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ABSTRACT: Owing to the major limitations of current antiviral therapies in HBV (hepatitis B virus) infection, there is a strong need for novel therapeutic approaches to this major health burden. Stimulation of the host's innate and adaptive immune responses in a way that results in the resolution of viral infection is a promising approach. A better understanding of the virus-host interaction in acute and chronic HBV infection revealed several possible novel targets for antiviral immunotherapy. In the present review, we will discuss the current state of the art in HBV immunology and illustrate how control of infection could be achieved by immunotherapeutic interventions.
Clinical Science 01/2013; 124(2):77-85. · 4.61 Impact Factor
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ABSTRACT: With up to 400 million affected people worldwide, chronic hepatitis B virus (HBV) infection is still a major health care problem. During the last decade, several novel therapeutic approaches have been developed and evaluated. In most regions of the world, interferon-α, and nucleos(t)ide analogues (NUCs) are currently approved. Despite major improvements, none of the existing therapies is optimal since viral clearance is rarely achieved. Recently, a better understanding of the HBV life cycle and the development of novel model systems of HBV infection have led to the development of novel antiviral strategies and drug targets. This review will focus on current and potential future drug targets in the HBV life cycle and strategies to modulate the virus-host interaction.
Hepatology International 06/2011; 5(2):644-53. · 2.64 Impact Factor
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ABSTRACT: Primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) are important causes of cholestatic liver disease. IgG4-associated cholangitis (IAC) also belongs to the same entity. Overlap syndromes combine characteristics of cholestatic liver diseases and autoimmune hepatitis. The diagnosis of PBC is based on the detection of anti-mitochondrial antibodies. PBC is frequently associated with other autoimmune disorders. The treatment of choice is ursodeoxycholic acid. PSC is frequently associated with inflammatory bowel disease (IBD). The cholangiography shows characteristic bile duct lesions. Bile duct strictures and bacterial cholangitis should be treated by dilatation and antibiotics, respectively. Cirrhosis may ultimately develop in PBC and PSC. In advanced PBC or PSC, liver transplantation might be indicated. The clinical course of IAC is similar to PSC. In contrast to PSC, however, there is no association with IBD.
Therapeutische Umschau 04/2011; 68(4):195-9.
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ABSTRACT: Interferon-mediated host responses are of great importance for controlling influenza A virus infections. It is well established that the interferon-induced Mx proteins possess powerful antiviral activities toward most influenza viruses. Here we analyzed a range of influenza A virus strains for their sensitivities to murine Mx1 and human MxA proteins and found remarkable differences. Virus strains of avian origin were highly sensitive to Mx1, whereas strains of human origin showed much weaker responses. Artificial reassortments of the viral components in a minireplicon system identified the viral nucleoprotein as the main target structure of Mx1. Interestingly, the recently reconstructed 1918 H1N1 "Spanish flu" virus was much less sensitive than the highly pathogenic avian H5N1 strain A/Vietnam/1203/04 when tested in a minireplicon system. Importantly, the human 1918 virus-based minireplicon system was almost insensitive to inhibition by human MxA, whereas the avian influenza A virus H5N1-derived system was well controlled by MxA. These findings suggest that Mx proteins provide a formidable hurdle that hinders influenza A viruses of avian origin from crossing the species barrier to humans. They further imply that the observed insensitivity of the 1918 virus-based replicon to the antiviral activity of human MxA is a hitherto unrecognized characteristic of the "Spanish flu" virus that may contribute to the high virulence of this unusual pandemic strain.
Journal of Virology 05/2008; 82(7):3624-31. · 5.40 Impact Factor
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Small 12/2007; 3(11):1900-5. · 8.35 Impact Factor
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ABSTRACT: Standing electronic wave formation inside single walled carbon nanotube Y-junction rings and quantum dots with a quantum-dot-like quadratic dispersion is reported. Remarkably, the detailed structural defect configurations play only a minor role and the standing wave oscillation dispersions are mainly triggered by the electronic properties of the pristine constituent tubes. This raises the possibility of using both structures as nanoscale tuneable electronic switching devices. Near the Fermi level, quantum dots show smooth dispersing oscillations reminiscent of the finite pristine tube eigenvalues. However, localized density of states peaks are found in YJRs, which are identified as interference effects of the double-slit interferometer. (© 2007 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)
physica status solidi (b) 09/2007; 244(11):4283 - 4287. · 1.32 Impact Factor
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ABSTRACT: The IFN-induced resistance factor Mx1 is a critical component of innate immunity against influenza A viruses (FLUAV) in mice. Animals carrying a wild-type Mx1 gene (Mx1(+/+)) differ from regular laboratory mice (Mx1(-/-)) in that they are highly resistant to infection with standard FLUAV strains. We identified an extraordinary variant of the FLUAV strain, A/PR/8/34 (H1N1) (designated hvPR8), which is unusually virulent in Mx1(+/+) mice. hvPR8 was well controlled in Mx1(+/+) but not Mx1(-/-) mice provided that the animals were treated with IFN before infection, indicating that hvPR8 exhibits normal sensitivity to growth restriction by Mx1. hvPR8 multiplied much faster than standard PR8 early in infection because of highly efficient viral gene expression in infected cells. Studies with reassortant viruses containing defined genome segments of both hvPR8 and standard PR8 demonstrated that the HA, neuraminidase, and polymerase genes of hvPR8 all contributed to virulence, indicating that efficient host cell entry and early gene expression renders hvPR8 highly pathogenic. These results reveal a surprisingly simple concept of how influenza viruses may gain virulence and illustrate that high speed of virus growth can outcompete the antiviral response of the infected host.
Proceedings of the National Academy of Sciences 04/2007; 104(16):6806-11. · 9.68 Impact Factor
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Daniel Grimm
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ABSTRACT: Das IFN-induzierte Mx1-Protein ist ein entscheidender Effektor der angeborenen Immunität gegen das Influenza-A-Virus in der Maus. Mausstämme, die ein funktionelles Mx1-Gen (Mx1+/+) tragen, unterscheiden sich von gewöhnlichen Labormäusen (Mx1-/-) durch eine hohe Resistenz gegen Infektionen mit Influenza-A-Virus. Im Rahmen dieser Arbeit wurde ein hochpathogenes Influenza A/PR/8/34-Virus untersucht, das auch in Mx1+/+-Mäusen ungewöhnlich virulent ist. Dieses Virus wurde highly virulent PR8, kurz hvPR8, genannt. Ich konnte nachweisen, dass die Replikation von hvPR8 in Mx1+/+-Mäusen, nicht aber in Mx1-/--Mäusen, gut kontrolliert werden konnte, sofern die Tiere mit IFN vorbehandelt wurden. Dies zeigt, dass hvPR8 sensitiv gegenüber der antiviralen Aktivität von Mx1 ist. Auch die Analyse der IFN-Induktion durch hvPR8 erbrachte keinen Unterschied zu einem gewöhnlichen PR8-Virus. Worin liegt also die Ursache für den hochvirulenten Phänotyp von hvPR8? Untersuchungen des Wachstums von hvPR8 in Zellkultur und in Mäusen zeigten eine effiziente Expression viraler Gene und verstärkte Bildung von Viruspartikeln zu frühen Zeitpunkten nach Infektion. Im Minireplikonassay konnte nachgewiesen werden, dass die virale Polymerase von hvPR8 eine erhöhte Aktivität zeigt. Dies weist darauf hin, dass die frühe Expression viraler Gene die hohe Virulenz von hvPR8 ausmacht. In Untersuchungenmit rekombinant hergestellten Reassortantenviren, die bestimmte Genomsegmente von hvPR8 in Kombination mit Segmenten eines niedrigvirulenten PR8-Virus tragen, wurde deutlich, dass neben den Untereinheiten der viralen Polymerase und der Neuraminidase vor allem das Hämagglutinin entscheidend zur Virulenz beiträgt. Zusammengenommen zeigen diese Daten einen überraschend einfachen Virulenzmechanismus eines hochpathogenen Influenza-A-Virus auf. Durch ein extrem schnelles Wachstum zu frühen Zeitpunkten der Infektion kann die angeborene antivirale Abwehr des Wirtes effektiv umgangen werden. The IFN-induced resistance factor Mx1 is a critical component of innate immunity against influenza A viruses (FLUAV) in mice. Animals carrying a wild-type Mx1 gene (Mx1(+/+)) differ from regular laboratory mice (Mx1(-/-)) in that they are highly resistant to infection with standard FLUAV strains. I identified an extraordinary variant of the FLUAV strain, A/PR/8/34 (H1N1) (designated hvPR8), which is unusually virulent in Mx1(+/+) mice. hvPR8 was well controlled in Mx1(+/+) but not Mx1(-/-) mice provided that the animals were treated with IFN before infection, indicating that hvPR8 exhibits normal sensitivity to growth restriction by Mx1. Interestingly, the analysis of IFN synthesis in infected cells showed that hvPR8 is indistinguishable with regard to inhibition of IFN synthesis in infected cells, compared with a standard FLUAV strain. So what could be an explanation of the highly virulent phenotype of hvPR8? Growth kinetics in cell culture and in mice showed an efficient viral gene expression and increased production of virus particles at early timepoints of infection. Minireplicon assays revealed an increased polymerase activity of hvPR8. These results show the relevance of early viral gene expression for the highly virulent phenotype. Analysis of recombinant reassortant virus showed a crucial role of the viral polymerase subunits, the neuramidase and especially of the viral hemagglutinin for pathogenicity. In conclusion, my work reveals a surprisingly simple and efficient virulence mechanism. hvPR8 successfully evades the IFN-induced innate immune system of the infected host because of its ability to replicate much faster than standard virus strains.
