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.
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.
Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, Stockholm S-141 86, Sweden.
Erwin Daniel
ED
Brenndörfer
Anette
A
Brass
Juliane
J
Karthe
Gustaf
G
Ahlén
Johannes Georg
JG
Bode
Matti
M
Sällberg
D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000998:Antiviral Agents / Q000494:pharmacology; D002454:Cell Differentiation / Q000187:drug effects; D054414:Chemokine CCL17 / Q000096:biosynthesis; D054422:Chemokine CCL22 / Q000096:biosynthesis; D054405:Chemokine CCL3 / Q000096:biosynthesis; D054371:Chemokine CXCL11 / Q000096:biosynthesis; D054370:Chemokine CXCL9 / Q000096:biosynthesis; D016174:Hepacivirus / Q000276:immunology*; D019698:Hepatitis C, Chronic / Q000276:immunology / Q000378:metabolism / Q000821:virology; D007371:Interferon-gamma / Q000096:biosynthesis; D016753:Interleukin-10 / Q000096:biosynthesis; D008099:Liver / Q000276:immunology; D051379:Mice; D008810:Mice, Inbred C57BL; D008808:Mice, Inbred CBA; D008822:Mice, Transgenic; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2 / Q000378:metabolism*; D012254:Ribavirin / Q000494:pharmacology*; D018417:Th1 Cells; D018418:Th2 Cells; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism; D017361:Viral Nonstructural Proteins / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases
D048868:Adaptor Proteins, Signal Transducing; D000998:Antiviral Agents; D054414:Chemokine CCL17; D054422:Chemokine CCL22; D054405:Chemokine CCL3; D054371:Chemokine CXCL11; D054370:Chemokine CXCL9; D007371:Interferon-gamma; D016753:Interleukin-10; D054578:Protein Tyrosine Phosphatase, Non-Receptor Type 2; D012254:Ribavirin; D014409:Tumor Necrosis Factor-alpha; D017361:Viral Nonstructural Proteins; C499538:Ccl17 protein, mouse; C515483:Ccl22 protein, mouse; C496534:Ccl3 protein, mouse; C515203:Cxcl11 protein, mouse; C485969:Cxcl9 protein, mouse; C556062:IL10 protein, mouse; C512612:MAVS protein, mouse; C084422:NS3 protein, hepatitis C virus; D012697:Serine Endopeptidases; D043583:Nucleoside-Triphosphatase; D053487:DEAD-box RNA Helicases; D000085242:Viral Proteases; C080106:NS4A protein, flavivirus; C516653:Ptpn2 protein, mouse