Conclusion: Specific modifications of the disulfide bond within the lipoic-acid-conjugated PDC-E2 moiety, i.e., by an electrophilic agent renders PDC-E2 immunogenic in a genetically susceptible host. (HEPATOLOGY 2013) Antimitochondrial autoantibodies (AMAs) to the E2 subunit of the pyruvate dehydrogenase complex (PDC-E2) are the serological hallmark of primary biliary cirrhosis (PBC).1-4 Previous analysis of the antibody specificity of anti-PDC-E2 revealed a number of subpopulations of anti-PDC-E2 antibodies that recognized either the PDC peptide, PDC peptide conjugated with lipoic acid,

or lipoic acid itself.5-7 Interestingly, PDC-E2-specific antibodies are present long before the onset of clinical symptoms and may represent a relic of initiating immunological events.8 Recent studies by quantitative structure-activity relationship (QSAR) analysis demonstrated that AMA-positive MLN0128 purchase PBC

sera, but not controls, reacted to a number selleck chemical of xenobiotic modified PDC-E2 structures,9-11 with a particularly striking level of reactivity against 6,8-bis(acetylthio) octanoic acid (SAc)-PDC-E2.12 This observation is critical because SAc is a modified form of lipoic acid in which both sulfur atoms of the disulfide bond of the lipoyl ring are modified by acetyl groups (Fig. 1), thereby maintaining PDC-E2 in a reduced state by preventing disulfide bond formation; this reduced state facilitates xenobiotic modification of PDC-E2.13 We hypothesized that the presence of antibodies directed against the SAc-PDC-E2 conjugate in sera from PBC patients suggests that this structure is involved in loss of tolerance. Such data would also support the thesis that chemical modification of self-proteins plays an important role in autoimmunity,7, 14-16 exemplified by minocycline-induced autoimmunity, whereby minocycline binding to self macromolecules produces immunogenic self antigens that become the target Galeterone of disease-generating, crossreactive autoantibodies.17, 18 Thus, to address our hypothesis

and define the antibody reactivity to the SAc moiety, we studied the serological reactivity of 241 AMA-positive PBC patients, 34 AMA-negative PBC patients, 86 patients with primary sclerosing cholangitis (PSC), 95 patients with autoimmune hepatitis (AIH), and 60 healthy controls against SAc-conjugated bovine serum albumin (BSA), 2-octynoic acid (2OA)-conjugated BSA, recombinant PDC-E2 (rPDC-E2), and BSA itself. Importantly, we mapped specific reactivities of a nested subset of 24 AMA-positive SAc-BSA-positive PBC sera, including use of various affinity-purified antisera and inhibition studies. Interestingly, our data suggest that immunoglobulin M (IgM) reactivity to SAc reflects the footprints of xenobiotic modification of PDC-E2. Finally, we report herein that the IgM reactivity to SAc persists from early- to late-stage PBC with only minimal IgG reactivity.

The presence Neratinib purchase of LAS improved Cu2+ removal by ~20%, and accelerated attainment of Cu2+ retention equilibrium. For the 2- mg · L−1 Cu2+ treatments, retention equilibrium occurred within 2 d and showed maximum Cu2+ removal of 1.83 mg · L−1. In the presence of LAS, the ratio of extracellular bound Cu2+ to intracellular Cu2+ taken up by the cells was lower (1.05–2.26) than corresponding ratios (2.46–7.85) in the absence of LAS. The percentages of extracellular bound Cu2+ to total Cu2+ removal (both bound and taken up by cells) in the presence of LAS ranged from 51.2% to 69.3%, which was lower than their corresponding percentages (71.1%–88.7%) in the absence of LAS. LAS promoted

biologically active Crizotinib transport of the extracellular bound form of Cu2+ into the cell. In contrast, the addition of LAS did not increase the maximum removal efficiency of Cu2+ (61.4% ± 5.6%) by heat-inactivated cells compared to that of living

cells (59.6% ± 6.0%). These results provide a theoretical foundation for designing bioremediation strategies using FACHB-834 for use in surface waters contaminated by both heavy metals and LAS. “
“Twenty-six strains morphologically identified as Cylindrospermum as well as the closely related taxon Cronbergia siamensis were examined microscopically as well as phylogenetically using sequence data for the 16S rRNA gene and the 16S-23S internal transcribed spacer (ITS) region. Phylogenetic analysis of the 16S rRNA revealed three distinct clades. The clade we designate as Cylindrospermum sensu stricto contained all five of the foundational species, C. maius, C. stagnale, C. licheniforme, C. muscicola, and C. catenatum. In addition to these taxa, three Methocarbamol species new to science in this clade were described: C. badium, C. moravicum, and C. pellucidum. Our evidence indicated that Cronbergia is a later synonym of Cylindrospermum. The phylogenetic

position of Cylindrospermum within the Nostocaceae was not clearly resolved in our analyses. Cylindrospermum is unusual among cyanobacterial genera in that the morphological diversity appears to be more evident than sequence divergence. Taxa were clearly separable using morphology, but had very high percent similarity among ribosomal sequences. Given the high diversity we noted in this study, we conclude that there is likely much more diversity remaining to be described in this genus. The genus Cylindrospermum Kütz. ex Bornet et Flahault (1886) is distinguished from other Nostocaceae by the presence of terminal heterocytes with paraheterocytic akinete development, and absence of aerotopes. It is often found associated with damp soils, but also occurs in periodically flooded soils (such as rice paddies) and some species have even been reported to be present in permanent aquatic habitats (Singh et al. 1980, Cronberg 2003). Akinetes in species of Cylindrospermum are large, thick-walled, and often bear spines or other ornamentation on the exospore.

Results: Fifty eight patients with 59 lesions underwent ESD successfully, 30(50.8%) lesions were en bloc resection, and 55(93.2%) lesions were removed completely. One ectopic pancreas on gastric antrum not completely removed as non-lifting sign positive after submucosal injection. Another two specimens form leiomyoma on corpus ventriculi and ectopic pancreas on gastric antrum removed incompletely.

Histological diagnosis of upper gastrointestinal lesions: 11 inflammation, 7 ectopic pancreas, 7 leiomyomas, Alisertib 3 polyps, 3 ulcer, a total of 5 cases of stromal tumors, fibrous histiocytoma, early carcinoma, solitary fibrous tumor, eosinophilic granuloma and hamartoma. Histological diagnosis of colorectal lesions: 16 adenoma, 5 carcinoid,1 inflammatory polyp, 2 canceration then received surgery. A total of 22 cases before the operation had histological biopsy, Consistent diagnosis rate before and after the procedure was 59.1% (n = 13), another 9 cases (40.9%) had a clear diagnosis relying on larger biopsy after the procedure. There were 3 cases (5.2%) with post-ESD bleeding, 2 of them occurred

within 24 h after ESD, 1 case showm symptoms On the sixth day after ESD. All of them were controled by endoscopic and medical treatment. One case (1.7%) with suspected gastric cancer had perforation during the procedure of ESD, JAK2 inhibitors clinical trials after tanium clipping and then received laparotomy successfully. Median follow-up period was 5.7 (range, 1–23.5) month. Follow-up rate was 41.1% (23/56). There was a recurrence case of rectal adenoma in 14 follow-up months. Conclusion: ESD is effective and minimal invasive endoscopic techniques for removing gastrointesinal lesions. It allows en-bloc removal of large lesion and is associated with a higher diagnostic rate and a lower recurrence rate compared with endoscopic mucosal resection (EMR). ESD is technically more difficult and can result in more complication that may occur more lately. There was

a hige incidence of post-ESD bleeding PLEK2 0n gastric antrum. Key Word(s): 1. ESD; 2. EMR; Presenting Author: NIANNIAN TIAN Additional Authors: HUILING XIANG, HONGMIN LV, FANG WANG, XINHUA NIE, YING LUO Corresponding Author: HUILING XIANG Affiliations: The Third Central Clinical College of Tianjin Medical University; the Third Central Hospital of Tianjin; Key Laboratory of Artificial Cells of Tianjin Objective: Endoscopic injection of cyanoacrylate is recognized as the preferred method for gastric variceal bleeding. Despite the extensive worldwide use, there are still differences related to the safety and long term results. The aim of this study is to evaluate the efficacy and safety in different types of gastric varices and discuss the right time for the first gastroscopy examination postoperatively.

“
“Peroxisome proliferator-activated receptor-γ (PPARγ), a nuclear receptor, when overexpressed in liver stimulates the induction of adipocyte-specific and lipogenesis-related genes and causes hepatic steatosis. We report here that Mediator 1 (MED1; also known as PBP or TRAP220), a key subunit of the Mediator complex, is required

for high-fat diet–induced hepatic steatosis as well as PPARγ-stimulated adipogenic hepatic steatosis. Mediator forms the bridge between transcriptional activators and RNA polymerase II. MED1 interacts with nuclear receptors Trichostatin A such as PPARγ and other transcriptional activators. Liver-specific MED1 knockout (MED1ΔLiv) mice, when fed a high-fat (60% kcal fat) diet for up to INCB024360 concentration 4 months failed to develop fatty liver. Similarly, MED1ΔLiv mice injected with adenovirus-PPARγ (Ad/PPARγ) by tail vein also did not develop fatty liver, whereas mice with MED1 (MED1fl/fl) fed a high-fat diet or injected with Ad/PPARγ developed severe hepatic steatosis. Gene expression profiling and northern blot analyses of Ad/PPARγ–injected mouse livers showed impaired induction in MED1ΔLiv mouse liver of adipogenic markers, such as aP2, adipsin, adiponectin, and lipid droplet-associated genes, including caveolin-1, CideA, S3-12, and others. These adipocyte-specific and lipogenesis-related genes are strongly induced in MED1fl/fl mouse liver in response to Ad/PPARγ. Re-expression

of MED1 using adenovirally-driven MED1 (Ad/MED1) in MED1ΔLiv mouse liver restored PPARγ-stimulated hepatic adipogenic response. These studies also demonstrate that disruption of genes encoding other coactivators such as SRC-1, PRIC285, PRIP, and PIMT had no effect on hepatic adipogenesis induced by PPARγ overexpression. Conclusion: We conclude that transcription coactivator MED1 is required for high-fat diet–induced and PPARγ-stimulated fatty liver development, which suggests that MED1 may be considered a potential therapeutic target for hepatic steatosis. (HEPATOLOGY 2011;) Nonalcoholic fatty liver

disease is becoming a common chronic liver disorder with a morphological spectrum of liver pathology commencing with hepatic steatosis and steatohepatitis which Fludarabine research buy may progress toward the development of cirrhosis and liver cancer.1, 2 Because the key aspects of lipid metabolism, including lipogenesis, fatty acid oxidation, lipoprotein uptake and secretion are regulated by the liver, an understanding of the regulatory mechanisms that influence hepatic lipid homeostasis and systemic energy balance is of paramount importance in gaining insights that might be useful in the management of fatty liver disease.1-4 In recent years, increasing attention is being focused on certain transcription factors/nuclear receptors that are known to serve as key regulatory molecules to influence hepatic lipid metabolism.

We constructed multi-locus phylogenies of all four Tamiops RO4929097 species on the basis of paternal (Y-chromosomal SRY and SMCY7), maternal (mitochondrial cytochrome b gene) and biparental (autosomal IRBP, RAG1 and PRKCI) sequences. Maximum likelihood and Bayesian tree-constructing methods resulted in phylogenies with similar topologies. All genetic markers supported diversification of three main lineages: (1) T. mcclellandii;

(2) T. rodolphii; (3) T. swinhoei–maritimus complex. On the basis of 24 T. maritimus from five localities and 10 T. swinhoei from four localities, T. swinhoei and T. maritimus were not reciprocally monophyletic. The six populations of the T. swinhoei–maritimus complex were monophyletic in all loci, except for autosomal loci in one T. maritimus population from Tam Dao, Vietnam. Autosomal phylogenies were more similar to Y-chromosomal than to mitochondrial phylogenies. Incongruence between nuclear and mitochondrial phylogenies indicates that either T. maritimus from Taiwan or T. maritimus from Phu Yen, Vietnam probably descended from ancient hybridization. Diversification of the three main Tamiops lineages was estimated to occur 8.8–6.7 million years ago (mya) and may have been affected by rapid uplift of the Himalayan Mountains in the western part of their range. Multiple

http://www.selleckchem.com/products/cx-4945-silmitasertib.html divergences from 5.8 to 1.7 mya likely led to the formation

of modern Tamiops species. All six populations of T. swinhoei–maritimus complex could be regarded as distinct species. Divergence among T. rodolphii populations in mitochondrial DNA was also at the interspecies level. Our analyses highlight the underestimation of species diversity in the genus Tamiops. “
“Sex allocation theory predicts that mothers benefit from adjusting the sex ratio of their offspring in relation to their offspring’s future reproductive success. In cooperative breeders, parents are expected to bias the sex ratio in relation to their current need for help and the benefit received from helpers of each sex as proposed by the local resource enhancement (LRE) and helper repayment hypotheses (HR). Consequently, as group size increases, sex ratios are expected to be biased towards the sex that is BCKDHA more likely to disperse to avoid competition as proposed in the local resource competition hypothesis (LRC). The current study aimed to investigate helper effects on breeder fecundity and offspring sex ratio adjustments in a eusocial mammal the Damaraland mole-rat Fukomys damarensis. Both sexes equally contribute to helping in this species, but breeding dispersal is male biased. We found no evidence for helper effects on maternal body mass and litter size. Offspring sex ratio was not affected by maternal mass or litter size.

2). Consequently, the proportion of patients showing a reduction of HVPG ≥10% from baseline (“responders”) was significantly lower in obese patients (24.5% versus 40.4% normal weight and 36.9% overweight, P = 0.019). Changes in HVPG at 1 year were not related to treatment (timolol or placebo) group. Table 3 shows the comparison between the 161 patients included in the present study in whom height (and consequently BMI) was available, and the 52 originally included in the RCT15 but in whom BMI could not be calculated because height was unavailable (missing information). As shown, there were no significant differences in baseline characteristics between the groups. Importantly, the incidence

of clinical decompensation in the follow-up (Fig. 3) did not differ in the two groups, suggesting that no inclusion bias Ganetespib molecular weight exists and that the population explored in the present study can be considered a random

sample from the original cohort. This is further supported by the findings of a multiple imputation analysis of missing values. This analysis showed that obesity was indeed an independent predictor of first clinical decompensation in the entire RCT cohort. A good nutritional status has been traditionally regarded as a positive prognostic indicator in cirrhosis,19 because malnutrition is a feature of late, Compound Library in vitro decompensated stages of the disease. In the present study we demonstrate for the first time that increased body adiposity, as indicated by an increased BMI, is a strong predictor of decompensation in patients with compensated cirrhosis of various

etiologies, independent of other previously described predictors such as albumin and HVPG, and independent of receiving placebo or active treatment with beta-blockers. The robustness of the findings was further confirmed by multiple imputation analysis18 of missing values of BMI in the whole cohort of the original RCT. Cryptogenic cirrhosis, possibly due to earlier nonalcoholic fatty liver disease (NAFLD)/nonalcoholic steatohepatitis (NASH), was more prevalent in our obese patients, so etiology might potentially confound the effect of BMI Edoxaban on outcome; nonetheless, the proportion of patients with this etiology was small (12% in the obese patients group), and, as confirmed by multivariate analysis, did not explain the poorer outcome in obese patients. Importantly, the analysis restricted to patients with HCV, the most common cause of cirrhosis, showed identical results compared to the whole study cohort, with BMI being an independent predictor of decompensation. A recent article by Everhart et al.13 showed that obesity-related variables (specifically insulin resistance and histological features of fatty liver), but not obesity itself, were independently associated with a worse outcome, as defined by histological and/or clinical events, in a large cohort of patients with advanced HCV liver disease.

Cardiovascular adverse events occurred in about 6% of patients in the treatment group compared with no patients in the control group. The frequency PD0325901 cell line is likely to be higher in unselected patient populations treated in everyday clinical practice. Accordingly, the monitoring of patients should include electrocardiography to detect cardiac ischemia or arrhythmia, especially in patients with hepatic encephalopathy or diabetes. Likewise, frequent observation

to detect peripheral ischemia with cyanosis, livedo reticularis, or skin necrosis of the fingers or extremities is necessary. Patients should be informed of the potential adverse events to meet demands for informed consent. Despite the treatments administered, the overall mortality when combining data on all patients treated with terlipressin plus albumin remained 57%. The discrepancy

between survival rates and number of patients with reversal of HRS suggests that some patients may die despite improved renal function. Because we did not have individual patient data, we were unable to identify the cause of death in patients with improved renal function. Future trials may explore potential predictors of a beneficial response as well as phase IV studies to determine the treatment effect and risk of adverse events in nonspecialized units. The combined evidence suggests that additional trials are needed to further optimize the treatment of patients with HRS. We thank the authors who provided us with additional information about their trials. We also thank Drs. Yan Gong and Maoling Wei for Decitabine cost assistance in the identification and translation of Chinese trials. “
“We previously reported that mice subjected to partial hepatectomy exhibit rapid development GPX6 of hypoglycemia followed by transient accumulation of fat in the early regenerating liver. We

also showed that disrupting these metabolic alterations results in impaired liver regeneration. The studies reported here were undertaken to further characterize and investigate the functional importance of changes in systemic adipose metabolism during normal liver regeneration. The results showed that a systemic catabolic response is induced in each of two distinct, commonly used experimental models of liver regeneration (partial hepatectomy and carbon tetrachloride treatment), and that this response occurs in proportion to the degree of induced hepatic insufficiency. Together, these observations suggest that catabolism of systemic adipose stores may be essential for normal liver regeneration. To test this possibility, we investigated the hepatic regenerative response in fatty liver dystrophy (fld) mice, which exhibit partial lipodystrophy and have diminished peripheral adipose stores. The results showed that the development of hypoglycemia and hepatic accumulation of fat was attenuated and liver regeneration was impaired following partial hepatectomy in these animals.

In addition, T cell-deficient mice and T and B cell-deficient mice had significantly reduced lung injury compared to wild-type controls. In contrast, severe lung selleck screening library injury was observed in B cell-deficient mice compared to controls, but the results were not statistically significant. Conclusion: T lymphocytes promote the development of pancreatic lesions in acute pancreatitis, but B lymphocytes mainly act to regulate immune response and reduce inflammation during the early course of AP through the functions of B10-cells. Key Word(s): 1. acute pancreatitis; 2. T cells; 3. immune response;

4. mice; Presenting Author: ZHANG NING-NING Additional Authors: GUO XIAO-ZHONG, LI HONG-YU, CUI ZHONG-MIN, SHAO XIAO-DONG Corresponding Author: GUO XIAO-ZHONG Affiliations: General Hospital of Shenyang Military Area Command Selleck Poziotinib Objective: To analyze the effect and safety of continuous renal replacement therapy (CRRT) in the treatment of severe acute pancreatitis (SAP) patients. Methods: Continuous renal replacement therapy was performed in 21 patients with SAP from 2008 to 2012. Clinical signs, seram urea nitrogen (BUN), creatinine (Scr), amylase, lipase, C-reactive protein and lactic acid were compared before and after treatment. Results: Among 2l patients, 3 patients were cured, 14 patients relieved and 4 patients died. There were remarkable improvement

in the abdomina1 pain, pancreatic encephalopathy, pleural effusion and renal injury. Compared with those before treatment, clinical signs, white blood cell (WBC) count, biochemistry indicato, seram urea nitrogen (BUN), creatinine (Scr), amylase, lipase, C-reactive

protein, lactic ADAM7 acid were decreased significantly (p < 0.05). The mortality was also decreased, prognosisy was improved. Conclusion: Continuous renal replacement therapy was safe and effective in severe acute pancreatitis patients. Key Word(s): 1. SAP; 2. CRRT; 3. treatment; Presenting Author: BAI YI-TONG Additional Authors: GUO XIAO-ZHONG, LI HONG-YU, SHAO XIAO-DONG, CUI ZHONG-MIN, WANG DI, ZHAO JIA-JUN Corresponding Author: GUO XIAO-ZHONG Affiliations: General Hospital of Shenyang Military Area Command Objective: To research the character of complication and therapy of severe acute pancreatitis in aging group and non aging group. Methods: Seventy-three patients of severe acute pancreatitis were divided into aging group (group I, <65) and non aging group (group II, ≥65). and the prevalence and incidence of complications were compared between the two groups. Results: The prevalence of SAP in group I was different from group II. In non aging group, the prevalence in male was higher than female, and in aging group, the prevalence in female was higher than male. The incidence of electrolyte disturbance, respiratory failure, renal failure, heart failure and alimentary tract hemorrhage in group I was different from group II, P < 0.05. But the incidence of dropsy of serous cavity and infectious shock had no difference, P > 0.05.

In our

series 80, 12, 14, 25 and 1 patients were respectively infected by HCV genotype 1,2,3,4 and 5. The mean viral load was 5.5.± 0.7 Log UI/mL. Thirty eight patients were IL28B (rs1 2979860) CC and 80 were either CT or TT. Mir-122 expression was assessed in Selleck GSK1120212 a total of 127 percutaneous liver biopsies and 83 serums, by RT-q-PCR. Results We found a significant decrease of hepatic mir-122 expression in F3 and F4 as compared to F1 and F2 patients within all HCV patients (p=0.01) and within the 80 HCV genotype 1 infected patients (p=0.04). Whereas a trend was found between hepatic mir-122 expression in mild (F1) fibrosis vs F2-4 within all HCV genotypes (p=0.06) a significant decreased hepatic mir-122 was observed in mild (F1) fibrosis when compared to F2-F4 patients infected by HCV genotype 1 (p=0.01). We found no association between hepatic and serum expression of mir-122 (p=0.21). We found no relationship between the expression

of serum mir-122 and the different stages of fibrosis. Among patients with F1 and F2, 29.3% and 70.7% were respectively CC and CT+TT. Among patients with F3 and F4, 36.5% were CC and 63.4% were CT+TT. A 2.5 fold increase in the mean expression of serum mir-122 was found in male compared to women (p=0.05 in univariate and p=0.009 in multivariate analysis). Conclusions The major novelty of our work selleck screening library consists in the description of decrease of hepatic mir-122 expression in patients with advances stages

of fibrosis. More specifically in patients with genotype 1, hepatic mir-122 expression is increased in mild (F1) fibrosis as compared to more advanced fibrosis, in HCV genotype 1. Mir-122 might play a role in fibrogenesis during chronic hepatitis C. Disclosures: Olivier Lada – Grant/Research Support: Gilead Dominique Valla – Board Membership: Sequana Medical; Independent Contractor: IRIS; Speaking and Teaching: Mayoly Spindler, MSD, Janssen Pharmaceuticals Patrick Marcellin – Consulting: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Boehringer, PFKL Pfizer, Abbott, Alios BioPharma; Grant/Research Support: Roche, Gilead, BMS, Novartis, Janssen-Tibotec, MSD, Alios BioPharma; Speaking and Teaching: Roche, Gilead, BMS, Vertex, Novartis, Janssen-Tibotec, MSD, Abbott Tarik Asselah – Consulting: BMS, Boehringer-Ingelheim, Roche, Merck-Schering Plough, Gilead, Janssen The following people have nothing to disclose: Emilie Estrabaud, Kevin Appourchaux, Philippe Broet, Martine Lapalus, Simon De Muynck, Michelle Martinot-Peignoux, Ivan Bieche, Pierre Bedossa, Michel Vidaud Background and aims: Liver fibrosis represents a complication of many chronic liver diseases and is linked with high morbidity and mortality. However, the molecular processes driving hepatic fibrogenesis are only incompletely understood.

3, right). In addition, sequential sequence analyses in two patients with acute-persistent HCV genotype 3a infection showed no evidence of viral escape mutations over a time of one or two years, respectively (data not shown). In line with the results from the cellular assays these data strongly suggest that there is no CD8+ T-cell pressure within the NS5B2841-2849 region in HCV genotype 3a-infected HLA-B27+ patients. Based on our immunological findings, it

is tempting to speculate that in contrast to HCV genotype 1 infection, lack of the immunodominant target of the HLA-B27-restricted CD8+ T-cell responses is associated with loss of the protective effect of HLA-B27 in genotype 3a infection. To address this question, we determined the frequency of HLA-B27 positivity in a large cohort of patients chronically infected check details with either HCV genotype 1 (265 patients) or 3a (98 patients). The frequency of HLA-B27

positivity was significantly higher in patients infected with genotype 3a (12/98 patients, 12.5%) compared with patients infected with genotype 1 (14/265 patients, 5.3%; P = 0.0363) (Fig. 5). Quizartinib research buy In this context, it is important to note that the frequency of HLA-B27 positivity in the general German population is ≈8.5% based on the analysis of 11,407 individuals in the German bone marrow registry (compare www.allelefrequencies.net).21 Thus, the protective effect of HLA-B27 in HCV genotype 1

infection is reflected by the low prevalence of HLA-B27 positivity in patients chronically infected with HCV genotype 1. In contrast, HLA-B27 has no protective effect (or may even have a disadvantageous effect) in HCV genotype 3a infection, reflected by the relatively high frequency of HLA-B27 positivity in patients infected with HCV genotype 3a. Importantly, we did not observe a significant difference between the frequencies in genotype 1 or 3a-infected patients for any other HLA-A or HLA-B allele (data not shown). Thus, the different frequency of HLA-B27 in HCV genotype Erastin 1 versus 3a infection is unique and consistent with the central role of the immunodominant NS5B2841-2849 epitope in mediating the protective effect of HLA-B27 in HCV genotype 1 infection. We have recently linked the protective effect of HLA-B27 in the outcome of HCV infection to an immunodominant HLA-B27-restricted HCV epitope.6 This epitope is located in a highly conserved and functionally constrained region within NS5B, the RNA-dependent RNA polymerase. In our previous study we showed that viral escape from this epitope is limited by viral fitness costs as well as cross-recognition by CD8+ T cells, thus requiring a complex mosaic of two or more mutations for significant viral escape.