Hepatitis C virus (HCV) employs multiple strategies to subvert the host innate antiviral response

Bode, Johannes G.; Brenndörfer, Erwin Daniel; Häussinger, Dieter

doi:10.1515/bc.2008.147

Cited by 40 publications

(30 citation statements)

References 62 publications

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“…In hepatitis C infection, upregulation of Fas on hepatocytes and FasL on activated T cells correlates with the severity of damage, and Fas expression was significantly higher on infected hepatocytes than on noninfected cells [35]. Fas expression could be induced in hepatocytes either by virus-specific proteins or by inflammatory cytokines such as IL-1β [36][37][38][39]. Activated cytotoxic T cells expressing FasL were then able to induce apoptosis in virus-infected hepatocytes and also in neighboring uninfected hepatocytes, leading to tissue damage.…”

Section: Death Receptors In Liver Pathologymentioning

confidence: 99%

Immune cell-mediated liver injury

2009

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Section: Death Receptors In Liver Pathologymentioning

confidence: 99%

Immune cell-mediated liver injury

2009

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“…Apart from participating in the viral life cycle, some HCV proteins facilitate viral persistence by interfering with intrahepatic signal transduction (17). HCV NS3/4A in particular was shown to block innate immune pathways through proteolytic cleavage of mitochondrial antiviral signaling protein (MAVS) (18,19) and Toll/IL-1R domain-containing adapter-inducing IFN-b (TRIF) (20).…”

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confidence: 99%

Cleavage of the T Cell Protein Tyrosine Phosphatase by the Hepatitis C Virus Nonstructural 3/4A Protease Induces a Th1 to Th2 Shift Reversible by Ribavirin Therapy

Brenndörfer

Brass

Karthe

et al. 2014

The Journal of Immunology

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Ribavirin has proven to be a key component of hepatitis C therapies both involving IFNs and new direct-acting antivirals. The hepatitis C virus–mediated interference with intrahepatic immunity by cleavage of mitochondrial antiviral signaling protein (MAVS) and T cell protein tyrosine phosphatase (TCPTP) suggests an avenue for compounds that may counteract these effects. We therefore studied the effects of ribavirin, with or without inhibition of the nonstructural (NS)3/4A protease, on intrahepatic immunity. The intrahepatic immunity of wild-type and NS3/4A-transgenic mice was determined by Western blot, ELISA, flow cytometry, and survival analysis. Various MAVS or TCPTP constructs were injected hydrodynamically to study their relevance. Ribavirin pretreatment was performed in mice expressing a functional or inhibited NS3/4A protease to analyze its effect on NS3/4A-mediated changes. Intrahepatic NS3/4A expression made mice resistant to TNF-α–induced liver damage and caused an alteration of the intrahepatic cytokine (IFN-γ and IL-10) and chemokine (CCL3, CCL17, CCL22, CXCL9, and CXCL11) profiles toward an anti-inflammatory state. Consistent with this, the number of intrahepatic Th1 cells and IFN-γ+ T cells in NS3/4A-transgenic mice decreased, whereas the amount of Th2 cells increased. These effects could be reversed by injection of uncleavable TCPTP but not uncleavable MAVS and were absent in a mouse expressing a nonfunctional NS3/4A protease. Importantly, the NS3/4A-mediated effects were reversed by ribavirin treatment. Thus, cleavage of TCPTP by NS3/4A induces a shift of the intrahepatic immune response toward a nonantiviral Th2-dominated immunity. These effects are reversed by ribavirin, supporting that ribavirin complements the effects of direct-acting antivirals as an immunomodulatory compound.

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“…In HCV-associated chronic liver disease, the immune system is unable to effectively clear the viral infection, despite the activation of the humoral and cellular immune response (10). A number of viral factors are involved in this process, such as the ability of HCV to modify its surface antigens and to exploit different entry mechanisms to infect the target cells (11).…”

Section: Discussionmentioning

confidence: 99%

Evaluation of circulating CD4+CD25+ and liver-infiltrating Foxp3+ cells in HCV-associated liver disease

et al. 2012

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Abstract. In hepatitis C virus (HCV)-associated liver disease, the immune system is unable to clear the viral infection. Previous studies have raised the possibility of an involvement of regulatory T cells (Tregs) + cells in the liver infiltrates showed significantly higher proportions of peripheral CD4 + CD25 low cells. Moreover, we found lower serum transaminase levels in the patients than in the controls, as shown by Foxp3 + immunohistochemistry, although these results were only statistically significant as regards alanine transaminase (ALT). In conclusion, these data suggest that the presence of Tregs infiltrating the liver is associated with high levels of activated/effector T cells in the peripheral blood and lower activity of hepatitis. Therefore, liver-infiltrating Tregs may play a role in limiting tissue damage and may thus support an effective immune response against HCV.

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Hepatitis C virus (HCV) employs multiple strategies to subvert the host innate antiviral response

Cited by 40 publications

References 62 publications

Immune cell-mediated liver injury

Immune cell-mediated liver injury

Cleavage of the T Cell Protein Tyrosine Phosphatase by the Hepatitis C Virus Nonstructural 3/4A Protease Induces a Th1 to Th2 Shift Reversible by Ribavirin Therapy

Evaluation of circulating CD4+CD25+ and liver-infiltrating Foxp3+ cells in HCV-associated liver disease

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