
...  
Keyword(s):  
Immune Response ◽  
Protease Inhibition ◽  
Antiviral Immune Response

scholarly journals Immunoglobulin G Antibody-Mediated Enhancement of Measles Virus Infection Can Bypass the Protective Antiviral Immune Response

2006 ◽  
Vol 80 (17) ◽  
pp. 8530-8540 ◽  
Author(s):  
Ianko D. Iankov ◽  
Manoj Pandey ◽  
Mary Harvey ◽  
Guy E. Griesmann ◽  
Mark J. Federspiel ◽  
...  
Keyword(s):  
Monoclonal Antibody ◽  
Immune Response ◽  
Immunoglobulin G ◽  
Measles Virus ◽  
Host Cells ◽  
Igg Antibodies ◽  
Inhibitory Peptide ◽  
Host Cell Membrane ◽  
Antiviral Immune Response

ABSTRACT Antibodies to viral surface glycoproteins play a crucial role in immunity to measles by blocking both virus attachment and subsequent fusion with the host cell membrane. Here, we demonstrate that certain immunoglobulin G (IgG) antibodies can also enhance the entry of measles virus (MV) into monocytes and macrophages. Antibody-dependent enhancement of infectivity was observed in mouse and human macrophages using virions opsonized by a murine monoclonal antibody against the MV hemagglutinin (H) glycoprotein, polyclonal mouse anti-MV IgG, or diluted measles-immune human sera. Neither H-specific Fab fragments nor H-specific IgM could enhance MV entry in monocytes or macrophages, indicating involvement of a Fc γ receptor (FcγR)-mediated mechanism. Preincubation with an anti-fusion protein (anti-F) monoclonal antibody or a fusion-inhibitory peptide blocked infection, indicating that a functional F protein was required for viral internalization. Classical complement pathway activation did not promote infection through complement receptors and inhibited anti-H IgG-mediated enhancement. In vivo, antibody-enhanced infection allowed MV to overcome a highly protective systemic immune response in preimmunized IfnarKo-Ge46 transgenic mice. These data demonstrate a previously unidentified mechanism that may contribute to morbillivirus pathogenesis where H-specific IgG antibodies promote the spread of MV infection among FcγR-expressing host cells. The findings point to a new model for the pathogenesis of atypical MV infection observed after immunization with formalin-inactivated MV vaccine and underscore the importance of the anti-F response after vaccination.

scholarly journals The Virus-Encoded Chemokine vMIP-II Inhibits Virus-Induced Tc1-Driven Inflammation

2003 ◽  
Vol 77 (13) ◽  
pp. 7393-7400 ◽  
Author(s):  
Morten Lindow ◽  
Anneline Nansen ◽  
Christina Bartholdy ◽  
Annette Stryhn ◽  
Nils J. V. Hansen ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Human Herpesvirus ◽  
Delayed Type Hypersensitivity ◽  
Intravenous Route ◽  
Antiviral Immune Response

ABSTRACT The human herpesvirus 8-encoded protein vMIP-II is a potent in vitro antagonist of many chemokine receptors believed to be associated with attraction of T cells with a type 1 cytokine profile. For the present report we have studied the in vivo potential of this viral chemokine antagonist to inhibit virus-induced T-cell-mediated inflammation. This was done by use of the well-established model system murine lymphocytic choriomeningitis virus infection. Mice were infected in the footpad, and the induced CD8+ T-cell-dependent inflammation was evaluated in mice subjected to treatment with vMIP-II. We found that inflammation was markedly inhibited in mice treated during the efferent phase of the antiviral immune response. In vitro studies revealed that vMIP-II inhibited chemokine-induced migration of activated CD8+ T cells, but not T-cell-target cell contact, granule exocytosis, or cytokine release. Consistent with these in vitro findings treatment with vMIP-II inhibited the adoptive transfer of a virus-specific delayed-type hypersensitivity response in vivo, but only when antigen-primed donor cells were transferred via the intravenous route and required to migrate actively, not when the cells were injected directly into the test site. In contrast to the marked inhibition of the effector phase, the presence of vMIP-II during the afferent phase of the immune response did not result in significant suppression of virus-induced inflammation. Taken together, these results indicate that chemokine-induced signals are pivotal in directing antiviral effector cells toward virus-infected organ sites and that vMIP-II is a potent inhibitor of type 1 T-cell-mediated inflammation.

scholarly journals The Role of β7 Integrins in CD8 T Cell Trafficking During an Antiviral Immune Response

1999 ◽  
Vol 189 (10) ◽  
pp. 1631-1638 ◽  
Author(s):  
Leo Lefrançois ◽  
Christina M. Parker ◽  
Sara Olson ◽  
Werner Muller ◽  
Norbert Wagner ◽  
...  
Keyword(s):  
Immune Response ◽  
T Cells ◽  
T Cell ◽  
Cd8 T Cells ◽  
Cd8 T Cell ◽  
Cell Immune Response ◽  
Peyer’S Patch ◽  
Peyer's Patch ◽  
Antiviral Immune Response

The requirement of β7 integrins for lymphocyte migration was examined during an ongoing immune response in vivo. Transgenic mice (OT-I) expressing an ovalbumin-specific major histocompatibility complex class I–restricted T cell receptor for antigen were rendered deficient in expression of all β7 integrins or only the αEβ7 integrin. To quantitate the relative use of β7 integrins in migration in vivo, equal numbers of OT-I and OT-I-β7−/− or OT-I-αE−/− lymph node (LN) cells were adoptively transferred to normal mice. Although OT-I-β7−/− LN cells migrated to mesenteric LN and peripheral LN as well as wild-type cells, β7 integrins were required for naive CD8 T cell and B cell migration to Peyer's patch. After infection with a recombinant virus (vesicular stomatitis virus) encoding ovalbumin, β7 integrins became critical for migration of activated CD8 T cells to the mesenteric LN and Peyer's patch. Naive CD8 T cells did not enter the lamina propria or the intestinal epithelium, and the majority of migration of activated CD8 T cells to the small and large intestinal mucosa, including the epithelium, was β7 integrin–mediated. The αEβ7 integrin appeared to play no role in migration during a primary CD8 T cell immune response in vivo. Furthermore, despite dramatic upregulation of αEβ7 by CD8 T cells after entry into the epithelium, long-term retention of intestinal intraepithelial lymphocytes was also αEβ7 independent.

scholarly journals Histone H2A Nuclear/Cytoplasmic Trafficking Is Essential for Negative Regulation of Antiviral Immune Response and Lysosomal Degradation of TBK1 and IRF3

2021 ◽  
Vol 12 ◽  
Author(s):  
Xiao Man Wu ◽  
Hong Fang ◽  
Jie Zhang ◽  
Yong Hong Bi ◽  
Ming Xian Chang
Keyword(s):  
Immune Response ◽  
Protein Degradation ◽  
Signaling Pathway ◽  
Early Stage ◽  
Negative Regulation ◽  
Histone H2a ◽  
Antiviral Immune Response ◽  
Functional Complex ◽  
Host Innate Immune Response

Histone H2A is a nuclear molecule tightly associated in the form of the nucleosome. Our previous studies have demonstrated the antibacterial property of piscine H2A variants against gram-negative bacteria Edwardsiella piscicida and Gram-positive bacteria Streptococcus agalactiae. In this study, we show the function and mechanism of piscine H2A in the negative regulation of RLR signaling pathway and host innate immune response against spring viremia of carp virus (SVCV) infection. SVCV infection significantly inhibits the expression of histone H2A during an early stage of infection, but induces the expression of histone H2A during the late stage of infection such as at 48 and 72 hpi. Under normal physiological conditions, histone H2A is nuclear-localized. However, SVCV infection promotes the migration of histone H2A from the nucleus to the cytoplasm. The in vivo studies revealed that histone H2A overexpression led to the increased expression of SVCV gene and decreased survival rate. The overexpression of histone H2A also significantly impaired the expression levels of those genes involved in RLR antiviral signaling pathway. Furthermore, histone H2A targeted TBK1 and IRF3 to promote their protein degradation via the lysosomal pathway and impair the formation of TBK1-IRF3 functional complex. Importantly, histone H2A completely abolished TBK1-mediated antiviral activity and enormously impaired the protein expression of IRF3, especially nuclear IRF3. Further analysis demonstrated that the inhibition of histone H2A nuclear/cytoplasmic trafficking could relieve the protein degradation of TBK1 and IRF3, and blocked the negative regulation of histone H2A on the SVCV infection. Collectively, our results suggest that histone H2A nuclear/cytoplasmic trafficking is essential for negative regulation of RLR signaling pathway and antiviral immune response in response to SVCV infection.

scholarly journals Lactococcus lactis Expressing Type I Interferon From Atlantic Salmon Enhances the Innate Antiviral Immune Response In Vivo and In Vitro

2021 ◽  
Vol 12 ◽  
Author(s):  
Carlos Muñoz ◽  
Josue González-Lorca ◽  
Mick Parra ◽  
Sarita Soto ◽  
Natalia Valdes ◽  
...  
Keyword(s):  
Immune Response ◽  
Viral Load ◽  
Atlantic Salmon ◽  
Oral Administration ◽  
Lactococcus Lactis ◽  
Type I Interferon ◽  
Type I ◽  
Antiviral Immune Response

In salmon farming, viruses are responsible for outbreaks that produce significant economic losses for which there is a lack of control tools other than vaccines. Type I interferon has been successfully used for treating some chronic viral infections in humans. However, its application in salmonids depends on the proper design of a vehicle that allows its massive administration, ideally orally. In mammals, administration of recombinant probiotics capable of expressing cytokines has shown local and systemic therapeutic effects. In this work, we evaluate the use of Lactococcus lactis as a type I Interferon expression system in Atlantic salmon, and we analyze its ability to stimulate the antiviral immune response against IPNV, in vivo and in vitro. The interferon expressed in L. lactis, even though it was located mainly in the bacterial cytoplasm, was functional, stimulating Mx and PKR expression in CHSE-214 cells, and reducing the IPNV viral load in SHK-1 cells. In vivo, the oral administration of this L. lactis producer of Interferon I increases Mx and PKR expression, mainly in the spleen, and to a lesser extent, in the head kidney. The oral administration of this strain also reduces the IPNV viral load in Atlantic salmon specimens challenged with this pathogen. Our results show that oral administration of L. lactis producing Interferon I induces systemic effects in Atlantic salmon, allowing to stimulate the antiviral immune response. This probiotic could have effects against a wide variety of viruses that infect Atlantic salmon and also be effective in other salmonids due to the high identity among their type I interferons.

scholarly journals Lonidamine potentiates the oncolytic efficiency of M1 virus independent of hexokinase 2 but via inhibition of antiviral immunity

2020 ◽  
Vol 20 (1) ◽  
Author(s):  
Jing Cai ◽  
Wenbo Zhu ◽  
Yuan Lin ◽  
Jun Hu ◽  
Xincheng Liu ◽  
...  
Keyword(s):  
Gene Expression ◽  
Immune Response ◽  
Metabolic Reprogramming ◽  
Host Cells ◽  
Hexokinase 2 ◽  
Antiviral Immune Response ◽  
Successful Infection ◽  
Mouse Xenograft Model ◽  
Oncolytic Effect

Abstract Background Viruses are obligate parasites that depend on host cells to provide the energy and molecular precursors necessary for successful infection. The main component of virus-induced metabolic reprogramming is the activation of glycolysis, which provides biomolecular resources for viral replication. However, little is known about the crosstalk between oncolytic viruses and host glycolytic processes. Methods A MTT assay was used to detect M1 virus-induced cell killing. Flow cytometry was used to monitor infection of M1 virus expressing the GFP reporter gene. qPCR and western blotting were used to detect gene expression. RNA sequencing was performed to evaluate gene expression under different drug treatments. Scanning electron microscopy was performed to visualize the endoplasmic reticulum (ER). Caspase activity was detected. Last, a mouse xenograft model was established to evaluate the antitumor effect in vivo. Most data were analyzed with a two-tailed Student’s t test or one-way ANOVA with Dunnett’s test for pairwise comparisons. Tumor volumes were analyzed by repeated measures of ANOVA. The Wilcoxon signed-rank test was used to compare nonnormally distributed data. Results Here, we showed that the glucose analog 2-deoxy-d-glucose (2-DG) inhibited infection by M1 virus, which we identified as a novel type of oncolytic virus, and decreased its oncolytic effect, indicating the dependence of M1 replication on glycolysis. In contrast, lonidamine, a reported hexokinase 2 (HK2) inhibitor, enhanced the infection and oncolytic effect of M1 virus independent of HK2. Further transcriptomic analysis revealed that downregulation of the antiviral immune response contributes to the lonidamine-mediated potentiation of the infection and oncolytic effect of M1 virus, and that MYC is the key factor in the pool of antiviral immune response factors inhibited by lonidamine. Moreover, lonidamine potentiated the irreversible ER stress-mediated apoptosis induced by M1 virus. Enhancement of M1′s oncolytic effect by lonidamine was also identified in vivo. Conclusions This research demonstrated the dependence of M1 virus on glycolysis and identified a candidate synergist for M1 virotherapy.

scholarly journals Impact and Regulation of Lambda Interferon Response in Human Metapneumovirus Infection

2014 ◽  
Vol 89 (1) ◽  
pp. 730-742 ◽  
Author(s):  
Ma. Del Rocío Baños-Lara ◽  
Lindsey Harvey ◽  
Alexander Mendoza ◽  
Dawn Simms ◽  
Vladimir N. Chouljenko ◽  
...  
Keyword(s):  
Immune Response ◽  
Protective Role ◽  
Human Metapneumovirus ◽  
Interferon Response ◽  
Antiviral Immune Response ◽  
Hmpv Infection ◽  
Experimental Mouse ◽  
Mouse Model Of Infection

ABSTRACTHuman metapneumovirus (hMPV) is a respiratory paramyxovirus that is distributed worldwide and induces significant airway morbidity. Despite the relevance of hMPV as a pathogen, many aspects of the immune response to this virus are still largely unknown. In this report, we focus on the antiviral immune response, which is critical for viral clearance and disease resolution. Usingin vitroandin vivosystems, we show that hMPV is able to induce expression of lambda interferon 1 (IFN-λ1), IFN-λ2, IFN-λ3, and IFN-λ4. The induction of IFN-λ expression by hMPV was dependent on interferon regulatory factor 7 (IRF-7) expression but not on IRF-3 expression. Treatment of hMPV-infected mice with IFN-λ reduced the disease severity, lung viral titer, and inflammatory response in the lung. Moreover, the IFN-λ response induced by the virus was regulated by the expression of the hMPV G protein. These results show that type III interferons (IFN-λs) play a critical protective role in hMPV infection.IMPORTANCEHuman metapneumovirus (hMPV) is a pathogen of worldwide importance. Despite the relevance of hMPV as a pathogen, critical aspects of the immune response induced by this virus remain unidentified. Interferons (IFNs), including IFN-λ, the newest addition to the interferon family, constitute an indispensable part of the innate immune response. Here, we demonstrated that IFN-λ exhibited a protective role in hMPV infectionin vitroand in an experimental mouse model of infection.

scholarly journals Induction of Long-Term Protective Antiviral Endogenous Immune Response by Short Neutralizing Monoclonal Antibody Treatment

2005 ◽  
Vol 79 (10) ◽  
pp. 6272-6280 ◽  
Author(s):  
Laurent Gros ◽  
Hanna Dreja ◽  
Anne Laure Fiser ◽  
Marc Plays ◽  
Mireia Pelegrin ◽  
...  
Keyword(s):  
Immune Response ◽  
Treatment Strategies ◽  
Humoral Response ◽  
Antiviral Effect ◽  
Adjunctive Treatment ◽  
Antibody Treatment ◽  
Antiviral Immune Response

ABSTRACT Long-term immune control of viral replication still remains a major challenge in retroviral diseases. Several monoclonal antibodies (MAbs) have already shown antiviral activities in vivo, including in the clinic but their effects on the immune system of treated individuals are essentially unknown. Using the lethal neurodegeneration induced in mice upon infection of neonates by the FrCasE retrovirus as a model, we report here that transient treatment by a neutralizing MAb shortly after infection can, after an immediate antiviral effect, favor the development of a strong protective host immune response containing viral propagation long after the MAb has disappeared. In vitro virus neutralization- and complement-mediated cell lysis assays, as well as in vivo viral challenges and serum transfer experiments, indicate a clear and essential contribution of the humoral response to antiviral protection. Our observation may have important therapeutic consequences as it suggests that short antibody-based therapies early after infection should be considered, at least in the case of maternally infected infants, as adjunctive treatment strategies against human immunodeficiency virus, not only for a direct effect on the viral load but also for favoring the emergence of an endogenous antiviral immune response.

scholarly journals Mutation in Irf8 Gene (Irf8R294C) Impairs Type I IFN-Mediated Antiviral Immune Response by Murine pDCs

2021 ◽  
Vol 12 ◽  
Author(s):  
Annesa Das ◽  
Kuldeep Singh Chauhan ◽  
Himanshu Kumar ◽  
Prafullakumar Tailor
Keyword(s):  
Immune Response ◽  
Point Mutation ◽  
Single Point ◽  
Costimulatory Molecules ◽  
Type I Interferons ◽  
Single Point Mutation ◽  
Type I ◽  
Type I Ifn ◽  
Antiviral Immune Response

Plasmacytoid dendritic cells (pDCs) are the key producers of type I interferons (IFNs), thus playing a central role in initiating antiviral immune response. Besides robust type I IFN production, pDCs also act as antigen presenting cells post immunogenic stimulation. Transcription factor Irf8 is indispensable for the development of both pDC and cDC1 subset. However, the mechanism underlying the differential regulation by IRF8 in cDC1- and pDC-specific genomic architecture of developmental pathways still remains to be fully elucidated. Previous studies indicated that the Irf8R294C mutation specifically abrogates development of cDC1 without affecting that of pDC. In the present study using RNA-seq based approach, we have found that though the point mutation Irf8R294C did not affect pDC development, it led to defective type I IFN production, thus resulting in inefficient antiviral response. This observation unraveled the distinctive roles of IRF8 in these two subpopulations—regulating the development of cDC1 whereas modulating the functionality of pDCs without affecting development. We have reported here that Irf8R294C mutation also caused defect in production of ISGs as well as defective upregulation of costimulatory molecules in pDCs in response to NDV infection (or CpG stimulation). Through in vivo studies, we demonstrated that abrogation of type I IFN production was concomitant with reduced upregulation of costimulatory molecules in pDCs and increased NDV burden in IRF8R294C mice in comparison with wild type, indicating inefficient viral clearance. Further, we have also shown that Irf8R294C mutation abolished the activation of type I IFN promoter by IRF8, justifying the low level of type I IFN production. Taken together, our study signifies that the single point mutation in Irf8, Irf8R294C severely compromised type I IFN-mediated immune response by murine pDCs, thereby causing impairment in antiviral immunity.

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