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Hepatitis: HELP
Articles by Hans-Dieter Nischalke
Based on 26 articles published since 2009
(Why 26 articles?)
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Between 2009 and 2019, Hans D. Nischalke wrote the following 26 articles about Hepatitis.
 
+ Citations + Abstracts
Pages: 1 · 2
1 Review Between Scylla and Charybdis: the role of the human immune system in the pathogenesis of hepatitis C. 2013

Spengler, Ulrich / Nischalke, Hans Dieter / Nattermann, Jacob / Strassburg, Christian P. ·Ulrich Spengler, Hans Dieter Nischalke, Jacob Nattermann, Christian P Strassburg, Department of Internal Medicine 1, University of Bonn, 53105 Bonn, Germany. ·World J Gastroenterol · Pubmed #24307779.

ABSTRACT: Hepatitis C virus (HCV) frequently elicits only mild immune responses so that it can often establish chronic infection. In this case HCV antigens persist and continue to stimulate the immune system. Antigen persistence then leads to profound changes in the infected host's immune responsiveness, and eventually contributes to the pathology of chronic hepatitis. This topic highlight summarizes changes associated with chronic hepatitis C concerning innate immunity (interferons, natural killer cells), adaptive immune responses (immunoglobulins, T cells, and mechanisms of immune regulation (regulatory T cells). Our overview clarifies that a strong anti-HCV immune response is frequently associated with acute severe tissue damage. In chronic hepatitis C, however, the effector arms of the immune system either become refractory to activation or take over regulatory functions. Taken together these changes in immunity may lead to persistent liver damage and cirrhosis. Consequently, effector arms of the immune system will not only be considered with respect to antiviral defence but also as pivotal mechanisms of inflammation, necrosis and progression to cirrhosis. Thus, avoiding Scylla - a strong, sustained antiviral immune response with inital tissue damage - takes the infected host to virus-triggered immunopathology, which ultimately leads to cirrhosis and liver cancer - the realm of Charybdis.

2 Article Increased peripheral CD4 2017

Langhans, Bettina / Nischalke, Hans Dieter / Krämer, Benjamin / Hausen, Annekristin / Dold, Leona / van Heteren, Peer / Hüneburg, Robert / Nattermann, Jacob / Strassburg, Christian P / Spengler, Ulrich. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany, and the German Center for Infection Research (DZIF), Partner Site Cologne-Bonn, Bonn, Germany. Electronic address: bettina.langhans@ukb.uni-bonn.de. · Department of Internal Medicine I, University of Bonn, Bonn, Germany, and the German Center for Infection Research (DZIF), Partner Site Cologne-Bonn, Bonn, Germany. ·J Hepatol · Pubmed #28040549.

ABSTRACT: BACKGROUND & AIMS: CD4 METHODS: We analyzed Tregs before (baseline), at end of therapy (EOT), 12 and 24weeks (SVR12, SVR24) and long-term (51±14weeks) after EOT in 26 genotype-1-infected patients who were successfully treated with sofosbuvir (SOF) plus interferon (IFN)/ribavirin (n=12) and IFN-free DAA regimens (SOF plus daclatasvir or simeprevir; n=14). Frequency, phenotype and suppressor function of peripheral Foxp3 RESULTS: Frequencies and activation status of Foxp3 CONCLUSION: Although IFN-based DAA therapy induced transient expansion of activated Foxp3 LAY SUMMARY: In chronic hepatitis C virus (HCV) infection, CD4

3 Article IL-28B Genetic Variants Determine the Extent of Monocyte-Induced Activation of NK Cells in Hepatitis C. 2016

Krämer, Benjamin / Finnemann, Claudia / Sastre, Beatriz / Lutz, Philipp / Glässner, Andreas / Wolter, Franziska / Goeser, Felix / Kokordelis, Pavlos / Kaczmarek, Dominik / Nischalke, Hans-Dieter / Strassburg, Christian P / Spengler, Ulrich / Nattermann, Jacob. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany. · German Center for Infection Research (DZIF), Bonn, Germany. · Department of Infectious Diseases, Institute for Health Research (IRYCIS), University Hospital Ramón y Cajal, Madrid, Spain. · AIDS Research Network (RIS-RETICS), Madrid, Spain. ·PLoS One · Pubmed #27583440.

ABSTRACT: BACKGROUND: Immuno-genetic studies suggest a functional link between NK cells and λ-IFNs. We recently showed that NK cells are negative for the IFN-λ receptor IFN-λR1 and do not respond to IFN-λ, suggesting a rather indirect association between IL-28B genotype and NK cell activity. METHODS: A total of 75 HCV(+) patients and 67 healthy controls were enrolled into this study. IL-28B (rs12979860) and IFNL-4 (rs368234815) genotypes were determined by rtPCR. Total PBMC, monocytes, and NK cells were stimulated with IL-29, the TLR-7/8 agonist R848, or a combination of both. NK cell IFN-γ response was analysed by FACS. IL-12 and IL-18 secretion of monocytes was studied by ELISA. In blocking experiments anti-IL-12/anti-IL-18 were used. RESULTS: Following stimulation of total PBMCs with R848 we found NK cell IFN- γ responses to vary with the IL-28B genotype, with carriers of a T/T genotype displaying the lowest frequency of IFN-γ(+)NK cells. When isolated NK cells were studied no such associations were observed, indicating an indirect association between IL-28B genotype and NK cell activity. Accordingly, we found R848-stimulated monocytes of patients with a T/T genotype to be significantly less effective in triggering NK cell IFN- γ production than monocytes from carriers of a non-T/T genotype. In line with these findings we observed monocytes from T/T patients to secrete significantly lower concentrations of IL-12 than monocytes from non-T/T individuals. CONCLUSIONS: Our data indicate that monocytes from carriers of an IL-28B T/T genotype display a reduced ability to stimulate NK cell activity and, thus, provide a link between IL-28B genotype and NK functions.

4 Article Hypoxia impairs anti-viral activity of natural killer (NK) cells but has little effect on anti-fibrotic NK cell functions in hepatitis C virus infection. 2015

Wolter, Franziska / Glässner, Andreas / Krämer, Benjamin / Kokordelis, Pavlos / Finnemann, Claudia / Kaczmarek, Dominik J / Goeser, Felix / Lutz, Philipp / Nischalke, Hans Dieter / Strassburg, Christian P / Spengler, Ulrich / Nattermann, Jacob. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research (DZIF), Bonn, Germany. ·J Hepatol · Pubmed #26297916.

ABSTRACT: BACKGROUND & AIMS: Natural killer (NK) cells have been shown to exert anti-viral as well as anti-fibrotic functions in hepatitis C virus (HCV) infection. Previous studies, however, analyzed NK cell functions exclusively under atmospheric oxygen conditions despite the fact that the liver microenvironment is hypoxic. Here, we analyzed the effects of low oxygen tension on anti-viral and anti-fibrotic NK cell activity. METHODS: Peripheral (n=34) and intrahepatic (n=15) NK cells from HCV(+) patients as well as circulating NK cells from healthy donors (n=20) were studied with respect to anti-viral and anti-fibrotic activity via co-culture experiments with HuH7 replicon cells and hepatic stellate cells, respectively. RESULTS: Anti-viral activity of resting NK cells from healthy controls was not affected by hypoxia. However, hypoxia significantly reduced the response of healthy NK cells to cytokine stimulation. In contrast to healthy controls, we observed resting and cytokine activated peripheral NK cells from HCV patients to display a significantly decreased anti-viral activity when cultured at 5% or 1% oxygen, suggesting HCV NK cells to be very sensitive to hypoxia. These findings could be confirmed when intrahepatic NK cells were tested. Finally, we show that anti-fibrotic NK cell activity was not affected by low oxygen tension. CONCLUSIONS: Our results show that anti-viral function of NK cells from HCV(+) patients is critically affected by a hypoxic microenvironment and, therefore, indicate that in order to obtain an accurate understanding of intrahepatic NK cell anti-HCV activity, the laboratory modelling should take into account the liver specific levels of oxygen.

5 Article A common polymorphism in the NCAN gene is associated with hepatocellular carcinoma in alcoholic liver disease. 2014

Nischalke, Hans Dieter / Lutz, Philipp / Krämer, Benjamin / Söhne, Jennifer / Müller, Tobias / Rosendahl, Jonas / Fischer, Janett / Berg, Thomas / Hittatiya, Kanishka / Fischer, Hans-Peter / Soyka, Michael / Semmo, Nasser / Nattermann, Jacob / Sauerbruch, Tilman / Strassburg, Christian P / Stickel, Felix / Spengler, Ulrich. ·Department of Internal Medicine I, University of Bonn, Germany. · Department of Internal Medicine I, University of Bonn, Germany; German Center for Infection Research, Germany. · Department of Gastroenterology, University Hospital Leipzig, Germany. · Department of Pathology, University Hospital Bonn, Germany. · Psychiatric Hospital Meiringen, Switzerland; Psychiatric Hospital, University of Munich, Germany. · Hepatology Unit, Klinik Beau-Site, Department of Visceral Surgery and Medicine Inselspital, University of Bern, Switzerland. · Department of Internal Medicine I, University of Bonn, Germany; German Center for Infection Research, Germany. Electronic address: ulrich.spengler@ukb.uni-bonn.de. ·J Hepatol · Pubmed #24946282.

ABSTRACT: BACKGROUND & AIMS: The genetic background of alcoholic liver diseases and their complications are increasingly recognized. A common polymorphism in the neurocan (NCAN) gene, which is known to be expressed in neuronal tissue, has been identified as a risk factor for non-alcoholic fatty liver disease (NAFLD). We investigated if this polymorphism may also be related to alcoholic liver disease (ALD) and hepatocellular carcinoma (HCC). METHODS: We analysed the distribution of the NCAN rs2228603 genotypes in 356 patients with alcoholic liver cirrhosis, 126 patients with alcoholic HCC, 382 persons with alcohol abuse without liver damage, 362 healthy controls and in 171 patients with hepatitis C virus (HCV) associated HCC. Furthermore, a validation cohort of 229 patients with alcoholic cirrhosis (83 with HCC) was analysed. The genotypes were determined by LightSNiP assays. The expression of NCAN was studied by RT-PCR and immunofluorescence microscopy. RESULTS: The frequency of the NCAN rs2228603 T allele was significantly increased in patients with HCC due to ALD (15.1%) compared to alcoholic cirrhosis without HCC (9.3%), alcoholic controls (7.2%), healthy controls (7.9%), and HCV associated HCC (9.1%). This finding was confirmed in the validation cohort (15.7% vs. 6.8%, OR=2.53; 95%CI: 1.36-4.68; p=0.0025) and by multivariate analysis (OR=1.840; 95%CI: 1.22-2.78; p=0.004 for carriage of the rs2228603 T allele). In addition, we identified and localised NCAN expression in human liver. CONCLUSIONS: NCAN is not only expressed in neuronal tissue, but also in the liver. Its rs2228603 polymorphism is a risk factor for HCC in ALD, but not in HCV infection.

6 Article CD27(+)CD56Bright natural killer cells may be involved in spontaneous clearance of acute hepatitis C in HIV-positive patients. 2014

Eisenhardt, Marianne / Glässner, Andreas / Wolter, Franziska / Krämer, Benjamin / Kokordelis, Pavlos / Nischalke, Hans-Dieter / Boesecke, Christoph / Rockstroh, Jürgen K / Spengler, Ulrich / Nattermann, Jacob. ·Department of Internal Medicine I, University of Bonn, German Center for Infection Research (DZIF), Bonn, Germany. ·AIDS · Pubmed #24922598.

ABSTRACT: OBJECTIVE: The objective of this study was to analyse the potential role of CD27 in natural killer (NK) cell-mediated control of hepatitis C virus (HCV) infection in HIV-positive patients. DESIGN: Frequency of CD27-expressing CD56 NK cells was analysed in HIV mono-infected individuals and HIV-positive patients with acute or chronic hepatitis C. Anti-HCV activity of CD27(+) and CD27(-) NK cells was compared. METHODS: NK cell mediated inhibition of HCV replication was analysed using the HUH7 HCV Replicon model. NK cell phenotype and interferon (IFN) secretion was studied by flowcytometry. RESULTS: High frequency of CD27(+)CD56 NK cells is associated with spontaneous clearance of acute hepatitis C in HIV-positive patients. Accordingly, we found CD27(+)CD56 NK cells to display strong anti-HCV activity. CONCLUSION: Our results underline the important role of NK cells in modulating outcome of HCV infection.

7 Article An effective interferon-gamma-mediated inhibition of hepatitis C virus replication by natural killer cells is associated with spontaneous clearance of acute hepatitis C in human immunodeficiency virus-positive patients. 2014

Kokordelis, Pavlos / Krämer, Benjamin / Körner, Christian / Boesecke, Christoph / Voigt, Esther / Ingiliz, Patrick / Glässner, Andreas / Eisenhardt, Marianne / Wolter, Franziska / Kaczmarek, Dominik / Nischalke, Hans Dieter / Rockstroh, Jürgen K / Spengler, Ulrich / Nattermann, Jacob. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany; German Center for Infection Research (DZIF), Bonn, Germany. ·Hepatology · Pubmed #24382664.

ABSTRACT: CONCLUSION: Our data suggest a strong IFN-γ-mediated antiviral NK cell response to be associated with a self-limited course of AHC in HIV(+) patients.

8 Article Association between the PNPLA3 (rs738409 C>G) variant and hepatocellular carcinoma: Evidence from a meta-analysis of individual participant data. 2014

Trépo, Eric / Nahon, Pierre / Bontempi, Gianluca / Valenti, Luca / Falleti, Edmondo / Nischalke, Hans-Dieter / Hamza, Samia / Corradini, Stefano Ginanni / Burza, Maria Antonella / Guyot, Erwan / Donati, Benedetta / Spengler, Ulrich / Hillon, Patrick / Toniutto, Pierluigi / Henrion, Jean / Franchimont, Denis / Devière, Jacques / Mathurin, Philippe / Moreno, Christophe / Romeo, Stefano / Deltenre, Pierre. ·Department of Gastroenterology, Hepatopancreatology and Digestive Oncology, Erasme Hospital, Université Libre de Bruxelles, Brussels, Belgium; Laboratory of Experimental Gastroenterology, Université Libre de Bruxelles, Brussels, Belgium. ·Hepatology · Pubmed #24114809.

ABSTRACT: CONCLUSION: Overall, these results suggest that rs738409 exerts a marked influence on hepatocarcinogenesis in patients with cirrhosis of European descent and provide a strong argument for performing further mechanistic studies to better understand the role of PNPLA3 in HCC development.

9 Article Variation in IFNL4 genotype and response to interferon-based therapy of hepatitis C in HIV-positive patients with acute and chronic hepatitis C. 2013

Krämer, Benjamin / Nischalke, Hans Dieter / Boesecke, Christoph / Ingiliz, Patrick / Voigt, Esther / Mauss, Stefan / Stellbrink, Hans-Jürgen / Baumgarten, Axel / Rockstroh, Juergen K / Spengler, Ulrich / Nattermann, Jacob. ·aDepartment of Internal Medicine I, German Center for Infection Research, University of Bonn, Bonn bMedical Center for Infectious Diseases (MIB), Berlin cPraxis am Ebertplatz, Cologne dCenter for HIV and Hepatogastroenterology, Duesseldorf eICH, Hamburg, Germany. *Benjamin Krämer and Hans Dieter Nischalke contributed equally to the writing of this article. ·AIDS · Pubmed #23939236.

ABSTRACT: The IFNL4 ss469415590 polymorphism has recently be shown to better predict treatment response in chronic hepatitis than the IL28B rs12979860 variant. However, no data exist in patients with HIV/hepatitis C virus (HCV) coinfection. Analysing 206 HCV(+)/HIV(+) and 162 HCV(+)/HIV(-) patients, we found that compared with IL28B rs12979860, IFNL4 ss469415590 was strongly associated with response to interferon/ribavirin therapy in HCV(+)/HIV(-) individuals but not in HIV(+)/HCV(+) patients. Thus, effects of the IFNL4 variant may differ in HIV(+) and HIV(-) patients.

10 Article Genetic analyses reveal a role for vitamin D insufficiency in HCV-associated hepatocellular carcinoma development. 2013

Lange, Christian M / Miki, Daiki / Ochi, Hidenori / Nischalke, Hans-Dieter / Bojunga, Jörg / Bibert, Stéphanie / Morikawa, Kenichi / Gouttenoire, Jérôme / Cerny, Andreas / Dufour, Jean-François / Gorgievski-Hrisoho, Meri / Heim, Markus H / Malinverni, Raffaele / Müllhaupt, Beat / Negro, Francesco / Semela, David / Kutalik, Zoltan / Müller, Tobias / Spengler, Ulrich / Berg, Thomas / Chayama, Kazuaki / Moradpour, Darius / Bochud, Pierre-Yves / Anonymous1630760 / Anonymous1640760. ·Division of Gastroenterology and Hepatology, Centre Hospitalier Universitaire Vaudois, University of Lausanne, Lausanne, Switzerland. lange_christian1@yahoo.de ·PLoS One · Pubmed #23734184.

ABSTRACT: BACKGROUND: Vitamin D insufficiency has been associated with the occurrence of various types of cancer, but causal relationships remain elusive. We therefore aimed to determine the relationship between genetic determinants of vitamin D serum levels and the risk of developing hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC). METHODOLOGY/PRINCIPAL FINDINGS: Associations between CYP2R1, GC, and DHCR7 genotypes that are determinants of reduced 25-hydroxyvitamin D (25[OH]D3) serum levels and the risk of HCV-related HCC development were investigated for 1279 chronic hepatitis C patients with HCC and 4325 without HCC, respectively. The well-known associations between CYP2R1 (rs1993116, rs10741657), GC (rs2282679), and DHCR7 (rs7944926, rs12785878) genotypes and 25(OH)D3 serum levels were also apparent in patients with chronic hepatitis C. The same genotypes of these single nucleotide polymorphisms (SNPs) that are associated with reduced 25(OH)D3 serum levels were found to be associated with HCV-related HCC (P = 0.07 [OR = 1.13, 95% CI = 0.99-1.28] for CYP2R1, P = 0.007 [OR = 1.56, 95% CI = 1.12-2.15] for GC, P = 0.003 [OR = 1.42, 95% CI = 1.13-1.78] for DHCR7; ORs for risk genotypes). In contrast, no association between these genetic variations and liver fibrosis progression rate (P>0.2 for each SNP) or outcome of standard therapy with pegylated interferon-α and ribavirin (P>0.2 for each SNP) was observed, suggesting a specific influence of the genetic determinants of 25(OH)D3 serum levels on hepatocarcinogenesis. CONCLUSIONS/SIGNIFICANCE: Our data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related hepatocarcinogenesis.

11 Article Impaired CD4⁺ T cell stimulation of NK cell anti-fibrotic activity may contribute to accelerated liver fibrosis progression in HIV/HCV patients. 2013

Glässner, Andreas / Eisenhardt, Marianne / Kokordelis, Pavlos / Krämer, Benjamin / Wolter, Franziska / Nischalke, Hans Dieter / Boesecke, Christoph / Sauerbruch, Tilman / Rockstroh, Jürgen K / Spengler, Ulrich / Nattermann, Jacob. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany. ·J Hepatol · Pubmed #23665286.

ABSTRACT: BACKGROUND & AIMS: HIV/HCV co-infection is characterized by a faster progression to liver fibrosis compared to HCV mono-infection. Epidemiologic studies found an association between low CD4(+) T cell counts and advanced stages of liver fibrosis. However, the mechanisms underlying this association remain unclear. CD4(+) T cells critically modulate NK cell activity. Of note, NK cells have been shown to display anti-fibrotic activity via killing of activated hepatic stellate cells (HSC). Thus, we speculated that CD4(+) T cells might modulate fibrosis progression by interacting with NK cells. METHODS: NK cells from HCV(+) (n=35), HIV(+)/HCV(+) (n=28), HIV(+) (n=8) patients, and healthy controls (n=30) were used in this study. NK cells were cultured in the presence or absence of supernatants from CD3/CD28-stimulated CD4(+) cells. Then, NK cells were co-incubated with activated HSC and studied for degranulation, IFN-γ secretion, and induction of HSC apoptosis. RESULTS: Following incubation with CD4(+) T cell supernatants, NK cells displayed a significantly increased activity against primary HSC as compared to unstimulated NK cells. This effect was, at least in part, mediated via an IL-2 dependent upregulation of NKG2D expression. HCV/HIV co-infection was associated with an impaired IL-2 secretion of CD4(+) T cells resulting in an ineffective stimulation of anti-fibrotic NK cell function. CONCLUSIONS: Here, we show that CD4(+) T cells are able to stimulate anti-fibrotic NK cell activity via IL-2 mediated upregulation of NKG2D. HIV-induced loss of CD4(+) T cells together with an impaired activity of CD4(+) T cells may contribute to accelerate progression of liver fibrosis observed in co-infection.

12 Article Intrahepatic IL-8 producing Foxp3⁺CD4⁺ regulatory T cells and fibrogenesis in chronic hepatitis C. 2013

Langhans, Bettina / Krämer, Benjamin / Louis, Marcell / Nischalke, Hans Dieter / Hüneburg, Robert / Staratschek-Jox, Andrea / Odenthal, Margarethe / Manekeller, Steffen / Schepke, Michael / Kalff, Jörg / Fischer, Hans-Peter / Schultze, Joachim L / Spengler, Ulrich. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany. bettina.langhans@ukb.uni-bonn.de ·J Hepatol · Pubmed #23624000.

ABSTRACT: BACKGROUND & AIMS: Regulatory CD4(+) T cells (Tregs) are considered to affect outcomes of HCV infection, because they increase in number during chronic hepatitis C and can suppress T-cell functions. METHODS: Using microarray analysis, in situ immunofluorescence, ELISA, and flowcytometry, we characterised functional differentiation and localisation of adaptive Tregs in patients with chronic hepatitis C. RESULTS: We found substantial upregulation of IL-8 in Foxp3(+)CD4(+) Tregs from chronic hepatitis C. Activated GARP-positive IL-8(+) Tregs were particularly enriched in livers of patients with chronic hepatitis C in close proximity to areas of fibrosis and their numbers were correlated with the stage of fibrosis. Moreover, Tregs induced upregulation of profibrogenic markers TIMP1, MMP2, TGF-beta1, alpha-SMA, collagen, and CCL2 in primary human hepatic stellate cells (HSC). HSC activation, but not Treg suppressor function, was blocked by adding a neutralizing IL-8 antibody. CONCLUSIONS: Our studies identified Foxp3(+)CD4(+) Tregs as an additional intrahepatic source of IL-8 in chronic hepatitis C acting on HSC. Thus, Foxp3(+)CD4(+) Tregs in chronic hepatitis C have acquired differentiation as regulators of fibrogenesis in addition to suppressing local immune responses.

13 Article Ribavirin exerts differential effects on functions of Cd4+ Th1, Th2, and regulatory T cell clones in hepatitis C. 2012

Langhans, Bettina / Nischalke, Hans Dieter / Arndt, Simone / Braunschweiger, Ingrid / Nattermann, Jacob / Sauerbruch, Tilman / Spengler, Ulrich. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany. bettina.langhans@ukb.uni-bonn.de ·PLoS One · Pubmed #22848715.

ABSTRACT: Ribavirin improves outcomes of therapy in chronic hepatitis C but its mode of action has still remained unclear. Since ribavirin has been proposed to modulate the host's T cell responses, we studied its direct effects on CD4(+) T cell clones with diverse functional polarization which had been generated from patients with chronic hepatitis C. We analysed in vitro proliferation ([(3)H] thymidine uptake) and cytokine responses (IL-10, IFN-gamma) at varying concentrations of ribavirin (0-10 µg/ml) in 8, 9 and 7 CD4(+) TH1, TH2 and regulatory T cell (Treg) clones, respectively. In co-culture experiments, we further determined effects of ribarivin on inhibition of TH1 and TH2 effector cells by Treg clones. All clones had been generated from peripheral blood of patients with chronic hepatitis C in the presence of HCV core protein. Ribavirin enhanced proliferation of T effector cells and increased production of IFN-gamma in TH1 clones, but had only little effect on IL-10 secretion in TH2 clones. However, ribavirin markedly inhibited IL-10 release in Treg clones in a dose dependent fashion. These Treg clones suppressed proliferation of T effector clones by their IL-10 secretion, and in co-culture assays ribavirin reversed Treg-mediated suppression of T effector cells. Our in vitro data suggest that--in addition to its immunostimulatory effects on TH1 cells--ribavirin can inhibit functions of HCV-specific Tregs and thus reverses Treg-mediated suppression of T effector cells in chronic hepatitis C.

14 Article The CXCR3(+)CD56Bright phenotype characterizes a distinct NK cell subset with anti-fibrotic potential that shows dys-regulated activity in hepatitis C. 2012

Eisenhardt, Marianne / Glässner, Andreas / Krämer, Benjamin / Körner, Christian / Sibbing, Bernhard / Kokordelis, Pavlos / Nischalke, Hans Dieter / Sauerbruch, Tilman / Spengler, Ulrich / Nattermann, Jacob. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany. ·PLoS One · Pubmed #22792160.

ABSTRACT: BACKGROUND: In mouse models, natural killer (NK) cells have been shown to exert anti-fibrotic activity via killing of activated hepatic stellate cells (HSC). Chemokines and chemokine receptors critically modulate hepatic recruitment of NK cells. In hepatitis C, the chemokine receptor CXCR3 and its ligands have been shown to be associated with stage of fibrosis suggesting a role of these chemokines in HCV associated liver damage by yet incompletely understood mechanisms. Here, we analyzed phenotype and function of CXCR3 expressing NK cells in chronic hepatitis C. METHODS: Circulating NK cells from HCV-infected patients (n = 57) and healthy controls (n = 27) were analyzed with respect to CXCR3 and co-expression of different maturation markers. Degranulation and interferon-γ secretion of CXCR3(+) and CXCR3(-) NK cell subsets were studied after co-incubation with primary human hepatic stellate cells (HSC). In addition, intra-hepatic frequency of CXCR3(+) NK cells was correlated with stage of liver fibrosis (n = 15). RESULTS: We show that distinct NK cell subsets can be distinguished based on CXCR3 surface expression. In healthy controls CXCR3(+)CD56Bright NK cells displayed strongest activity against HSC. Chronic hepatitis C was associated with a significantly increased frequency of CXCR3(+)CD56Bright NK cells which showed impaired degranulation and impaired IFN-γ secretion in response to HSC. Of note, we observed intra-hepatic accumulation of this NK cell subset in advanced stages of liver fibrosis. CONCLUSION: We show that distinct NK cell subsets can be distinguished based on CXCR3 surface expression. Intra-hepatic accumulation of the functionally impaired CXCR3(+)CD56Bright NK cell subset might be involved in HCV-induced liver fibrosis.

15 Article Natural killer p46High expression defines a natural killer cell subset that is potentially involved in control of hepatitis C virus replication and modulation of liver fibrosis. 2012

Krämer, Benjamin / Körner, Christian / Kebschull, Moritz / Glässner, Andreas / Eisenhardt, Marianne / Nischalke, Hans-Dieter / Alexander, Michael / Sauerbruch, Tilman / Spengler, Ulrich / Nattermann, Jacob. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany. ·Hepatology · Pubmed #22532190.

ABSTRACT: CONCLUSIONS: NKp46(High) expression defines a specific NK-cell subset that may be involved in both the suppression of HCV replication and HCV-associated liver damage underpinning the role of NK cells in the immunopathogenesis of HCV.

16 Article TRAIL receptor I (DR4) polymorphisms C626G and A683C are associated with an increased risk for hepatocellular carcinoma (HCC) in HCV-infected patients. 2012

Körner, Christian / Riesner, Katarina / Krämer, Benjamin / Eisenhardt, Marianne / Glässner, Andreas / Wolter, Franziska / Berg, Thomas / Müller, Tobias / Sauerbruch, Tilman / Nattermann, Jacob / Spengler, Ulrich / Nischalke, Hans Dieter. ·Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Str, 25, 53127 Bonn, Germany. ·BMC Cancer · Pubmed #22401174.

ABSTRACT: BACKGROUND: Tumour surveillance via induction of TRAIL-mediated apoptosis is a key mechanism, how the immune system prevents malignancy. To determine if gene variants in the TRAIL receptor I (DR4) gene affect the risk of hepatitis C virus (HCV)-induced liver cancer (HCC), we analysed DR4 mutations C626G (rs20575) and A683C (rs20576) in HCV-infected patients with and without HCC. METHODS: Frequencies of DR4 gene polymorphisms were determined by LightSNiP assays in 159 and 234 HCV-infected patients with HCC and without HCC, respectively. 359 healthy controls served as reference population. RESULTS: Distribution of C626G and A683C genotypes were not significantly different between healthy controls and HCV-positive patients without HCC. DR4 variants 626C and 683A occurred at increased frequencies in patients with HCC. The risk of HCC was linked to carriage of the 626C allele and the homozygous 683AA genotype, and the simultaneous presence of the two risk variants was confirmed as independent HCC risk factor by Cox regression analysis (Odds ratio 1.975, 95% CI 1.205-3.236; p = 0.007). Furthermore HCV viral loads were significantly increased in patients who simultaneously carried both genetic risk factors (2.69 ± 0.36 × 10(6) IU/ml vs. 1.81 ± 0.23 × 10(6) IU/ml, p = 0.049). CONCLUSIONS: The increased prevalence of patients with a 626C allele and the homozygous 683AA genotype in HCV-infected patients with HCC suggests that these genetic variants are a risk factor for HCC in chronic hepatitis C.

17 Article The CXCL1 rs4074 A allele is associated with enhanced CXCL1 responses to TLR2 ligands and predisposes to cirrhosis in HCV genotype 1-infected Caucasian patients. 2012

Nischalke, Hans Dieter / Berger, Cordula / Luda, Carolin / Müller, Tobias / Berg, Thomas / Coenen, Martin / Krämer, Benjamin / Körner, Christian / Trebicka, Jonel / Grünhage, Frank / Lammert, Frank / Nattermann, Jacob / Sauerbruch, Tilman / Spengler, Ulrich. ·Department of Internal Medicine I, University of Bonn, Sigmund-Freud-Str. 25, 53127 Bonn, Germany. ·J Hepatol · Pubmed #22173151.

ABSTRACT: BACKGROUND & AIMS: CXCL1 is a ligand for CXC chemokine-receptor 2 expressed on hepatic stellate cells (HSC). Thus, CXCL1 might contribute to HSC activation and fibrogenesis. Here, we investigated whether the CXCL1 rs4074 polymorphism affects CXCL1 expression and progression of chronic hepatitis C virus (HCV) infection towards cirrhosis. METHODS: The study involved 237 patients with chronic HCV genotype 1 infection (75 with cirrhosis) and 342 healthy controls. The CXCL1 rs4074 polymorphism was determined by a LightSNiP assay on the LightCycler system. CXCL1 serum levels and induction in response to HCV proteins were studied by ELISA. RESULTS: Distributions of CXCL1 genotypes (GG/GA/AA) matched the Hardy-Weinberg equilibrium in all subgroups (HCV-associated cirrhosis: 29.3%/54.7%/16.0%; non-cirrhotic HCV infection: 45.1%/44.4%/10.5%, healthy controls: 46.2%/40.9%/12.9%). HCV-infected cirrhotic patients had a significantly greater CXCL1 rs4074 A allele frequency (43.3%) than patients without cirrhosis (32.7%, OR=1.573, p=0.03) and healthy controls (33.3%, OR=1.529, p=0.02). In vitro carriers of the A allele produced greater amounts of CXCL1 in response to TLR2-ligands including HCV core and NS3, and HCV-infected carriers of the CXCL1 rs4074 A allele had higher CXCL1 serum levels than those with the G/G genotype. Moreover, multivariate Cox-regression analysis confirmed age and the presence of a CXCL1 rs4074 A allele as risk factors for cirrhosis. CONCLUSIONS: Enhanced production of CXCL1 in response to HCV antigens in carriers of the rs4074 A allele together with its increased frequency in cirrhotic patients with hepatitis C suggest the CXCL1 rs4074 A allele as a genetic risk factor for cirrhosis progression in hepatitis C.

18 Article The toll-like receptor 2 (TLR2) -196 to -174 del/ins polymorphism affects viral loads and susceptibility to hepatocellular carcinoma in chronic hepatitis C. 2012

Nischalke, Hans-Dieter / Coenen, Martin / Berger, Cordula / Aldenhoff, Katharina / Müller, Tobias / Berg, Thomas / Krämer, Benjamin / Körner, Christian / Odenthal, Margarete / Schulze, Falko / Grünhage, Frank / Nattermann, Jacob / Sauerbruch, Tilman / Spengler, Ulrich. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany. nischalke@ukb.uni-bonn.de ·Int J Cancer · Pubmed #21500195.

ABSTRACT: Chronic hepatitis C virus (HCV) infection is a major risk factor for hepatocellular carcinoma (HCC). HCV proteins core and NS3 can bind to toll-like receptor 2 (TLR2) and trigger inflammatory responses. Polymorphisms in the TLR2 gene predispose to various forms of malignancy but have not been studied in HCV-associated HCC. Here, we investigated whether single nucleotide polymorphisms (SNPs), rs4696480, rs5743708, rs5743704 and the -196 to -174 del/ins polymorphism of the TLR2 gene affect the risk for HCC in chronic hepatitis C. The study involved 189 and 192 HCV genotype 1 infected patients with and without HCC, respectively, as well as 347 healthy controls. TLR2 alleles were determined by hybridization probe assays and allele-specific short fragment polymerase chain reaction on a LightCycler system. All TLR2 polymorphisms matched the Hardy-Weinberg equilibrium in each study group. Although TLR2 SNPs showed no effect, the frequency of the TLR2 -196 to -174 del allele was significantly higher in patients with HCV-associated HCC (22.5%) than in HCV-infected patients without HCC (15.6%, p = 0.016) and healthy controls (15.3%, p = 0.003). HCV-infected carriers of a TLR2 -196 to -174 del allele had significantly higher HCV viral loads than TLR2 -196 to -174 ins/ins homozygous patients (p = 0.031). Finally, in carriers of the TLR2 -196 to -174 del allele, stimulation of monocytes resulted in significantly lower TLR2 expression levels and interleukin-8 (IL-8) induction than in individuals with the TLR2 -196 to -174 ins/ins genotype (p < 0.05). Our data suggest the TLR2 -196 to -174 del allele to affect HCV viral loads and to increase the risk for HCC in HCV genotype1-infected patients.

19 Article The PNPLA3 rs738409 148M/M genotype is a risk factor for liver cancer in alcoholic cirrhosis but shows no or weak association in hepatitis C cirrhosis. 2011

Nischalke, Hans Dieter / Berger, Cordula / Luda, Carolin / Berg, Thomas / Müller, Tobias / Grünhage, Frank / Lammert, Frank / Coenen, Martin / Krämer, Benjamin / Körner, Christian / Vidovic, Natascha / Oldenburg, Johannes / Nattermann, Jacob / Sauerbruch, Tilman / Spengler, Ulrich. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany. ·PLoS One · Pubmed #22087248.

ABSTRACT: BACKGROUND: An isoleucine>methionine mutation at position 148 in the PNPLA3 gene (p.I148M, rs738409) has recently been identified as a susceptibility factor for liver damage in steatohepatitis. Here, we studied whether the PNPLA3 rs738409 polymorphism also affects predisposition to hepatocellular carcinoma (HCC). METHODS: We compared distributions of PNPLA3 genotypes in 80 and 81 Caucasian patients with alcoholic and hepatitis C virus (HCV)-associated HCC to 80 and 81 age- and sex-matched patients with alcohol-related and HCV-related cirrhosis without HCC, respectively. PNPLA3 genotypes in 190 healthy individuals from the same population served as reference. Potential confounders obesity, diabetes, HCV genotype and HBV co-infection were controlled by univariate and multivariate logistic regression with forward variable selection. RESULTS: PNPLA3 genotypes were in Hardy-Weinberg equilibrium for all study groups. The frequency of the 148M allele was significantly (p<0.001) increased in alcoholic cirrhosis with (53.7%) and without HCC (36.2%) but was not different between healthy controls (22.9%) and patients with cirrhosis (25.3%; p = 0.545) and HCC (30.2%; p = 0.071) due to hepatitis C. HCC risk was highest in 148M/M homozygous patients with alcoholic liver disease (odds ratio (OR) 16.8 versus healthy controls; 95% confidence interval (CI) 6.68-42.43, p<0.001). Finally, multivariate regression confirmed 148M/M homozygosity (OR 2.8; 95%-CI: 1.24-6.42; p = 0.013) as HCC risk factor in alcoholic cirrhosis. In HCV-related cirrhosis only HCV genotype 1 was confirmed as a HCC risk factor (OR 4.2; 95%-CI: 1.50-11.52; p = 0.006). CONCLUSION: The PNPLA3 148M variant is a prominent risk factor for HCC in patients with alcoholic cirrhosis, while its effects are negligible in patients with cirrhosis due to HCV. This polymorphism provides an useful tool to identify individuals with particularly high HCC risk in patients with alcoholic liver disease that should be taken into account in future HCC prevention studies.

20 Article The predictive value of IL28B gene polymorphism for spontaneous clearance in a single source outbreak cohort is limited in patients carrying the CCR5Δ32 mutation. 2011

Nattermann, Jacob / Timm, Jörg / Nischalke, Hans Dieter / Olbrich, Anne / Michalk, Monika / Tillmann, Hans L / Berg, Thomas / Wedemeyer, Heiner / Tenckhoff, Hannelore / Wiese, Manfred / Kullig, Ulrike / Göbel, Uwe / Capka, Emanuela / Schiefke, Ingolf / Güthof, Wolfgang / Grüngreiff, Kurt / König, Ingrid / Roggendorf, Michael / Sauerbruch, Tilman / Spengler, Ulrich / Anonymous4100698. ·Department of Internal Medicine, University of Bonn, Bonn, Germany. jacob.nattermann@ukb.uni-bonn.de ·J Hepatol · Pubmed #21703201.

ABSTRACT: BACKGROUND & AIMS: The CCR5Δ32 mutation has been suspected to adversely affect outcomes of HCV infection, although reports have remained controversial. Here, we investigated the relative genetic contributions of the CCR5Δ32 deletion and the IL28B rs12979860 polymorphisms to spontaneous clearance of hepatitis C in a single-source outbreak. METHODS: We retrieved 396 Caucasian women (119 women with spontaneous HCV clearance) who had been infected with HCV genotype 1-contaminated anti-D immunoglobulin in 1978, and determined their IL28B and CCR5 alleles. RESULTS: IL28B CC, CT, and TT genotypes were found in 35.4%, 50%, and 14.6% of patients and corresponded to spontaneous clearance rates of 50%, 21.2%, and 12.1% (Chi(2)=38.7, p=5.0×10(-10)), respectively. CCR5 WT/WT, WT/Δ32, and Δ32/Δ32 genotypes were observed in 76%, 22.7%, and 1.3% of patients and corresponded to clearance rates of 33.2%, 21.2%, and 0% (Chi(2)=6.9, p=0.009), respectively. In a stepwise forward-conditional multivariate regression model both CCR5 (OR 2.1, p=0.01 for WT/WT) and IL28B genetic variants (OR 4.3, p=4.6×10(-10) for the C/C genotype) were identified as independent predictors of spontaneous HCV clearance. Importantly, favorable response rates were associated with the IL28B CC genotype only in CCR5 wild-type homozygous women, while HCV clearance in CCR5Δ32 carriers remained poor even in patients with the rs12979860 CC genotype. CONCLUSIONS: Both IL28B rs1297860 and CCR5Δ32 allelic variants are independent genetic determinants of spontaneous HCV clearance. The variable relative distribution between IL28B rs1297860 and CCR5Δ32 allelic variants in different populations may have masked the role of the CCR5Δ32 mutation in some studies.

21 Article Hepatitis C virus core protein induces fibrogenic actions of hepatic stellate cells via toll-like receptor 2. 2011

Coenen, Martin / Nischalke, Hans Dieter / Krämer, Benjamin / Langhans, Bettina / Glässner, Andreas / Schulte, Daniela / Körner, Christian / Sauerbruch, Tilman / Nattermann, Jacob / Spengler, Ulrich. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany. ·Lab Invest · Pubmed #21537327.

ABSTRACT: Hepatic stellate cells (HSCs) represent the main fibrogenic cell type accumulating extracellular matrix in the liver. Recent data suggest that hepatitis C virus (HCV) core protein may directly activate HSCs. Therefore, we examined the influence of recombinant HCV core protein on human HSCs. Primary human HSCs and the human HSC line LX-2 were stimulated with recombinant HCV proteins core and envelope 2 protein. Expression of procollagen type I α-1, α-smooth muscle actin, cysteine- and glycine-rich protein 2, glial fibrillary acidic protein, tissue growth factor β1, matrix metalloproteinases 2 (MMP2) and 13, tissue inhibitor of metalloproteinases 1 and 2 was investigated by real-time PCR. Intracellular signaling pathways of ERK1/2, p38 and, jun-amino-terminal kinase (JNK) were analyzed by western blot analysis. Recombinant HCV core protein induced upregulation of procollagen type I α-1, α-smooth muscle actin, MMP 2 and 13, tissue inhibitor of metalloproteinases 1 and 2, tissue growth factor β1, cysteine- and glycine-rich protein 2, and glial fibrillary acidic protein mRNA expression, whereas HCV envelope 2 protein did not exert any significant effect. Blocking of toll-like receptor 2 (TLR2) with a neutralizing antibody prevented mRNA upregulation by HCV core protein confirming that the TLR2 pathway was involved. Furthermore, western blot analysis revealed HCV-induced phosphorylation of the TLR2-dependent signaling molecules ERK1/2, p38 and JNK mitogen-activated kinases. Our in vitro results demonstrate a direct effect of HCV core protein on activation of HSCs toward a profibrogenic state, which is mediated via the TLR2 pathway. Manipulating the TLR2 pathway may thus provide a new approach for antifibrotic therapies in HCV infection.

22 Article Genetic variation in IL28B and treatment-induced clearance of hepatitis C virus in HIV-positive patients with acute and chronic hepatitis C. 2011

Nattermann, Jacob / Vogel, Martin / Nischalke, Hans Dieter / Danta, Mark / Mauss, Stefan / Stellbrink, Hans-Jörg / Baumgarten, Axel / Mayr, Christoph / Bruno, Raffaele / Tural, Cristina / Klausen, Gerd / Clotet, Bonaventura / Naumann, Uwe / Lutz, Thomas / Rausch, Michael / Schewe, Knud / Bienek, Bernhard / Haerter, Georg / Sauerbruch, Tilman / Rockstroh, Juergen K / Spengler, Ulrich. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany. jacob.nattermann@ukb.uni-bonn.de ·J Infect Dis · Pubmed #21257738.

ABSTRACT: Recently, a IL28B (rs 12979860) gene polymorphism was identified as a predictor for response to hepatitis C virus-specific treatment in human immunodeficiency virus (HIV)-uninfected and -infected patients with chronic hepatitis C. In an analysis of HIV-infected patients with acute hepatitis C, we found that the IL28B genotype was associated with serum levels of hepatitis C virus RNA, g-GT, and CD4 cell count. In contrast to HIV-infected patients with chronic hepatitis C, the IL28B genotype was not significantly associated with treatment response rates in patients with acute hepatitis C. Thus, effects of the IL28B single-nucleotide polymorphism may differ in HIV-infected patients with chronic and acute hepatitis C.

23 Article Interferon-lambda serum levels in hepatitis C. 2011

Langhans, Bettina / Kupfer, Bernd / Braunschweiger, Ingrid / Arndt, Simone / Schulte, Wibke / Nischalke, Hans Dieter / Nattermann, Jacob / Oldenburg, Johannes / Sauerbruch, Tilman / Spengler, Ulrich. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany. bettina.langhans@ukb.uni-bonn.de ·J Hepatol · Pubmed #21145813.

ABSTRACT: BACKGROUND & AIMS: Dendritic cells (DCs) trigger adaptive immune responses and are an important source of antiviral cytokines. In hepatitis C virus (HCV) infection DC function is markedly impaired. Thus far, studies have focused on types I and II interferon (IFN). We studied IFN-lambda1 (IL-29) and IFN-lambda2/3 (IL-28A/B) serum levels in patients with different outcomes of HCV infection. METHODS: IFN-lambdas were measured by ELISAs detecting IL-29 or IL-28A and IL-28B, respectively. Results were stratified with respect to the recently discovered rs12979860 T/C polymorphism upstream of the IL-28B gene. RESULTS: In general IL-29 serum levels exceeded IL-28A/B at least twofold, with IL-29 and IL-28A/B levels being significantly higher in carriers of the rs12979860 C allele than in TT homozygous individuals (p<0.02). IL-29 levels were substantially lower in patients with chronic hepatitis C than in healthy controls (p=0.005) and patients with spontaneously resolved hepatitis (p=0.001). Patients with acute hepatitis C showed IL-29 levels intermediate between chronic hepatitis C and normal controls; and IL-29 serum levels were higher in patients who spontaneously resolved hepatitis C than in those who became chronic. In vitro HCV proteins NS3 and E2 directly inhibited IL-29 production in poly I:C-stimulated purified DCs. CONCLUSIONS: Our data suggest that HCV proteins modify IFN-lambda production in DCs. Carriers of the rs12979860 C allele associated with resolution of HCV infection exhibited increased IFN-lambda levels. Moreover, high IFN-lambda levels predisposed to spontaneous resolution of HCV infection. Thus, IFN-lambdas seem to play an important role in the control of hepatitis C.

24 Article A polymorphism near IL28B is associated with spontaneous clearance of acute hepatitis C virus and jaundice. 2010

Tillmann, Hans L / Thompson, Alex J / Patel, Keyur / Wiese, Manfred / Tenckhoff, Hannelore / Nischalke, Hans D / Lokhnygina, Yuliya / Kullig, Ulrike / Göbel, Uwe / Capka, Emanuela / Wiegand, Johannes / Schiefke, Ingolf / Güthoff, Wolfgang / Grüngreiff, Kurt / König, Ingrid / Spengler, Ulrich / McCarthy, Jeanette / Shianna, Kevin V / Goldstein, David B / McHutchison, John G / Timm, Jörg / Nattermann, Jacob / Anonymous60666. ·Duke Clinical Research Institute, Duke University, Durham, North Carolina, USA. hans.tillmann@duke.edu ·Gastroenterology · Pubmed #20637200.

ABSTRACT: BACKGROUND & AIMS: A single nucleotide polymorphism (SNP) upstream of the IL28B gene has been associated with response of patients with chronic hepatitis C to therapy with pegylated interferon and ribavirin and also with spontaneous clearance of acute hepatitis C in a heterogeneous population. We analyzed the association between IL28B and the clinical presentation of acute hepatitis C virus (HCV) infection in a homogeneous population. METHODS: We analyzed the SNP rs12979860 in 190 women from the German anti-D cohort (infected with HCV genotype 1b via contaminated rhesus prophylaxis) and its association with spontaneous clearance. Clinical data were available in 136 women with acute infection who were also evaluated for IL28B genotype. Based on results of a TaqMan polymerase chain reaction assay, the rs12979860 SNP genotypes studied were C/C, C/T, or T/T. RESULTS: Spontaneous clearance was more common in patients with the C/C genotype (43/67; 64%) compared with C/T (22/90; 24%) or T/T (2/33; 6%) (P < .001). Jaundice during acute infection was more common among patients with C/C genotype (32.7%) than non-C/C patients (with C/T or T/T) (16.1%; P = .032). In C/C patients, jaundice during acute infection was not associated with an increased chance of spontaneous clearance (56.3%) compared with those without jaundice (60.6%). In contrast, in non-C/C patients, jaundice was associated with a higher likelihood of spontaneous clearance (42.9%) compared with those without jaundice (13.7%). CONCLUSIONS: The SNP rs12979860 upstream of IL28B is associated with spontaneous clearance of HCV. Women with the C/T or T/T genotype who did not develop jaundice had a lower chance of spontaneous clearance of HCV infection.

25 Article The cytotoxic lymphocyte antigen 4 polymorphisms affect response to hepatitis C virus-specific therapy in HIV(+) patients with acute and chronic hepatitis C virus co-infection. 2010

Nischalke, Hans Dieter / Vogel, Martin / Mauss, Stefan / Baumgarten, Axel / Lutz, Thomas / Danta, Marc / Naumann, Uwe / Coenen, Martin / Sauerbruch, Tilman / Rockstroh, Jürgen K / Spengler, Ulrich / Nattermann, Jacob. ·Department of Internal Medicine I, University of Bonn, Bonn, Germany. ·AIDS · Pubmed #20588168.

ABSTRACT: OBJECTIVE: Cytotoxic lymphocyte antigen 4 (CTLA4), a co-receptor expressed on T lymphocytes, is involved in the regulation of T-cell functions. Here, we analyzed the potential impact of the CTLA4 polymorphisms on response to hepatitis C virus (HCV)-specific treatment in HIV(+) patients co-infected with HCV. PATIENTS AND METHODS: A total of 184 HIV/HCV co-infected Caucasian patients were enrolled into this study, including 109 patients with chronic and 75 patients with acute hepatitis C. CTLA4 genotypes were determined by LightCycler PCR. RESULTS: We found the CTLA4 -318 C/C genotype to be associated with sustained virological response in HCV/HIV co-infection (P = 0.035). Moreover, response rates were significantly higher in patients with a +49G/G genotype [23/29 (79.3%)] than in carriers of other +49 genotypes [59/155 (38.1%); OR 6.2; P = 0.00005]. Of note, the CTLA4 +49G/G genotype was confirmed as an independent predictor for treatment response in both patients with acute and chronic hepatitis C. CONCLUSION: CTLA4 polymorphisms are associated with treatment-induced resolution of HCV infection in HIV co-infected patients. These findings underline the impact of genetic host factors for successful treatment.

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