The secondary outcome was two-year cirrhosis-related mortality T

The secondary outcome was two-year cirrhosis-related mortality. The study

was approved by the Partners Human Research Committee (protocol 2012P001912). Results: Seventy-eight patients (19.7%) had at least one cirrhosis-related hospital admission within one year. The following were significant predictors in the multivariable model (Table 1): Model for End-Stage Liver Disease (MELD) score > 15, diagnosis of hepatocellular carcinoma (HCC), diuretic use, at least one cirrhosis-related admission during the check details baseline year, and being unmarried. Conclusions: Higher MELD score and diuretic use were associated with cirrhosis-related hospital admissions in an ambulatory cirrhosis cohort. Our findings suggest that patients with

inadequately or overzealously treated ascites could benefit from intensified outpatient management aimed at chronic disease management and reducing preventable admissions. Disclosures: James M. Richter – Consulting: Axcan Pharma Raymond T. Chung – Advisory Committees or Review Panels: Idenix; Consulting: Enanta; Grant/Research Support: Gilead, Merck, Mass Biologic, Gilead The following people have nothing to disclose: Kara B. Johnson, Emily J. Campbell, Heng Chi, Hui Zheng, Lindsay Y. King, Ying Wu, Andrew deLemos, Abu Selleck EPZ-6438 Hurairah, Kathleen E. Corey BACKGROUND: The ECHO model allows for the treatment of hepatitis C by primary care providers in remote rural sites with ongoing teleconferencing support. Current therapy, particularly with the addition of protease inhibitors, involves increasingly complex management of response milestones and adverse event management. HCVNET Arizona is a Project ECHO site focused around a 14 site FQHC based in Flagstaff. Because of the rapid growth in patient numbers and treatment sites, it was elected to define specific starting dates at which all patients being readied for treatment would receive their first pegylated interferon injection. This allowed for each patient at each site to obtain their laboratory studies on the same day of the week and have their side

effects managed and their treatment milestones coordinated simultaneously across the treatment network. This approach afforded the opportunity Metformin molecular weight to coordinate all associated treatment activities such as pre-treatment work-up, patient training, and medication authorization. METHODS: A total of five cohorts among twelve sites have thus far been initiated at 2 month intervals with an average of 8 patients per cohort. No single clinic site had more than 3 patients starting at any one time. 70% of patients were genotype 1 and received telaprevir-based therapy. The hepatology team at St. Joseph’s Hospital and Medical Center teleconferences with all providers on a weekly basis every Wednesday. Patients generally had complete blood counts and chemistry panels drawn on the prior Mondays. Each patient is then reviewed with the local provider during the teleconference.

Patel, Christine Bernsmeier, Jennifer M Ryan, Laura J Blackmore

Patel, Christine Bernsmeier, Jennifer M. Ryan, Laura J. Blackmore, Xiaohong Huang, Victoria T. Kronsten, Nicholas J. Taylor, Georg Auzinger, Christopher Willars, Yun Ma, Barbara Bain, Alice Warley Background: Acute-on-chronic liver failure (ACLF) is associated with increased short and long-term mortality. Currently, orthotropic

liver transplantation remains the only definitive therapy for patients with ACLF. Several animal models of liver failure have demonstrated that granulocytecolony Rucaparib stimulating factor (G-CSF) accelerates the liver regeneration process and improves survival. The objective of this systematic review was to assess the benefits and harms of G-CSF in patients with acute-on-chronic liver failure. Material and methods: The research

was made in The Cochrane Central Register of Controlled Trials (CENTRAL), MEDLINE, EMBASE and LILACS until November 2013. Additionally, the references from the identified studies were handsearched. Randomized clinical trials comparing the use of G-CSF against placebo or no intervention in patients with ACLF were selected. Three authors independently assessed the quality of the studies, evaluated the risk of bias, and extracted the data. Results: Two trials with a total of 102 patients were included. One trial compared the use of G-CSF against Selleckchem SB525334 placebo. The second trial compared G-CSF against no intervention. Compared with the control group, the group that received G-CSF presented a significant reduction in short-term mortality (RR 0.56; 95% CI 0.39 to 0.80). There is not enough evidence PAK5 to show an effect of G-CSF therapy on mortality secondary to gastrointestinal bleeding (RR 1.45; 95% CI 0.50 to 4.27). The adverse effects reported included: fever, rash, zoster, headache and nausea. Conclusions: The use of G-CSF for the treatment of patients with ACLF significantly reduced short-term mortality. Forest Plot: G-CSF vs. placebo or no intervention: all cause mortality Disclosures: The following people have nothing

to disclose: Victoria J. Ornelas-Arroyo, Desiree Vidaña-Pérez, Guadalupe Delgado-Sánchez, Indira R. Mendiola Pastrana, Camilo Noreña-Herrera, Tonatiuh Barrientos-Gutierrez, Eva Juárez Hernández, Nahum Méndez-Sanchéz, Misael N. Uribe-Esquivel, Norberto C. Chavez-Tapia [Aims] Novel diagnostic criteria for “acute liver failure (ALF)” were established in 2011 in Japan, which include the disease entity of “fulminant hepatitis”. Based on these, a nationwide survey was executed to clarify the etiology, clinical features and outcome of ALF patients seen between 2010 and 2012. [Methods] Total of 757 ALF patients were enrolled from 742 institutes. All patients showed a prothrombin time (INR) of 1.5 or more within 8 weeks after the onset of deaese symptoms. [Results] (1) Disease Types: 757 patients were classified into 385 patients (50.9%) without hepatic coma and 372 patients (49.

Other accessions that showed particularly useful differentiating

Other accessions that showed particularly useful differentiating ability were Olathe and 51051. Of these, only Redlands Pioneer has been included in the 2002 differential set. The PCoA grouping of the African races was similar to that of the southern African race-groups. “
“The Cerrado biome represents a hotspot of biodiversity. Despite this, the nematofauna in this biome has not been well characterized, especially that related to root-knot nematodes. This work aimed to identify Meloidogyne species present in different

cerrado vegetations and to investigate potential hosts of Meloidogyne javanica in this biome. Soil samples (250) were collected in native areas of cerrado vegetation located at the National Park of Brasília (PNB) (125 samples) and Água Limpa Farm (FAL) (125 samples), and transferred to sterile pots. Single tomato selleck products plants cv. Santa Clara (susceptible) were transplanted into individual pots and maintained for 90 days under glasshouse. Females of Meloidogyne spp. were extracted from tomato roots and identified based upon esterase phenotypes and confirmed

with PCR using specific sequence characterized amplified regions (SCAR) primers. Native plants were inoculated with 10 000 individuals (eggs + J2) of a pure culture of M. javanica and maintained under glasshouse for 6 months. From the 250 samples collected, 57 (22.8%) presented Meloidogyne spp. A total of 66 Meloidogyne populations were identified as follows: M. javanica (75.76%),

M. incognita (10.60%), M. hapla (9.1%), M. morocciensis (3.03%) and M. arenaria (1.51%). The following esterase phenotypes were detected: M. javanica AZD1208 mw (J3 and J2), M. incognita (I1 and I2), M. hapla (H1), M. morocciensis (A3) and M. arenaria (A2). The SCAR primers incK14F/incK14R, Fjav/Rjav and Fh/Rh amplified specific fragments in M. incognita (399 bp), M. javanica (670 bp) and M. hapla (610 bp) and can be used for identification of indigenous Meloidogyne spp. from cerrado. The primer set Far/Rar is not specific for M. arenaria due Quinapyramine to the amplification of DNA in M. morocciensis. Mimosa caesalpiniifolia was the only native plant in which M. javanica developed a high reproductive rate, and it is probably a host for this nematode in cerrado. “
“Three isolates of Tomato torrado virus (ToTV) were found in Poland. The isolates were characterized on the basis of their symptomatology on plant species, serological reactions, electron microscopy, and nucleotide and amino acid sequence analyses of coat protein subunit genes. In comparative tests, the Polish ToTV isolates were shown to be closely related to each other and also to the isolate from Spain. “
“Powdery mildews, caused by Golovinomyces cichoracearum and Podosphaera xanthii, are the most common and severe diseases of cucurbits in the Mediterranean basin. In southern Italy, only P. xanthii is apparently present.

control) for age (49 5±8 7 vs 51 5±8 6), male gender (69 1 vs 5

control) for age (49.5±8.7 vs. 51.5±8.6), male gender (69.1 vs. 58.8%), bilirubin (13.3 [8.9-23.5] vs. 11.9 [6.9-21.5] mg/dL), INR (1.8 [1,6-2.1] vs. 1,8 [1.6-2.1]), mDF (52.3 [40.9-70.2] vs. 54 [42-68.5]) and MELD score (22.8 [21.4-26.3] vs. 22.4 [20.2-25.1]). Mean kcal intake was 2206±754 vs. 1754±656 kcal/day (p=0.001) and mean protein intake was 106±37 vs. 80±32 g/day Selleckchem Idelalisib (p<0.001). In intention-to-treat (ITT) analysis, 6-month survival was not statistically different between the two groups: 55.9 vs. 47.0% (p=0.316). In the intensive group, 43/68 (63.2%) patients received at least

80% of the planned kcal intake defined by the protocol, and were considered in the per-protocol analysis. In per-protocol analysis, 6-month survival was higher in the intensive group: 69.8 vs. 46.8% (p=0.015). In addition, mean kcal intake/kg/day > 26.4 (median value) was associated with a higher 6-month survival (68.3 vs. 42.4%, p=0.002). In ITT multivariable analysis, a mean kcal intake/kg/day > 26.4, baseline mDF, serum sodium, MELD and the Lille scores remained independently associated with 6-month survival. Conclusions. Intensive enteral nutrition by feeding tube does not improve 6-month survival in patients with severe AH. However, Ganetespib solubility dmso adequate nutritional support is associated with a better short-term prognosis.

Adequate nutritional intake should be targeted in AH patients treated with corticosteroids. Disclosures: Christophe Moreno – Consulting: Abbvie, Janssen, Gilead, MSD, Novartis, BMS; Grant/Research Support: Janssen, Gilead, Roche, MSD, Novartis, Astellas

sabelle Colle – Advisory Committees or Review Panels: MSD, Janssen, MSD, Gilead; Grant/Research Support: Bayer; Patent Held/Filed: Trombogenics; Speaking and Teaching: BMS, Janssen Hendrik Reynaert – Advisory Committees or Review Panels: MSD, Gillead, Janssen, BMS, Abbvie; Grant/Research Support: Roche Pierre Aprepitant Deltenre – Consulting: Janssen, Gilead, BMS The following people have nothing to disclose: Eric Trépo, Alexandre Louvet, Delphine Degré, Boris Bastens, Axel Hittelet, Marie-Astrid Piquet, Wim Laleman, Hans Orlent, Luc Lasser, Thomas Sersté, Peter Starkel, Xavier Dekoninck, Sergio Negrin Dastis, Jean Delwaide, Chantal de Galocsy, Sven M. Francque, Philippe Langlet, Virginie Putzeys, Thierry Gustot Background: Macrophage activation plays and important role in alcoholic liver disease (ALD). The mannose receptor (CD206, MR, MRC1), expressed primarily by subsets of macrophages and dendritic cells, is known to mediate endocytosis, antigen presentation, and induction of immune responses. A soluble form (sCD206, sMR,) has recently been identified in human serum. Aim: To study blood sCD206 and its correlation with clinical endpoints and macrophage activation marker sCD163 in patients with alcoholic liver disease.

Presumably, inhibitors will form in some patients upon exposure t

Presumably, inhibitors will form in some patients upon exposure to the deficient factor independent of

any co-existent pro-inflammatory signals, whereas in others these signals will be significant modifiers. In some subjects, only minor inflammatory signals will be needed, whereas in others a more pronounced pro-inflammatory state will be required. A third group of patients will, presumably, never develop inhibitors despite how, when, and with what replacement product they are treated, as long as the agent itself is not immunogenic. One approach is to avoid the deficient factor at start of treatment, since without this exposure antibodies will not be formed. This approach has been tested, but so far without success. Rivard and colleagues evaluated the use of recombinant Ivacaftor factor VIIa to postpone exposure to FVIII until after the age of 2 years, Autophagy pathway inhibitors but succeeded in only 3 of 11 children treated a mean

of 5.5 months (median 4, range 0–12) [28]. Therefore, to use this approach other treatment options than currently available will probably be needed. Another emerging method is the use of low dose prophylaxis in the absence of any tissue damage. This includes very small doses, such as 5–10 IU/kg body weight, as these doses may not only protect against bleeding in a cost-effective manner, but also sensitize the immune system and thereby minimize the risk for inhibitors in the event of a major trauma and bleed. Although, in the context of inhibitors, prophylaxis will be neither required nor of benefit for all, its use should continue to be the state-of-the-art treatment for all patients. In summary, there has been major progress during the last decade in the understanding of how and why patients develop inhibitory antibodies to the deficient factor. However,

a substantial number of issues remain to be resolved including how to better identify patients at high risk before start of treatment using a genetic risk score. New treatment options in the pipeline may emerge in the near future and be offered to patients who are at high risk. Gene therapy may provide another attractive approach. However, from logistic and health-economic selleck compound perspectives, this potentially curative option will likely not be widely available. New – less expensive – therapeutic options need to be continually evaluated and the resources available must be used in the most optimal way. On the basis of current knowledge, this includes low dose prophylaxis initiated prior to the onset of bleeds. Studies to evaluate doses even lower than those currently utilized should be performed in countries in which this treatment modality is not currently available. The authors stated that they had no interests which might be perceived as posing a conflict or bias. “
“Summary.

39 More intrahepatic lymphocytes were detected than expected in n

39 More intrahepatic lymphocytes were detected than expected in normal liver and may represent the response to handling of see more the liver during harvesting and implantation. The reason behind the reduction in sinusoidal cell telomere length with age (in Kupffer cells and hepatic stellate cells) was beyond the scope of this study. Sinusoidal cells have a different origin, namely bone marrow,40, 41 and are subject to constant immune stimulation through contact with portal blood. Others have demonstrated that hepatocyte telomeres shorten in cirrhotic liver

but that hepatic stellate cells and lymphocytes in regions of liver fibrosis have longer telomeres.24 These studies have only looked at small numbers of each hepatic cell lineage and may not be representative, particularly given the heterogeneity seen in liver tissue. They may also reflect the recruitment

of cells with longer telomeres to the injured liver from bone marrow. In chimeric mice, hepatic stellate cells originate from hematopoetic bone marrow stem cells, particularly following hepatic injury.42 Finally, progestogen antagonist telomere shortening in sinusoidal cells may reflect a reduction in hepatic blood flow, which is especially marked after the age of 50.43, 44 It has been suggested that reduced hepatic flow alone could explain delayed hepatic regeneration after injury.45 Kupffer cells populating the liver originate from bone marrow in both mice and humans after bone marrow transplant46 and constitute a large intrahepatic population. Quantitative study of monocyte production in bone marrow and transit through the circulation showed that in the normal steady state, over 50% of monocytes leaving the circulation

become Kupffer cells. Considering the Kupffer cells as kinetically homogeneous, gives a mean turnover time of the total population of Kupffer cells of 21 days.47 Further studies in normal rat liver revealed an age-related decline in antigen presentation ability by Kupffer cells,48 and Liothyronine Sodium these cells in mice have been shown to have a stimulatory role in liver regeneration.49 In conclusion, we developed a robust, high-volume Q-FISH method for analysis of telomeres in different hepatic cell lineages that highlighted the pitfall of using liver homogenates in the study of aging and senescence. Furthermore, we demonstrated very long telomeres in cholangiocytes in normal liver over a wide age range and age-related telomere attrition restricted to sinusoidal cells. Understanding the normal process of aging in the liver is important in many aspects of hepatology from pharmacology to selection of older donors, and the findings encourage careful selection of older liver donors. Additional Supporting Information may be found in the online version of this article.

Methods: In a cohort study, data from 229 well-characterized pati

Methods: In a cohort study, data from 229 well-characterized patients with biopsy-proven NAFLD were collected. Mean follow-up was 26.4 (± 5.6, range 6-33) years. A reference population was obtained from the National Registry of Population, and information on time and cause of death were obtained from the Registry of Causes of Death. Main results: NAFLD patients had an increased mortality compared with the reference population (HR 1.29, CI 1.04-1.59, p=0.020), with increased risk of cardiovascular disease

LY294002 solubility dmso (HR 1.55, CI 1.11-2.15, p=0.01), hepatocellular carcinoma (HR 6.55, CI 2.14-20.03, p=0.001), infectious disease (HR 2.71, CI 1.02-7.26, p=0.046), and cirrhosis (HR 3.2, CI 1.05-9.81, p=0.041). Overall mortality was not increased in patients with NAS 5-8 and fibrosis stage 0-2 (HR 1.41, CI 0.97-2.06, p=0.07), whereas patients with fibrosis stage 3-4, irrespective of NAS, had increased mortality (HR 3.3, CI 2.27-4.76,

p<0.001). Conclusions: NAFLD patients have increased risk of death, with a high risk of death from cardiovascular disease and liver-related disease. The NAS was not able to predict overall mortality, whereas fibrosis stage predicted both overall and disease-specific https://www.selleckchem.com/products/Y-27632.html mortality. 2 (Hepatology 2014;) “
“A 66-year old man with obstructive jaundice was found to have an unresectable pancreatic tumour on contrast-enhanced CT scan. Sagittal (Figure 1) and 3-D (Figure 2) reconstructions of the CT scan images revealed complete agenesis of the coeliac axis, with the splenic and hepatic arteries arising directly from the superior mesenteric artery. The arterial Ribonuclease T1 supply of the gastrointestinal tract develops in week 4 of embryological life. The future blood vessels of the GI tract are formed from the vitelline system, which is composed of two bilateral arterial plexuses which coalesce to form arteries from the dorsal aorta to GI tract. Above the diaphragm the vitelline channels amalgamate to form about 5 pairs of arteries which supply the thoracic oesophagus. Below the diaphragm the vitelline system condenses

to form the three major abdominal arteries of the foregut, midgut and hindgut. The coeliac artery is the most superior of these arteries; it leaves the aorta at the seventh cervical level in the embryo but later descends to the twelfth thoracic level during development. In addition to supplying the abdominal foregut proper, the coeliac artery also supplies its endodermal derivatives; the hepatic diverticulum (future liver), the cystic diverticulum (future gallbladder), and the dorsal and ventral pancreatic bud (future pancreas). It also supplies the mesodermally derived spleen. The anatomical variation in the celiac trunk is assumed to be caused by different patterns of vitelline reduction.

For example, HNF4α and C/EBPα, two important regulators of miR-12

For example, HNF4α and C/EBPα, two important regulators of miR-122 identified in our studies, were not

found to be significant in their data. The physiological role of miR-122 in liver development is currently unknown, primarily because no appropriate targets have been identified. Understanding the molecular mechanisms that regulate cellular proliferation and differentiation is a central theme of developmental biology.9, 23 In this report, we identified that a group of genes involved in proliferation and differentiation regulation are miR-122 targets. Several target genes are considered key regulators of development, such as the two transcription factors (CUTL1 and CCCTC-binding factor [CTCF]) and two mitogen-activated protein kinase kinase kinase (MAP3K) members25, 30, 31 that have been shown to be targets of miRNA. Therefore,

our work this website is significant because it provides important clues for understanding the role of miR-122 during liver development. During the development of a multicellular organism, cells proliferate for a defined length of time before they begin functional differentiation.23 The process of differentiation of primitive cells into more specialized cells involves an increasing restriction in proliferative capacity, culminating in cell cycle exit.23 Precise regulation of terminal cell division is needed to ensure production of proper numbers of differentiated cells at the appropriate time.23 CUTL1, the target we focused on, is a conserved transcriptional repressor that regulates the balance between cell division and differentiation of multiple cell lineages during Selleck Apitolisib embryonic development.20, 25 CUTL1 knockout and transgenic

mouse models have confirmed this role.25 The majority of homozygous mice die at or shortly after birth due to severe hypoplasia, whereas transgenic mice constitutively expressing CUTL1 develop multiorgan organomegaly (including the heart, kidney, testis, spleen, seminal vesicle, and liver).25 In hepatomegaly, constitutively expressing CUTL1 results in an excessive increase in the number of immature hepatocytes.32 These studies suggest that CUTL1 is necessary for embryonic development at an early stage, whereas failure to turn off its activity leads to excessive proliferation, as well as differentiation blocking of primitive cells. Researchers have determined that CUTL1 activity (also known Etomidate as HiNF-D binding activity) is down-regulated during fetal liver development, coinciding with the exit from the cell cycle and terminal differentiation.33 However, the mechanism is unclear. Here, we show that CUTL1 expression is silenced posttranscriptionally during mouse liver development, likely due to repression by miR-122. Therefore, our study not only reveals the mechanism regulating CUTL1 during liver development, but also supports the role of miR-122 in the precise regulation of terminal cell division and differentiation of hepatocytes.

One study has shown the development of anti-HBs to have no influe

One study has shown the development of anti-HBs to have no influence Vorinostat in vivo over the subsequent occurrence

of HCC.4 Besides providing important clinical data on serologic and virologic parameters before spontaneous HBsAg seroclearance, our present study also offers a reference for future studies investigating the usefulness of serum HBsAg measurements of CHB patients undergoing antiviral therapy. Serum HBsAg levels have already been shown to be useful in predicting favorable outcomes in Peg-IFN therapy.28, 29 In contrast, patients commenced on nucleoside analog therapy do not show significant decline in serum HBsAg up to 2 years,30 although a 0.5-log reduction in HBsAg is also predictive of subsequent HBsAg seroclearance.31 The achievement of low HBsAg levels or a strong reduction in HBsAg should thus be investigated in the future for suitability as treatment endpoints. Future studies should also consider matching baseline HBsAg and HBV DNA levels for a more detailed comparison of HBsAg kinetics. A limitation of our study is that our patient population might not be totally representative of all treatment-naïve CHB populations, with no

HBeAg-positive patients at initial presentation included. Although HBsAg loss is possible shortly after HBeAg seroconversion,16 the average age of HBeAg seroconversion in our population is 35 years32 and the average age of HBsAg seroclearance is 50 years4; hence, the proportion LY294002 manufacturer of patients with HBsAg seroclearance within 3 years of HBeAg seroconversion is likely to be small. Therefore, the validity of our study results, when applied to spontaneous HBsAg

seroclearance, should not be affected by the absence of HBeAg-positive patients. In addition, HBV genotyping was not performed in all patients. Nevertheless, the lack of significant difference in genotype distribution among the two patient groups is in line with findings suggesting HBV Racecadotril genotypes as not being a key factor in determining HBsAg seroclearance.16 Further studies on this aspect are needed. In conclusion, in CHB patients with spontaneous HBsAg seroclearance, low levels of serum HBsAg could be detected up to 3 years before HBsAg seroclearance and were more predictive of HBsAg seroclearance than low levels of serum HBV DNA. Serum HBsAg levels <200 IU/mL already offered a good prediction of eventual HBsAg seroclearance in 3 years. In patients with serum HBsAg ≥200 IU/mL, an annual 0.5-log reduction in serum HBsAg increases the prediction of HBsAg seroclearance. Both absolute and serial measurements of serum HBsAg would offer valuable clinical data in determining the probability of long-term seroclearance. These may also serve as good indicators for the consideration of treatment duration and cessation for CHB. Additional Supporting Information may be found in the online version of this article.

Next, 1:100,

Next, 1:100, Dinaciclib mouse 1:200, and 1:400 dilutions of the same panel of genotype 2 sera were tested against the six genotype 2 Core-NS2 recombinant viruses. Despite the significant ability

to reduce the number of ffu against HVR1-deleted viruses, the sera had limited or no neutralization capacity against the WT genotype 2 viruses. Only five sera showed neutralizing potential. C58(2b), K1118(2c), K2592(2c), and K1475(2j) neutralized J6/JFH1(2a) by ≥50% in 1:100 and/or 1:200 dilutions. In addition, K1118(2c) and C294(2b) neutralized S83/JFH1(2c) and DH8/JFH1(2b), respectively, in 1:200 dilutions. The remaining 14 sera were not able to neutralize any of the studied genotype 2 recombinants ≥50% at 1:100 or higher dilutions. The percentage of ffu reduction at 1:200 dilutions of patient serum samples for HVR1-deleted viruses and the unmodified culture viruses are shown in Table 2. To confirm that the reduction in ffu of HVR1-deleted viruses was IgG dependent, we performed a neutralization assay of J6/JFH1 and J6/JFH1ΔHVR1 with purified IgG and the IgG-depleted serum from sample C294(2b), K2052(2c), K413(2j), and K1475(2j). IgG from these Ku0059436 four sera was able to reduce the number of ffu of J6/JFH1ΔHVR1 in a dose-dependent manner, with IC50 values of 0.1-0.5 μg/mL. In contrast, IgG neutralized J6/JFH1 ≥50% at only the highest concentration of 100 μg/mL for C294, K2052, and K1475; K413 neutralized

J6/JFH1 by 50% at ∼20 μg/mL. IgG-depleted serum was not able to affect the infectivity for J6/JFH1 or J6/JFH1ΔHVR1. Thus, ffu reduction against the HVR1-deleted virus was apparently IgG dependent.

The lack of neutralization of the WT virus could not be explained by infectivity enhancing factors in the human sera. Recently, it was demonstrated that two unique HMAbs (AR4A and HC84.26), recognizing conformational epitopes, had broad neutralizing potential against several HCV genotypes.[9, 10] To study these HMAbs against the genotype 2 panel, each recombinant virus was tested in Ribonucleotide reductase a concentration-response assay with Ab concentrations ranging from 0.008 to 25.0 μg/mL. AR4A neutralized J6(2a), T9(2a), J8(2b), DH8(2b), and S83(2c), with IC50 values of 1.8-8.7 μg/mL; only DH10(2b) had IC50 values >25 μg/mL (Fig. 5A). HC84.26 neutralized the recombinant viruses, with IC50 values of 0.1-8.2 μg/mL; in contrast to ARA4, DH10(2b) was efficiently neutralized by HC84.26 (Fig. 5B). A comparison with the amount of polyclonal IgG purified from selected patients able to neutralize 50% of J6/JFH1 is shown in Table 3. Thus, the genotype 2 virus panel found resistant to NAbs in genotype 2 chronic-phase sera could be neutralized efficiently by HMAbs AR4A and HC84.26. To investigate Ab neutralization susceptibility of HCV, we developed HCV genotype 2a, 2b, and 2c Core-NS2 culture viruses. The S83/JFH1 recombinant represents the first culture system for genotype 2c, a subtype frequently found in Southern Europe.