Alternatively, it is possible that Treg-associated cytokine blockade in rapid

progressors did not increase effector HCV-specific T-cell responses because T cells became anergic upon long-term immunosuppression. However, no differences in effector HCV-specific T-cell responses were observed between the groups without Treg cytokine blockade or in response to mitogen. The immunosuppressive effect appeared to be predominantly mediated by HCV-specific TGFβ rather than IL-10. This is consistent with our previous results with a different cohort of HCV subjects, where blocking TGFβ significantly increased IFNγ response to HCV, whereas IL-10 blockade did not have a significant effect,25 confirming the predominant involvement of TGFβ in this suppressive activity, rather than IL-10. T-cell secretion of TGFβ in response to HCV check details has been described for CD4+CD25+22 and CD8+CD25-Foxp3−25 Tregs in subjects with CHC and an antiinflammatory role for TGFβ during chronic HCV infection has been suggested.22 Interestingly, in HCV-HIV coinfection, high levels of plasma TGFβ, but not CD4+Foxp3+ cells, is associated

INCB024360 with low levels of liver fibrosis.33 Here, we provide a plausible mechanistic explanation for this observation, because we studied HCV-specific TGFβ T-cell production in relation to liver inflammation and fibrosis. Not only do we confirm an inverse correlation of HCV-specific TGFβ (not IL-10) with histological liver inflammation, but we also found significant inverse correlation with liver fibrosis stage and progression. Together, these findings support the hypothesis that locally HCV-specific T-cell-produced TGFβ may play a role in controlling the chronic inflammatory response,

and consequently may even have an antifibrotic role, thereby attenuating hepatic scarring in chronic HCV infection. Intriguingly, MCE公司 our data also suggest involvement of IL-17 as antifibrotic in this setting, because we found a strong inverse correlation of liver fibrosis stage with HCV-specific IL-17. Other cytokines that we found in substantial amounts in HCV-stimulated supernatants, IL-1β and IL-6, might be concurrently expressed in vivo and influence T-cell lineage commitment. Together, these observations underline the complexity of the system, because IL-17 is a proinflammatory cytokine and TGFβ, generally assumed to be antiinflammatory, can become proinflammatory in combination with other cytokines such as IL-1 and IL-6.26, 34 In this context the ability of TGFβ-producing Treg to readily lose Foxp3 and acquire IL-17 expression in Th17-polarizing conditions has been described.34, 35 Because of the lack of definitive surface marker(s) for TGFβ-producing Treg, and therefore, currently an absence of methods allowing their depletion, direct demonstration of the effect of their elimination was not possible.

4D). In contrast, there were no detectable α-SMA-positive cells in PBS/CFA/2-OA, α-GC, or α-GC/CFA control mice (Fig. 4E). PBS/CFA/2-OA controls had minimal to mild (score = 1-2) liver inflammation, portal inflammation, and bile duct damage. Three of nine PBS/CFA/2-OA controls had minimal selleck chemical (score

= 1) granulomas (Fig. 4C; Table 1). Ductular proliferation was also found in 7/9 PBS/CFA/2-OA controls (Table 1). Only 1/9 PBS CFA/2-OA mice had fibrosis (Fig. 4D; Table 1). α-GC and α-GC/CFA control mice had none to minimal (score = 0-1) liver inflammation, portal inflammation, bile duct damage, or granulomas. Only one α-GC/CFA mouse had any evidence of fibrosis, and that was mild. The total liver mononuclear cell infiltrates were higher in α-GC/CFA/2-OA mice as compared to that of PBS/CFA/2-OA, α-GC, and α-GC/CFA control mice (Fig. 5A). In addition, significantly increased numbers of conventional T (CD3+ NK1.1−) cells and B cells were noted in α-GC/CFA/2-OA mice (Fig. 5B). Importantly, significantly increased frequency and absolute numbers of CD8+ T cells were noted in α-GC/CFA/2-OA mice compared to that of PBS/CFA/2-OA mice (Fig. 5C). Our previous Belinostat purchase work in human PBC and in the dnTGF-βRII mouse model of PBC suggested that activation of

iNKT cells is a critical factor in accelerating disease.18-20 However, the mechanism is still unknown. In the present study we investigated the effects of activated iNKT cells stimulated with α-GalCer in the pathogenesis of murine PBC by xenobiotic chemical immunization. α-GalCer injection exacerbated autoimmune cholangitis in 2-OA-BSA-immunized mice, including increased AMA medchemexpress production, portal inflammation, and bile duct damage. Our data suggest that iNKT cell activation is a critical factor in modulating the natural history of PBC. We note that human PBC has a long latency time. For example,

serum AMAs precede disease by many years.1, 23 The results herein suggest that the evolution from subclinical to clinical disease, i.e., from an adaptive to an overwhelming innate or bystander response, may depend on exposure to a natural ligand that activates NKT cells. It is important to note that this model has been based on a careful selection of the immunogen, 2-OA. We have previously performed a quantitative structural activity relationship analysis and rigorous epitope analysis of human PBC sera against extensive panels of chemicals that were coupled to the lysine residue (137K) of PDC-E2.8-10, 24, 25 The advantage of this study is the ability to elucidate the early events of autoimmune cholangitis. Our data imply that PBC requires loss of tolerance to PDC-E2 and thus an adaptive multilineage antimitochondrial response. However, it also includes an overwhelming innate immune response and we submit that the innate immune response, combined with the unique biologic properties of bile duct cells and apotopes, are sufficient to explain the recurrence of PBC following liver transplantation.

Comparisons with the other breeding colonies of NZ sea lions are presented and data are discussed in the context of the recolonization of the NZ mainland. Overall, the most suitable terrestrial habitat configuration for a breeding aggregation of NZ sea lions appears to be a sandy beach, with a wide area above high tide and moderate intertidal zone (for breeding), backed with vegetated

sand dunes and forest on primarily flat terrain (for later dispersion). “
“Toothed whales (crown Odontoceti) are unique among mammals in their ability to echolocate underwater, using specialized tissue structures. The melon, a structure composed of fat and connective tissue, is an important selleck chemicals component in the production of an echolocation beam; it is known to focus high frequency, short duration echolocation clicks. Here, we report on the morphology of the odontocete melon to provide a comprehensive understanding of melon structure across odontocete taxa. This study examined nine odontocete species (12 individual specimens), from five of the ten extant odontocete families. We established standardized definitions using computed tomography scans of the melon to investigate structure without losing geometric integrity. The morphological features that relate to the focusing capacity of the melon include internal density

topography, melon size and shape, and relationship to other forehead structures. The potential for melon structure to act as a 5-Fluoracil filter is discussed: establishing a lower limit

to the frequency of sounds that can be propagated through the head. Collectively, the results of MCE this study provide a robust, quantitative and comparative framework for evaluating tissue structures that form a key component of the echolocation apparatus. “
“Many pinniped populations precipitously declined during the 19th and 20th centuries due to overharvesting. In Uruguay, the South American sea lion (SASL) was harvested until 1986. Birth rates in two nearby breeding colonies have had opposite trends for at least 20 yr. We assessed different mechanisms that could explain opposite trends in birth rates in the two SASL colonies. We compared feeding habits (δ15N and δ13C) of breeding females, birth mass, individual growth rate and early survival of pups and the social structure between colonies. Breeding females from the two colonies did not differ in their feeding habits. However, male and female pups grew faster but had a lower survival in the second month in the smallest colony. We found differences in the social structures, with a higher proportion of males in the smallest colony. The latter is important because peripheral SASL males may abduct and kill pups, which may explain the lower survival of pups in smaller colonies.

[83-85] IFNβ is a natural non-pegylated agent that is administered three or more times per week either by intravenous injection or infusion. IFNβ binds to the same type I IFN receptors as IFNα and exhibits the same antiviral effect, but with a different adverse reaction profile. It is recommended for patients affected by depression who are considered unsuitable for IFNα. In a meta-analysis (n = 837) of randomized clinical controlled trials conducted overseas in 1993, the

IFN therapy group had an HBeAg negative conversion rate of 33% and an HBV DNA negative conversion rate of 37%. The corresponding rates for the untreated group were 12% and 17% respectively. These findings demonstrate the benefit of IFN therapy.[86] AZD8055 manufacturer Negative conversion for HBsAg was also higher at 7.8% for the IFN group compared to 1.8% for the untreated group. Sustained ongoing HBeAg seroconversion was observed in almost 90% of Navitoclax mw cases, as well as delayed seroconversion (occurring one or two years after the conclusion of therapy) in 10%–15% of cases.[87-89] Thus, in cases where IFN therapy in HBeAg positive patients successfully bring about HBeAg seroconversion, there is an ongoing effect that acts to hinder progression to cirrhosis and HCC, and the prognosis is therefore much improved.[90] Reports from Asia however suggest that the effect is not sustained

in the long term, with negative conversion of HBsAg being relatively rare.[87, 90] This may be attributable to host-specific factors such as race as well as genotype, infection period, and route of infection. Collation of 24 studies of therapeutic outcomes in HBeAg positive patients with chronic hepatitis B in Japan[91] yielded HBeAg negative conversion rates of 29% after one year of IFN therapy and 55% after two years, and HBeAg seroconversion rates of 12% after one year and 29% after two years. These figures are higher than the corresponding natural conversion rates of 10% and 5% respectively, indicating the efficacy of IFN therapy. However, there have

also been reports of cases that revert to HBeAg positive status after completion of treatment, and hepatitis fails to subside. It should be noted that at the time these studies were conducted, most IFN MCE therapy regimens in Japan lasted only four weeks. With a longer IFN treatment regimen, the HBeAg negative conversion rate six months after the completion of the therapy is considerably higher at 29%.[91] Japanese national medical insurance does not cover conventional IFN therapeutic agents for the treatment of HBeAg negative chronic hepatitis B. Overseas studies, mainly from Europe, report impressive biochemical and virological therapeutic benefit rates of 60%–90% in HBeAg negative patients following IFN therapy.

Severity of histological damage was graded according to the strength of inflammatory PLX3397 cell infiltration and liver cellular necrosis. TNF-α and INF-γ levels in supernatant fluid released from

lymphocytes of the spleens were also measured. Results: Results: The EAIHs induced by peak II protein plus CFA and S100 plus CFA had significantly higher histological grades (2.8 and 2.6 on average) than those induced by peak I proteins plus CFA and peak III proteins plus CFA or by CFA alone and saline alone (2.2, 1.6, 1.0 and 0.2 respectively) (p < 0.05). T-cell reactivity increased after the stimulation with hapten peak I protein as compared with those of other groups. TNF-α and INF-γ levels in supernatant fluid from the lymphocytes of the spleens were increased significantly with the development of EAIH (p < 0.05). Conclusion: Conclusion:

Syngeneic hapten protein S100, and its three VX809 separated peak proteins had different immunopathological potentials on the pathogenesis of EAIH with peak II protein being more liver-specific than the others. Key Word(s): 1. liver; 2. antoimmune; 3. autoantigen; Presenting Author: WEIMIN XU Corresponding Author: WEIMIN XU Affiliations: Gastroenteroiogy Objective: To investigate the clinical value of detection of autoantibodies in 103 patients with elevated liver enzymes. Methods: three group patients (103 patients with elevated liver enzymes,85 patients with chronic hepatitis B, 80 healthy subjects) were examined for autoantibodies respectively. Antinuclear antibody (ANA), antimitochondrial antibody (AMA) and anti-smooth muscle antibody (SMA) were tested by indrect immunofluorescence; Antibodies to soluble liver antigen/liver

pancreas (SLA/LP), liver kidney microsomal type 1(LKM-1), liver cytosol type 1(LC-1) and mitochondrial type II (AMA-M2) were tested by Western blot. Results: Among 103 patients with elevated liver enzymes, LKM-1 was positive in 2 patients and SLA/LP in 1 patient and AMA-M2 in 3 patients. The positive rates of ANA, AMA, SMA in chronic hepatitis B group were 12.9%, 1.1%, 2.3% respectively; that in patients with elevated liver enzymes group were 34.9%, 8.7%, 12.6% respectively; that MCE公司 in control group were 5.0%, 0, 0 respectively. The positive rates of ANA, AMA, SMA in chronic hepatitis B group and in patients with elevated liver enzymes group were significantly increased as compared with those of control group (p < 0.05). 6 patients with primary biliary cirrhosis (PBC) and 4 patients with autoimmune hepatitis (AIH) were diagnosed in 103 patients with elevated liver enzymes. Conclusion: The autoantibodies detection in patients with elevated liver enzymes has an important significance in clinical diagnosis.

Severity of histological damage was graded according to the strength of inflammatory 17-AAG mouse cell infiltration and liver cellular necrosis. TNF-α and INF-γ levels in supernatant fluid released from

lymphocytes of the spleens were also measured. Results: Results: The EAIHs induced by peak II protein plus CFA and S100 plus CFA had significantly higher histological grades (2.8 and 2.6 on average) than those induced by peak I proteins plus CFA and peak III proteins plus CFA or by CFA alone and saline alone (2.2, 1.6, 1.0 and 0.2 respectively) (p < 0.05). T-cell reactivity increased after the stimulation with hapten peak I protein as compared with those of other groups. TNF-α and INF-γ levels in supernatant fluid from the lymphocytes of the spleens were increased significantly with the development of EAIH (p < 0.05). Conclusion: Conclusion:

Syngeneic hapten protein S100, and its three SCH 900776 order separated peak proteins had different immunopathological potentials on the pathogenesis of EAIH with peak II protein being more liver-specific than the others. Key Word(s): 1. liver; 2. antoimmune; 3. autoantigen; Presenting Author: WEIMIN XU Corresponding Author: WEIMIN XU Affiliations: Gastroenteroiogy Objective: To investigate the clinical value of detection of autoantibodies in 103 patients with elevated liver enzymes. Methods: three group patients (103 patients with elevated liver enzymes,85 patients with chronic hepatitis B, 80 healthy subjects) were examined for autoantibodies respectively. Antinuclear antibody (ANA), antimitochondrial antibody (AMA) and anti-smooth muscle antibody (SMA) were tested by indrect immunofluorescence; Antibodies to soluble liver antigen/liver

pancreas (SLA/LP), liver kidney microsomal type 1(LKM-1), liver cytosol type 1(LC-1) and mitochondrial type II (AMA-M2) were tested by Western blot. Results: Among 103 patients with elevated liver enzymes, LKM-1 was positive in 2 patients and SLA/LP in 1 patient and AMA-M2 in 3 patients. The positive rates of ANA, AMA, SMA in chronic hepatitis B group were 12.9%, 1.1%, 2.3% respectively; that in patients with elevated liver enzymes group were 34.9%, 8.7%, 12.6% respectively; that MCE公司 in control group were 5.0%, 0, 0 respectively. The positive rates of ANA, AMA, SMA in chronic hepatitis B group and in patients with elevated liver enzymes group were significantly increased as compared with those of control group (p < 0.05). 6 patients with primary biliary cirrhosis (PBC) and 4 patients with autoimmune hepatitis (AIH) were diagnosed in 103 patients with elevated liver enzymes. Conclusion: The autoantibodies detection in patients with elevated liver enzymes has an important significance in clinical diagnosis.

The top 10 ions that were significantly altered in MCD diet–treated mice selected by contribution analysis are listed in Table 1. Of these, the top three decreased ions were 1-palmitoyl-sn-glycero-3-phosphocholine

(palmitoyl-lysophosphatidylcholine [LPC]; 16:0-LPC), 1-stearoyl-sn-glycero-3-phosphocholine (stearoyl-LPC; 18:0-LPC), and 1-oleoyl-sn-glycero-3-phosphocholine (oleoyl-LPC; 18:1-LPC) (d1, d2, and d3 in Fig. 1B, respectively). Serum 16:0-, 18:0-, and 18:1-LPC levels in MCD diet–treated mice were significantly decreased to approximately 40%, 30%, and 15%, respectively, of such levels in MCS diet–treated mice (Fig. 1C). Furthermore, the top three increased ions were tauro-β-muricholate, tauocholate, and 12-hydroxyeicosatetraenoic acid (12-HETE) (i1, i2, and i3 in Fig. 1B, respectively, and Fig. 1C). Similar results were obtained using AZD6244 price the UPLC-ESI-QTOFMS find more positive mode data (data not shown). To rule out the possibility that such

metabolite changes are simply the result of advancement of NASH, the same analysis was performed using mice with 2-week MCD and MCS diet treatment. PCA showed clear separation between the two groups (Fig. 2A). The top 10 ions that changed in the MCD diet–treated mice are listed in Supporting Table 2. Interestingly, the top three increased and decreased ions were completely identical to those in the 8-week MCD diet treatment: decreased ions were 16:0-LPC, 18:0-LPC, and 18:1-LPC (d1, d2, and d3 in Fig. 2B, respectively, and Fig. 2C),

and increased ions were tauro-β-muricholate, tauocholate, and 12-HETE (i1, i2, and i3 in Fig. 2B, respectively, and Fig. 2C). These results indicate that MCD diet treatment significantly decreases serum LPC levels and increases serum levels of bile acids and 12-HETE. To determine the mechanism of the changes in metabolites, hepatic mRNA levels of the genes associated with LPC metabolism were examined in mice treated with the MCD diet for 8 weeks. LPC is catabolized by lysophosphatidylcholine acyltransferase (Lpcat) 1-4, lysophospholipase A1 (Lypla1), and ectonucleotide pyrophosphatase/phosphodiesterase 2 (Enpp2). Of these, the mRNAs encoding Lpcat1-4, key enzymes that convert LPC into phosphatidylcholine (PC; i.e., Lands’ cycle), were significantly increased in MCD MCE diet–treated mice (Fig. 3A). The mRNA levels of Lypla1, Enpp2, and lecithin cholesterol acyltransferase (Lcat), an enzyme that converts PC into LPC, did not differ between the groups. These results suggest that decreased serum LPC is associated with hepatic up-regulation of Lpcat1-4. Next, hepatic mRNA levels of the genes related to bile acid metabolism were measured. The mRNAs encoding cholesterol 7α-hydroxylase (Cyp7a1) and 8β-hydroxylase (Cyp8b1) were unchanged, and those encoding sterol 27-hydroxylase (Cyp27a1) were decreased by MCD diet treatment (Fig. 3B).

Moreover, inhibition of BRAF signaling with a selective BRAF inhibitor (PLX4720) induced ERK activation without any cyto-toxicity in HCC cells. Co-immunoprecipitation Selleckchem Vemurafenib revealed that sorafenib-induced ERK activation was a result of BRAF heterod imerization with CRAF. The activation of ERK

after sorafenib was confirmed in vivo in spontaneous models of HCC. Moreover, combination treatment with sorafenib and selumetinib delayed primary tumor growth, while monotherapy of selume-tinib did not inhibit tumor growth. Gene silencing with siRNA of CRAF or ERK in combination with sorafenib also delayed primary tumor growth, but RNA interference of either CRAF or ERK did not affect the tumor growth. We found that cell apop-tosis (evaluated by TUNEL staining) was increased when siRNA for CRAF was combined with sorafenib in tumors, while siRNA for CRAF alone did not increase

apoptosis in vivo. Conclusion: We demonstrate that HCC cell viability is independent PD-0332991 purchase of RAF/ ERK activity. Sorafenib treatment leads to RAF dimerization, ERK activation and converts HCC cell survival dependence on the RAF/MEK/ERK pathway. Thus, reversing the drug-induced mechanism of resistance using MEK inhibitors such as selume-tinib may increase the efficacy of sorafenib in HCC. Disclosures: Thomas Reiberger – Grant/Research Support: Roche, Gilead, MSD, Phenex; Speaking and Teaching: Roche, Gilead, MSD Rakesh K. Jain – Board Membership: XTuit, H&Q Healthcare Investors, H&Q Life Sciences Investors; Consulting: Enlight Biosciences,

Noxxon, Zyngenia; Grant/ Research Support: Dyax, MedImmune, Roche; Stock Shareholder: Enlight Biosci-ences, SynDevRx, XTuit Dan G. Duda – Advisory Committees or Review Panels: Hexal The following people have nothing to MCE公司 disclose: Rakesh R. Ramjiawan, Yunching Chen, Annique M. Duyverman, Peigen Huang, Keith Flaherty, Andrew X. Zhu Background. Cholangiocarcinoma (CCA) is an aggressive liver malignancy characterized by early and strong invasiveness. We have recently showed that S100A4 protein is a major determinant of CCA invasiveness when expressed in the nucleus of CCA cells. We aimed at studying whether manipulation of S100A4 nuclear expression by Paclitaxel (PTX), a microtubule stabilizing agent, hampers CCA cell invasiveness both in vitro and in vivo. Methods. Human CCA cells expressing nuclear S100A4 were treated with PTX at increasing doses. We studied nuclear and cytosolic expression of S100A4, cyto-skeletal integrity, cell proliferation, apoptosis, motility and inva-siveness. Functional effects of PTX were tested on the activity of Rho GTPases. CCA cells were xenotrasplantated in SCID mice by spleen injection. Once tumor engraftment was confirmed by bioluminescence imaging, mice were treated with PTX at 2 different low-dose metronomic regimens (1,3 and 2,6mg/kg/ die) for 14 days and compared with non-treated mice (n=5 for each group).

Steady-state was achieved within 5 days of MK-87425-100 mg QD administration. KPT-330 manufacturer The range of accumulation ratios (day 5/1) for AUC0-24hr was 1.2-3.0. MK-8742 was generally well-tolerated, with all AEs transient and mild in intensity. The most common AE was headache. There were no clinically significant laboratory abnormalities, changes in vital signs or ECG readings. Conclusions: MK-8742 exhibits potent antiviral activity during 5 days of monotherapy in patients with GT-1 and GT-3 chronic HCV infection. The

safety, pharmacokinetics, and antiviral data support the continued clinical investigation of MK-8742 as a once-daily component of an all-oral, interferon-free regimen for the treatment of chronic HCV-infection. Disclosures: Wendy W. Yeh – Employment: Ipilimumab research buy Merck & Co. Patricia Jumes – Employment: Merck; Stock Shareholder: Merck Inge M. De Lepeleire – Management Position: MSD (Europe) Inc. ; Stock Shareholder: Merck & co., Inc. Luzelena Caro – Employment: Merck & Co., Inc. Eric Mangin – Employment: Merck & Co., Inc. Robert B. Nachbar – Employment: Merck Sharp & Dohme Corp.; Stock Shareholder: Merck Sharp &

Dohme Corp. Edward J. Gane-Advisory Committees or Review Panels: Roche, AbbVie, Novartis, Tibotec, Gilead Sciences, Janssen Cilag, Vertex, Achillion; Speaking and Teaching: Novartis, Gilead Sciences, Roche Joan R. Butterton – Employment: Merck Sharp & Dohme Corp.; Stock Shareholder: Merck Sharp & Dohme Corp. The following people have nothing to disclose: Concetta Lipardi, Nick Van Den Bulk, Xiaobi Huang, Serghei Popa, Nelea Ghicavii, Frank D. Wagner About 3 % of world population is persistently infected with hepatitis C virus (HCV) and at increased risk of fatal chronic liver diseases such as cirrohsis and hepatocellular carcinoma. Because the efficacy of current therapy with pegylated IFN and ribavirin is insufficient and depends medchemexpress in part on viral genotypes, there is great interest in development

of novel HCV-specific inhibitors. The development of new molecule that targets HCV protein called direct-acting antivirals is ongoing. Nonstructural protein 5A (NS5A) of HCV plays multiple and diverse roles in the viral lifecycle, and is currently recognized as a novel target for anti-viral therapy. In 2010, the first-generation NS5A inhibitor has been reported as to reduce the viral titer significantly after oral administration. However, it shows limited effects on genotype 2 HCV strains other than JFH-1 strain in cell culture system. Recently, to overcome this disadvantage, the second-generation NS5A inhibitors have been developed. The aim of this study was to evaluate the genotype-specific antiviral effects of these novel NS5A inhibitors. To assess the genotype-specificity of NS5A inhibitors, recombinant JFH-1 viruses replaced with NS5A of genotypes 1 (H77; 1a and Con1; 1b) and 2 (J6CF; 2a, MA; 2b and J8; 2b) were used.

Steady-state was achieved within 5 days of MK-87425-100 mg QD administration. Idasanutlin supplier The range of accumulation ratios (day 5/1) for AUC0-24hr was 1.2-3.0. MK-8742 was generally well-tolerated, with all AEs transient and mild in intensity. The most common AE was headache. There were no clinically significant laboratory abnormalities, changes in vital signs or ECG readings. Conclusions: MK-8742 exhibits potent antiviral activity during 5 days of monotherapy in patients with GT-1 and GT-3 chronic HCV infection. The

safety, pharmacokinetics, and antiviral data support the continued clinical investigation of MK-8742 as a once-daily component of an all-oral, interferon-free regimen for the treatment of chronic HCV-infection. Disclosures: Wendy W. Yeh – Employment: Small molecule library Merck & Co. Patricia Jumes – Employment: Merck; Stock Shareholder: Merck Inge M. De Lepeleire – Management Position: MSD (Europe) Inc. ; Stock Shareholder: Merck & co., Inc. Luzelena Caro – Employment: Merck & Co., Inc. Eric Mangin – Employment: Merck & Co., Inc. Robert B. Nachbar – Employment: Merck Sharp & Dohme Corp.; Stock Shareholder: Merck Sharp &

Dohme Corp. Edward J. Gane-Advisory Committees or Review Panels: Roche, AbbVie, Novartis, Tibotec, Gilead Sciences, Janssen Cilag, Vertex, Achillion; Speaking and Teaching: Novartis, Gilead Sciences, Roche Joan R. Butterton – Employment: Merck Sharp & Dohme Corp.; Stock Shareholder: Merck Sharp & Dohme Corp. The following people have nothing to disclose: Concetta Lipardi, Nick Van Den Bulk, Xiaobi Huang, Serghei Popa, Nelea Ghicavii, Frank D. Wagner About 3 % of world population is persistently infected with hepatitis C virus (HCV) and at increased risk of fatal chronic liver diseases such as cirrohsis and hepatocellular carcinoma. Because the efficacy of current therapy with pegylated IFN and ribavirin is insufficient and depends MCE公司 in part on viral genotypes, there is great interest in development

of novel HCV-specific inhibitors. The development of new molecule that targets HCV protein called direct-acting antivirals is ongoing. Nonstructural protein 5A (NS5A) of HCV plays multiple and diverse roles in the viral lifecycle, and is currently recognized as a novel target for anti-viral therapy. In 2010, the first-generation NS5A inhibitor has been reported as to reduce the viral titer significantly after oral administration. However, it shows limited effects on genotype 2 HCV strains other than JFH-1 strain in cell culture system. Recently, to overcome this disadvantage, the second-generation NS5A inhibitors have been developed. The aim of this study was to evaluate the genotype-specific antiviral effects of these novel NS5A inhibitors. To assess the genotype-specificity of NS5A inhibitors, recombinant JFH-1 viruses replaced with NS5A of genotypes 1 (H77; 1a and Con1; 1b) and 2 (J6CF; 2a, MA; 2b and J8; 2b) were used.