- Email: [email protected]
P0504 : De novo nucleotide biosynthesis pathway tightly regulates hepatitis E virus infection
POSTERS P0502 RECOMBINANT NEUROLIGIN 4 (NLG4) ACTIVATES NK CELLS AND ATTENUATES FIBROGENESIS IN NONALCOHOLIC FATTY LIVER DISEASE J. Amer1 , A. Salhab1 , R. Safadi1 . 1 Liver & Gastroenterology Units, Hadassah Hebrew University Medical Center, Jerusalem, Israel E-mail: [email protected] Background and Aims: Among the anti-fibrotic responses NK cells induce hepatic stellate cell (HSCs) apoptosis (J Hep 2004). NK cell lose their killing effects in advanced fibrosis and cirrhosis (Gut 2011). NK cells from nonalcoholic fatty liver disease (NAFLD) patients exert high expressions of neuroligin-4 receptors (NLG4) and are thought to interfere with NK functionality (AASLD 2011 and EASL 2013). NLG4 receptor immune synapse interactions with its ligand b-neuroxin (cell-adhesion molecules) are thought to play an important step in fibrogenesis. We aimed to develop NK activation tool to ehance anti-fibrotic effects via NLG4 pathway in an in vitro co-culture condition. Methods: NK cells isolated form peripheral blood of NAFLD patients lacking metabolic syndrome were incubated with 10 nM of recombinant NLG4 for 3 hours prior to incubations with HSCs; LX2- cell line. Following 24 hours, cells were trypsinized and analyzed by flow-cytometry for NK activity by CD107a [Lysosomalassociated membrane protein 1 (LAMP1) – degranulation marker – a marker for NK activation] and LX2 activities (a-smooth-muscle intensities). Interleukin-4 (IL4) quantity expressions were also assessed in NK cells. Results: LX2 cell line express 75% of b-neuroxin. In co-cultures, recombinant NLG4 significantly increased lysosomal-associated membrane protein-1 (CD107a, NK activation marker) from 10% to 48% (P < 0.01). Compared to LX2 mono-cultures, elevations of NK cells CD107a activity was associated with increased LX2 killing; as aSMA mean fluorescence intensities of HSCs decreased from 3938 in cultures without the recombinant to 2432 with the recombinant (P < 0.01). NK cells pre-treated with the recombinant NLG4 showed decreased in IL-4 secretions by the flow cytometry technique (1.8-folds, P = 0.02). Conclusions: NLG4-b-neurexin recognition mediates HSCs-NK immune synapse to control release of NK vesicles. Recombinant NLG4 activates NK cells to promote anti-fibrotic effects through increased HSCs killing. These effects were associated with decreased expression of the pro-fibrogenic marker IL4 in the NAFLD NK cells. NLG4 immune modulation of CD107a activity of NK cells extends the understandment and therapeutic strategies in fatty liver disease. P0503 DENDRITIC CELL SUBSETS AND EXPRESSION OF DC-SIGN IN PROGRESSION OF HEPATITIS B INFECTION FROM ACUTE TO CHRONIC INFECTION: A NOVEL INSIGHT THROUGH TLRS AND RELATED INTRACELLULAR SIGNALLING MOLECULES S. Sukriti1 , N. Trehanpati1 , M. Kumar1 , S. Hissar1 , S.K. Sarin1 . 1 Research, Institute of Liver and Biliary Sciences, New Delhi, India E-mail: [email protected] Background and Aims: DC-specific intercellular adhesion molecule 3-grabbing nonintegrin (DCSIGN) and Toll-like receptors (TLRs) which are pathogen recognition receptors (PRRs), present on Dendritic cells (DC) to promote pathogen recognition, uptake and presentation of antigen and potentiates the interaction with T cells. We hypothesize, insufficient generation of immune surveillance in chronic hepatitis B might be because of impairment of frequencies and functional ability of DC’s and PRR’s. We aimed to monitor temporal changes in DC’s during acute phase in comparison to chronic hepatitis B infection. Methods: Twenty-eight subjects were included; acute viral hepatitis B (AVH-B, n = 8) were serially followed up; chronic
hepatitis B (CHB, n = 10) and healthy controls (HC, n = 10). PBMCs were immunostained before and after stimulating with polyI:C, CpGODN and LPS with flourochrome labelled antibodies. The frequency of myeloid DC’s (mDC) (CD11c+, BDCA1+), plasmacytoid DC’s (pDC’s) (CD123+, BDCA1+), intracellular IFN-g production and expression of DCSIGN, TLR2,3,4 and TLR9 was evaluated. mRNA levels of adaptor molecules of TLR pathway; Myd88, TRAF6 and cytokines IL-2, IL-6, TNF-a, IFN-a was measured by RT-PCR. Results: Frequencies of both subsets of DC’s i.e. mDC’s and pDC’s, were found significantly higher in acute and naïve chronic HBV patients than healthy controls (p < 0.00, p < 0.01) but no difference among AVH-B vs CHB. Functionally impaired DC’s were seen with significant low IFN-g production and low DCSIGN expression (p < 0.04, 0.00) in CHB patients. Even after stimulations by TLR agonist, no changes were found. The adaptor molecule of TLR’s, the MyD88 mRNA levels were also downregulated along with the cytokines IL-6, IFN-a. On follow-up of AVH-B patients, found temporal changes in DC’s while mDC’s frequency was significantly highest at wk 4, whereas pDC’s at wk 6, than wk0 (p < 0.02, 0.01) along with the DCSIGN on mDC’s expression increased linearly from wk 0 to wk 4 during acute phase (wk 0 28% to wk 4 72%, p < 0.00). Conclusions: (i) Subsets of dendritic cells are phenotypically intact but functionally impaired in CHB compared to seroconverted AVH-B patients. (ii) During acute phase pDC’s comes late in generation of effective immune response. (iii) DC SIGN expression is temporally increased in acute phase HBV infection, while is significantly low in CHB, indicating its key role in persistent infection. These novel observations would pave way for prognostication and development of antiviral strategies for chronic HBV infection.
Figure 1. INF-g production was significantly low in persistent CHB patients. No significant difference was found in frequency of mDC’s and pDC’s in acute and chronic HBV infection.
P0504 DE NOVO NUCLEOTIDE BIOSYNTHESIS PATHWAY TIGHTLY REGULATES HEPATITIS E VIRUS INFECTION Y. Wang1 , W. Wang1 , X. Zhou1 , D. Sprengers1 , M.J. Herold1 , M.P. Peppelenbosch1 , Q. Pan1 . 1 Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands E-mail: [email protected] Background and Aims: Despite an emerging global health issue, no approved drug is available for treating hepatitis E virus (HEV) infection. Since nucleotides are key components involved in host cell metabolism and virus infection, inhibitors of nucleotide synthesis enzymes may be potential drugs against HEV. Biosynthesis of purine nucleotides requires guanosine, which can
Journal of Hepatology 2015 vol. 62 | S263–S864
S503
POSTERS be phosphorylated into GMP, GDP and GTP. Pyrimidine nucleotides synthesis requires uridine, which can be catalyzed into UDP and UTP. We thus investigated the effects and mechanism-of-action of targeting de novo nucleotide synthesis in cell culture models of HEV infection. Methods: A subgenomic HEV replication model expressing luciferase reporter gene and a full-length infectious model were used. Results: Supplementation of exogenous guanosine, but not uridine, promoted HEV replication in both subgenomic (2.6fold) and infectious (2.0-fold) models. We thus focused on sequentially targeting key enzymes involved in purine synthesis pathway. Surprisingly, 6-thiohuanine, an inhibitor of Amido phosphoribosyltransferase (APRTase), stimulated HEV replication by 3.6±0.87 folds (Mean±SEM, n = 10, P < 0.0001). Lometrexol, an inhibitor of GAR Transformylase, also promoted HEV replication in both models. ATIC is a bifunctional protein that exerts AICAR transformylase activity and IMP cyclohydrolase activity in this pathway. Methotrexate (MTX) and Fludarabine (FA) are inhibitors of AICAR transformylase and IMP cyclohydrolase, respectively. Both compounds potently increased HEV genome RNA by 5.01±1.4fold and 5.06±0.3-fold, respectively (n = 5, P < 0.05). Consistently, silencing of ATIC resulted in dramatic increase of HEV RNA by 4.2±2.5-fold and abolished the ability of MTX to activate HEV. This demonstrated that ATIC has anti-HEV activity, which explains the proviral effects of MTX and FA. However, Mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase (IMPDH), could effectively inhibit HEV replication by 65% (10 ug/ml). Conclusions: Purine but not pyrimidine synthesis pathway regulates HEV infection. Unexpectedly, targeting the early steps of this pathway led to enhancement of HEV infection. Whereas targeting the late step (IMPDH enzyme) resulted in potent antiviral activity against HEV. P0505 IDENTIFICATION OF IL-17 POSITIVE INTRAHEPATIC NK CELLS IN HUMAN LIVER AND RELATIONSHIP WITH CHRONIC LIVER DISEASES Z. Macek Jilkova1,2 , H. Marche1,2 , C. Gierczak2 , V. Leroy1,2,3 , J.-P. Zarski1,2,3 , T. Decaens1,2,3 , P.N. Marche1,2 , N. Sturm1,2,4 , E. Jouvin-Marche1,2 . 1 INSERM U823, 2 Univ. Grenoble Alpes, IAB, 3 D´epartement d’H´epato-Gastro-Ent´erologie, 4 D´epartement d’Anatomie et de Cytologie Pathologiques, CHU-Grenoble, Grenoble, France E-mail: [email protected] Background and Aims: The production of pro-inflammatory IL-17 cytokine plays an important role in many inflammatory diseases and is not restricted to Th17 cells. However, in liver diseases, it has not yet been investigated if intrahepatic (IH)-natural killer (NK) cells, the major subset of innate immune cells, produce IL-17 and thereby contribute to liver inflammation. Methods: To analyze production of IL-17 by IH-immune cells, we performed flow cytometry analyses of fresh liver biopsies from 54 patients: NASH, HCV and HBV-infected and non-inflammatory subjects. Localization of IL-17+ NK cells was studied by double immunohistochemical and triple immunofluorescence analyses. Frequency of IL-17 producing NK cell was compared with INFg production and correlated with clinical parameters. Results: Flow cytometry analyses revealed that, in addition to T lymphocytes, IH-NK and IH-NKT cells produced IL-17 cytokine with frequency from 0.1% to 6.0%, depending on liver environment. The population of IL-17+ IH-NK cells was significantly higher compared to IFNg producing IH-NK cells (p = 0.009) and mainly specific to the NKp46+ NK cells subset (p < 0.001). Immunohistology of livers showed that 85% of IL-17+ NKp46+ IH-NK cells were localized in septal or portal fibrous area. Finally, the proportion of IH-NK cells producing IL-17 increased during the critical A2 Metavir necroS504
inflammatory grade, suggesting a specific role of IL-17+ IH-NK cells in the development of liver inflammation. Conclusions: Our study provides evidence that in human liver, NK cells produce IL-17+ and thus play an active role in shaping the local inflammatory response, in addition of their cytotoxic and regulatory functions. P0506 IMPAIRED HCV-SPECIFIC CYTOTOXIC T CELL REACTIVITY DUE TO 4-1BB SIGNALLING ADAPTER (TRAF1) DOWN-REGULATION DURING PERSISTENT HCV INFECTION IS RESTORED BY IL-7 PLUS 4-1BBL TREATMENT E. Moreno-Cubero1 , E. Sanz-de-Villalobos1 , J. M´ıquel1 , R. Borobia1 , 1 1 S. Garc´ıa-Garzon ´ 1 , A. Lazaro ´ , A. Gonzalez-Pretorious ´ , C. Perna1 , 1 1 1 1 M. Torralba , T. Hocine , J.R. Larrubia . Translational Hepatology Unit, Guadalajara University Hospital. University of Alcal´ a, Guadalajara, Spain E-mail: [email protected] Background and Aims: During persistent hepatitis C virus (HCV) infection, HCV-specific cytotoxic T cell (CTL) response is impaired and featured by IL-7 receptor (CD127) down-regulation. IL-7 could impact on T cell reactivity by regulating 4-1BB signalling adapter (TRAF1). In this study, TRAF-1 expression on HCV-specific CTL according to viral control and, the role of IL-7 on TRAF-1/4-1BB signalling and CTL reactivity were addressed. Methods: Peripheral blood mononuclear cells (PBMC) from 6 healthy donors (HD), 12 HLA-A2+ genotype-1 HCV+ sustained viral responders after treatment (SVR) and 16 HLA-A2+ chronic naïve genotype-1 HCV+ (CHC) patients were obtained. In HD, TRAF1 expression on CD8+ cells according to CD45RO/CCR7 phenotype was tested after either aCD3/aCD28 or IL-7 stimulation. On HCVspecific CTLs from SVR and CHC, directly ex-vivo TRAF1/CD127 expression was tested and proliferation ability and TRAF1 level after specific stimulation without any treatment and in presence of IL-7 and/or 4-1BBL was checked. HCV-specific CTLs were visualised by staining with labelled HLA-A2/epitope multimeric complexes (Pentamer) and CD8 mAb. TRAF1/CD45RO/CCR7/CD127 labelling was performed by staining with different mAb. Flow-cytometric analysis was carried-out. Results: On total CD8+ cells from HD, TRAF1 expression was significantly higher on naïve and central memory T cells than in RA and RO effector memory T cells after aCD3/aCD28 in-vitro challenge (p < 0.05). Interestingly, IL-7 in-vitro treatment increased TRAF1 expression on all CD8 populations (p < 0.05). HCV-specific CTLs (CD8+ /Pentamer+ ) from CHC showed lower CD127 and TRAF1 expression than in SVR (p < 0.01 and p < 0.05, respectively). A positive correlation between CD127 and TRAF1 on CD8+ /Pentamer+ cells was observed (r = 0.7, p < 0.05). HCV-specific CTL proliferation after specific in-vitro challenge was lower in CHC than in SVR (p < 0.05). Specific in-vitro simulation in presence of IL-7/4-1BBL improved HCV-specific CTL proliferation ability in CHC, showing a similar post-treatment TRAF1 expression than SVR, while treatment with either IL-7 or 4-1BBL alone induced a lower effect (p < 0.05). Conclusions: TRAF1 expression is down-regulated on exhausted T cells but IL-7 can induce its up-regulation. In CHC, there is a TRAF1/CD127 down-regulation associated to low reactivity on HCVspecific CTLs. IL-7/4-1BBL treatment can improve HCV-specific CTL response in CHC by TRAF1/4-1BB signalling enhancement.
Journal of Hepatology 2015 vol. 62 | S263–S864
hepatitis B (CHB, n = 10) and healthy controls (HC, n = 10). PBMCs were immunostained before and after stimulating with polyI:C, CpGODN and LPS with flourochrome labelled antibodies. The frequency of myeloid DC’s (mDC) (CD11c+, BDCA1+), plasmacytoid DC’s (pDC’s) (CD123+, BDCA1+), intracellular IFN-g production and expression of DCSIGN, TLR2,3,4 and TLR9 was evaluated. mRNA levels of adaptor molecules of TLR pathway; Myd88, TRAF6 and cytokines IL-2, IL-6, TNF-a, IFN-a was measured by RT-PCR. Results: Frequencies of both subsets of DC’s i.e. mDC’s and pDC’s, were found significantly higher in acute and naïve chronic HBV patients than healthy controls (p < 0.00, p < 0.01) but no difference among AVH-B vs CHB. Functionally impaired DC’s were seen with significant low IFN-g production and low DCSIGN expression (p < 0.04, 0.00) in CHB patients. Even after stimulations by TLR agonist, no changes were found. The adaptor molecule of TLR’s, the MyD88 mRNA levels were also downregulated along with the cytokines IL-6, IFN-a. On follow-up of AVH-B patients, found temporal changes in DC’s while mDC’s frequency was significantly highest at wk 4, whereas pDC’s at wk 6, than wk0 (p < 0.02, 0.01) along with the DCSIGN on mDC’s expression increased linearly from wk 0 to wk 4 during acute phase (wk 0 28% to wk 4 72%, p < 0.00). Conclusions: (i) Subsets of dendritic cells are phenotypically intact but functionally impaired in CHB compared to seroconverted AVH-B patients. (ii) During acute phase pDC’s comes late in generation of effective immune response. (iii) DC SIGN expression is temporally increased in acute phase HBV infection, while is significantly low in CHB, indicating its key role in persistent infection. These novel observations would pave way for prognostication and development of antiviral strategies for chronic HBV infection.
Figure 1. INF-g production was significantly low in persistent CHB patients. No significant difference was found in frequency of mDC’s and pDC’s in acute and chronic HBV infection.
P0504 DE NOVO NUCLEOTIDE BIOSYNTHESIS PATHWAY TIGHTLY REGULATES HEPATITIS E VIRUS INFECTION Y. Wang1 , W. Wang1 , X. Zhou1 , D. Sprengers1 , M.J. Herold1 , M.P. Peppelenbosch1 , Q. Pan1 . 1 Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, Netherlands E-mail: [email protected] Background and Aims: Despite an emerging global health issue, no approved drug is available for treating hepatitis E virus (HEV) infection. Since nucleotides are key components involved in host cell metabolism and virus infection, inhibitors of nucleotide synthesis enzymes may be potential drugs against HEV. Biosynthesis of purine nucleotides requires guanosine, which can
Journal of Hepatology 2015 vol. 62 | S263–S864
S503
POSTERS be phosphorylated into GMP, GDP and GTP. Pyrimidine nucleotides synthesis requires uridine, which can be catalyzed into UDP and UTP. We thus investigated the effects and mechanism-of-action of targeting de novo nucleotide synthesis in cell culture models of HEV infection. Methods: A subgenomic HEV replication model expressing luciferase reporter gene and a full-length infectious model were used. Results: Supplementation of exogenous guanosine, but not uridine, promoted HEV replication in both subgenomic (2.6fold) and infectious (2.0-fold) models. We thus focused on sequentially targeting key enzymes involved in purine synthesis pathway. Surprisingly, 6-thiohuanine, an inhibitor of Amido phosphoribosyltransferase (APRTase), stimulated HEV replication by 3.6±0.87 folds (Mean±SEM, n = 10, P < 0.0001). Lometrexol, an inhibitor of GAR Transformylase, also promoted HEV replication in both models. ATIC is a bifunctional protein that exerts AICAR transformylase activity and IMP cyclohydrolase activity in this pathway. Methotrexate (MTX) and Fludarabine (FA) are inhibitors of AICAR transformylase and IMP cyclohydrolase, respectively. Both compounds potently increased HEV genome RNA by 5.01±1.4fold and 5.06±0.3-fold, respectively (n = 5, P < 0.05). Consistently, silencing of ATIC resulted in dramatic increase of HEV RNA by 4.2±2.5-fold and abolished the ability of MTX to activate HEV. This demonstrated that ATIC has anti-HEV activity, which explains the proviral effects of MTX and FA. However, Mycophenolic acid (MPA), an inhibitor of inosine monophosphate dehydrogenase (IMPDH), could effectively inhibit HEV replication by 65% (10 ug/ml). Conclusions: Purine but not pyrimidine synthesis pathway regulates HEV infection. Unexpectedly, targeting the early steps of this pathway led to enhancement of HEV infection. Whereas targeting the late step (IMPDH enzyme) resulted in potent antiviral activity against HEV. P0505 IDENTIFICATION OF IL-17 POSITIVE INTRAHEPATIC NK CELLS IN HUMAN LIVER AND RELATIONSHIP WITH CHRONIC LIVER DISEASES Z. Macek Jilkova1,2 , H. Marche1,2 , C. Gierczak2 , V. Leroy1,2,3 , J.-P. Zarski1,2,3 , T. Decaens1,2,3 , P.N. Marche1,2 , N. Sturm1,2,4 , E. Jouvin-Marche1,2 . 1 INSERM U823, 2 Univ. Grenoble Alpes, IAB, 3 D´epartement d’H´epato-Gastro-Ent´erologie, 4 D´epartement d’Anatomie et de Cytologie Pathologiques, CHU-Grenoble, Grenoble, France E-mail: [email protected] Background and Aims: The production of pro-inflammatory IL-17 cytokine plays an important role in many inflammatory diseases and is not restricted to Th17 cells. However, in liver diseases, it has not yet been investigated if intrahepatic (IH)-natural killer (NK) cells, the major subset of innate immune cells, produce IL-17 and thereby contribute to liver inflammation. Methods: To analyze production of IL-17 by IH-immune cells, we performed flow cytometry analyses of fresh liver biopsies from 54 patients: NASH, HCV and HBV-infected and non-inflammatory subjects. Localization of IL-17+ NK cells was studied by double immunohistochemical and triple immunofluorescence analyses. Frequency of IL-17 producing NK cell was compared with INFg production and correlated with clinical parameters. Results: Flow cytometry analyses revealed that, in addition to T lymphocytes, IH-NK and IH-NKT cells produced IL-17 cytokine with frequency from 0.1% to 6.0%, depending on liver environment. The population of IL-17+ IH-NK cells was significantly higher compared to IFNg producing IH-NK cells (p = 0.009) and mainly specific to the NKp46+ NK cells subset (p < 0.001). Immunohistology of livers showed that 85% of IL-17+ NKp46+ IH-NK cells were localized in septal or portal fibrous area. Finally, the proportion of IH-NK cells producing IL-17 increased during the critical A2 Metavir necroS504
inflammatory grade, suggesting a specific role of IL-17+ IH-NK cells in the development of liver inflammation. Conclusions: Our study provides evidence that in human liver, NK cells produce IL-17+ and thus play an active role in shaping the local inflammatory response, in addition of their cytotoxic and regulatory functions. P0506 IMPAIRED HCV-SPECIFIC CYTOTOXIC T CELL REACTIVITY DUE TO 4-1BB SIGNALLING ADAPTER (TRAF1) DOWN-REGULATION DURING PERSISTENT HCV INFECTION IS RESTORED BY IL-7 PLUS 4-1BBL TREATMENT E. Moreno-Cubero1 , E. Sanz-de-Villalobos1 , J. M´ıquel1 , R. Borobia1 , 1 1 S. Garc´ıa-Garzon ´ 1 , A. Lazaro ´ , A. Gonzalez-Pretorious ´ , C. Perna1 , 1 1 1 1 M. Torralba , T. Hocine , J.R. Larrubia . Translational Hepatology Unit, Guadalajara University Hospital. University of Alcal´ a, Guadalajara, Spain E-mail: [email protected] Background and Aims: During persistent hepatitis C virus (HCV) infection, HCV-specific cytotoxic T cell (CTL) response is impaired and featured by IL-7 receptor (CD127) down-regulation. IL-7 could impact on T cell reactivity by regulating 4-1BB signalling adapter (TRAF1). In this study, TRAF-1 expression on HCV-specific CTL according to viral control and, the role of IL-7 on TRAF-1/4-1BB signalling and CTL reactivity were addressed. Methods: Peripheral blood mononuclear cells (PBMC) from 6 healthy donors (HD), 12 HLA-A2+ genotype-1 HCV+ sustained viral responders after treatment (SVR) and 16 HLA-A2+ chronic naïve genotype-1 HCV+ (CHC) patients were obtained. In HD, TRAF1 expression on CD8+ cells according to CD45RO/CCR7 phenotype was tested after either aCD3/aCD28 or IL-7 stimulation. On HCVspecific CTLs from SVR and CHC, directly ex-vivo TRAF1/CD127 expression was tested and proliferation ability and TRAF1 level after specific stimulation without any treatment and in presence of IL-7 and/or 4-1BBL was checked. HCV-specific CTLs were visualised by staining with labelled HLA-A2/epitope multimeric complexes (Pentamer) and CD8 mAb. TRAF1/CD45RO/CCR7/CD127 labelling was performed by staining with different mAb. Flow-cytometric analysis was carried-out. Results: On total CD8+ cells from HD, TRAF1 expression was significantly higher on naïve and central memory T cells than in RA and RO effector memory T cells after aCD3/aCD28 in-vitro challenge (p < 0.05). Interestingly, IL-7 in-vitro treatment increased TRAF1 expression on all CD8 populations (p < 0.05). HCV-specific CTLs (CD8+ /Pentamer+ ) from CHC showed lower CD127 and TRAF1 expression than in SVR (p < 0.01 and p < 0.05, respectively). A positive correlation between CD127 and TRAF1 on CD8+ /Pentamer+ cells was observed (r = 0.7, p < 0.05). HCV-specific CTL proliferation after specific in-vitro challenge was lower in CHC than in SVR (p < 0.05). Specific in-vitro simulation in presence of IL-7/4-1BBL improved HCV-specific CTL proliferation ability in CHC, showing a similar post-treatment TRAF1 expression than SVR, while treatment with either IL-7 or 4-1BBL alone induced a lower effect (p < 0.05). Conclusions: TRAF1 expression is down-regulated on exhausted T cells but IL-7 can induce its up-regulation. In CHC, there is a TRAF1/CD127 down-regulation associated to low reactivity on HCVspecific CTLs. IL-7/4-1BBL treatment can improve HCV-specific CTL response in CHC by TRAF1/4-1BB signalling enhancement.
Journal of Hepatology 2015 vol. 62 | S263–S864