The results of our study suggest a new function for hepcidin in modulating acute inflammatory responses. (HEPATOLOGY 2011 ) De Domenico I, Zhang TY, Koening CL, Branch RW, London N, Lo E, et al. Hepcidin mediates transcriptional changes that modulate acute cytokine-induced inflammatory responses in mice. J Clin Invest 2010; 120:2395-2405. (Reprinted with permission.) Hepcidin is a peptide hormone that

regulates iron homeostasis selleck chemical and acts as an antimicrobial peptide. It is expressed and secreted by a variety of cell types in response to iron loading and inflammation. Hepcidin mediates iron homeostasis by binding to the iron exporter ferroportin, inducing its internalization and degradation via activation of the protein kinase Jak2 and the subsequent phosphorylation of ferroportin. Here we have shown that hepcidin-activated Jak2 also phosphorylates the transcription factor Stat3, resulting in a transcriptional response. Hepcidin treatment of ferroportin-expressing mouse macrophages showed changes in mRNA expression levels of a wide variety of genes. The changes in transcript

levels for half of these genes were a direct effect of hepcidin, as shown by cycloheximide insensitivity, and dependent on the presence of Stat3. Hepcidin-mediated HDAC inhibition transcriptional changes modulated LPS-induced transcription in both cultured macrophages and in vivo mouse models, as demonstrated by suppression of IL-6 and TNF-α transcript and secreted protein. Hepcidin-mediated transcription in mice also suppressed toxicity and morbidity due to single doses of LPS, poly(I:C), and turpentine, which is used to model chronic inflammatory disease. Most notably, we demonstrated that hepcidin pretreatment protected mice from a lethal dose of LPS and that hepcidin-knockout mice could be rescued from LPS toxicity by injection of hepcidin. The results of our study suggest a new function for hepcidin in modulating acute inflammatory responses. Hepcidin is a peptide

hormone primarily known as the key regulator of iron homeostasis. This peptide, which binds the only known cellular iron MCE exporter, ferroportin (Fpn), leads to its internalization and degradation in hepatocytes, enterocytes, and macrophages, prevents iron transport to plasma, and causes cellular retention of iron.1 Hepcidin is also an amphipathic peptide with antimicrobial activity similar to that of the defensin family of proteins.2 Hepcidin expression is up-regulated in response to iron stores, inflammation, and endoplasmic reticulum stress and is inhibited by anemia, erythropoiesis, hypoxia, and oxidative stress.3 Other factors that have been proposed to regulate hepcidin expression include leptin,4 p53,5 estradiol,6 and circadian rhythms.

We also propose that the excess PC thus generated is catabolized, leading to TG synthesis and steatosis by way of diglyceride (DG) generation. We observed that Gnmt−/− mice Smoothened Agonist supplier present with normal hepatic lipogenesis and increased TG release. We also observed that the flux from PE to PC is stimulated in the liver of Gnmt−/− mice and that this results in a reduction in PE content and a marked increase in DG and TG. Conversely, reduction of hepatic SAMe following the administration of a methionine-deficient diet reverted the flux from PE to PC of Gnmt−/− mice to that of

wildtype animals and normalized DG and TG content preventing the development of steatosis. Gnmt−/− mice with an additional deletion of perilipin2, the predominant lipid droplet protein, maintain high SAMe levels, with a concurrent increased flux from PE to PC, but do not develop liver steatosis. Conclusion: These findings indicate that excess SAMe reroutes PE towards PC and TG synthesis and lipid sequestration. (Hepatology 2013;58:1296–1305) find more Nonalcoholic fatty liver disease (NAFLD) is the most common liver disease in Western countries,[1] frequently being associated with obesity, dyslipidemia, and insulin resistance, a group of disorders that constitute the metabolic syndrome.[2] Although these aforementioned

conditions predispose the individual to develop NAFLD, our understanding of the mechanisms by which fat accumulates in the liver is not fully understood. Decreased content of S-adenosylmethionine (SAMe),

the major 上海皓元 biological methyl donor, has been linked to the development of NAFLD in different experimental models of steatosis in rodents and in humans.[3] For instance, deletion of methionine adenosyltransferase 1A (Mat1a), the principal gene involved in hepatic SAMe biosynthesis,[3] leads to a chronic reduction in liver SAMe level and to the spontaneous development of NAFLD.[4] The mechanisms linking SAMe with lipid homeostasis are not obvious at first glance. However, two recent publications have shed light on this process by showing: (1) that low hepatic SAMe reduces phosphatidylcholine (PC) content, leading to SREBP-1 activation and lipogenesis[5]; and (2) that low liver SAMe disrupts very low density lipoprotein (VLDL) assembly, leading to the synthesis of small, lipid-poor VLDL particles, and to a decrease in the secretion of triglycerides (TG).[6] The antisteatotic theory of SAMe has been challenged by the observation that deletion in mice of glycine N-methyltransferase (Gnmt), the main enzyme involved in hepatic SAMe catabolism,[7] results in a marked increase in hepatic SAMe content and rapid NAFLD development.[8] The Gnmt−/− mice show elevated serum aminotransferases at both 3 and 8 months of age. Histological examination of the livers of 3-month-old mutant mice showed steatosis and fibrosis, which were more pronounced in the livers of 8-month-old animals.

Two studies provided proof-of-concept support for the use of IFN-free regimens utilizing

a DAA or combinations of DAAs.[56, 57] More recently, the combination of sofosbuvir and daclatasvir (with or without RBV) was studied in a phase 2 trial that included both treatment-naïve patients and patients who had failed a prior course of IFN-based therapy that included telaprevir selleck chemicals llc or boceprevir.[58] In both treatment-naïve patients and prior non-responders, the combination of sofosbuvir and daclatasvir (for 12 or 24 weeks) was associated with a 100% SVR24 rate, even without the use of RBV.[58] Similar SVR rates were observed in the phase 2 LONESTAR study, in which 60 treatment-naïve, non-cirrhotic patients were given a once-daily, fixed-dose combination of sofosbuvir and ledipasvir (an NS5A inhibitor) with or without RBV.[59] In this study, 95% of treatment-naïve patients in the no RBV arms achieved SVR12 whether they were treated for 8 or 12 weeks. In the 12-week arm with RBV, 100% of patients achieved MG-132 cost SVR12. This study also evaluated an additional cohort of 40 patients (50% with compensated cirrhosis) who had failed previous DAA therapy; 100% of patients who received a 12-week course of fixed-dose sofosbuvir and ledipasvir

with RBV achieved SVR12 compared with 95% in the RBV-free arm.[59] The phase 2 ELECTRON study included treatment-naïve patients and prior null responders with genotype 1 HCV who were treated with 12 weeks of sofosbuvir plus RBV and either ledipasvir or GS-9669 (a non-nucleoside NS5B inhibitor).[60, 61] Results indicate that 100% of treatment-naïve (25/25) and 100% of prior non-responders (9/9) achieved SVR12 when ledipasvir was added to the sofosbuvir plus RBV regimen.[60] The addition MCE公司 of GS-9669 to sofosbuvir and RBV

also yielded a 92% SVR12 rate (23/25) in treatment-naïve patients;[61] 100% of treatment-experienced patients with F3/F4 fibrosis achieved SVR12 when sofosbuvir and ledipasvir were combined with either RBV or GS-9669.[61] The phase 2a COSMOS trial evaluated the all-oral combination of sofosbuvir and simeprevir, with and without RBV, in cirrhotic and non-cirrhotic treatment-naïve or prior null responder patients with genotype-1 (GT-1) HCV. Interim analysis of cohort 1 (non-cirrhotic prior null responders), showed that 93% and 96% of those treated with or without RBV for 12 weeks achieved SVR12 and 93% and 79% of those treated for 24 weeks achieved SVR12. Early results from cohort 2 (prior null responders and treatment-naïve, F3-F4) showed that 100% of treatment-naive patients treated with or without RBV achieved SVR4 after 12 weeks of treatment, as did 93% and 100% of prior null responders. For both cohorts, relapse occurred only in those GT-1a patients with known Q80K mutations, and treatment was generally safe and well tolerated with approximately 3% of patients experiencing serious adverse events.

Two studies provided proof-of-concept support for the use of IFN-free regimens utilizing

a DAA or combinations of DAAs.[56, 57] More recently, the combination of sofosbuvir and daclatasvir (with or without RBV) was studied in a phase 2 trial that included both treatment-naïve patients and patients who had failed a prior course of IFN-based therapy that included telaprevir selleck screening library or boceprevir.[58] In both treatment-naïve patients and prior non-responders, the combination of sofosbuvir and daclatasvir (for 12 or 24 weeks) was associated with a 100% SVR24 rate, even without the use of RBV.[58] Similar SVR rates were observed in the phase 2 LONESTAR study, in which 60 treatment-naïve, non-cirrhotic patients were given a once-daily, fixed-dose combination of sofosbuvir and ledipasvir (an NS5A inhibitor) with or without RBV.[59] In this study, 95% of treatment-naïve patients in the no RBV arms achieved SVR12 whether they were treated for 8 or 12 weeks. In the 12-week arm with RBV, 100% of patients achieved DAPT manufacturer SVR12. This study also evaluated an additional cohort of 40 patients (50% with compensated cirrhosis) who had failed previous DAA therapy; 100% of patients who received a 12-week course of fixed-dose sofosbuvir and ledipasvir

with RBV achieved SVR12 compared with 95% in the RBV-free arm.[59] The phase 2 ELECTRON study included treatment-naïve patients and prior null responders with genotype 1 HCV who were treated with 12 weeks of sofosbuvir plus RBV and either ledipasvir or GS-9669 (a non-nucleoside NS5B inhibitor).[60, 61] Results indicate that 100% of treatment-naïve (25/25) and 100% of prior non-responders (9/9) achieved SVR12 when ledipasvir was added to the sofosbuvir plus RBV regimen.[60] The addition 上海皓元医药股份有限公司 of GS-9669 to sofosbuvir and RBV

also yielded a 92% SVR12 rate (23/25) in treatment-naïve patients;[61] 100% of treatment-experienced patients with F3/F4 fibrosis achieved SVR12 when sofosbuvir and ledipasvir were combined with either RBV or GS-9669.[61] The phase 2a COSMOS trial evaluated the all-oral combination of sofosbuvir and simeprevir, with and without RBV, in cirrhotic and non-cirrhotic treatment-naïve or prior null responder patients with genotype-1 (GT-1) HCV. Interim analysis of cohort 1 (non-cirrhotic prior null responders), showed that 93% and 96% of those treated with or without RBV for 12 weeks achieved SVR12 and 93% and 79% of those treated for 24 weeks achieved SVR12. Early results from cohort 2 (prior null responders and treatment-naïve, F3-F4) showed that 100% of treatment-naive patients treated with or without RBV achieved SVR4 after 12 weeks of treatment, as did 93% and 100% of prior null responders. For both cohorts, relapse occurred only in those GT-1a patients with known Q80K mutations, and treatment was generally safe and well tolerated with approximately 3% of patients experiencing serious adverse events.

Further, cholestatic diseases are associated with Metformin supplier deficiencies of anti-oxidant vitamins. Despite these associations PBC is not associated with an increase in cardiovascular mortality. The aim of this study is to assess if primary biliary cirrhosis is associated with oxidative stress, endothelial dysfunction and alteration of vascular compliance which is

a surrogate marker for cardiovascular risk. Methods:  Fifty-one PBC patients and 34 control subjects were studied. Lipid soluble vitamins A, and E in addition to ascorbate and carotenoids were measured to assess anti-oxidant status. C-reactive protein, hydroperoxides and adhesion molecules sICAM-l/sVCAM-l were assessed as click here serological measures of endothelial function. Finally, measures of vascular compliance were assessed by applanation tonometer. Results:  CRP, sICAM and sVCAM were all significantly higher in PBC patients (469.14 vs 207.13, P < 0.001; 768.12 vs 308.03,P < 0.001; 708.40 vs 461.31, P < 0.001) whilst anti-oxidant vitamin levels were lower in PBC patients, with ascorbate, vitamin E and vitamin A all significantly lower in PBC patients (39.91 vs 72.68, P < 0.001; 2.63 vs 3.14, P = 0.02; 1.08 vs 1.81, P < 0.001). Despite these findings PBC patients have a lower pulse wave velocity than control subjects (8.22 m/s vs 8.78 m/s,

P = 0.022). Conclusion:  PBC patients appear to have reduced vascular risk as assessed by pulse wave velocity but concurrently have evidence of endothelial dysfunction, inflammation and anti-oxidant deficiency. “
“The response to critical illness involves alterations in all aspects of metabolic control, favoring catabolism of body protein. In particular, body protein loss occurring as a result of the alteration of protein metabolism has been reported to be inversely correlated with the survival of critically ill patients. Despite the availability of various therapeutic modalities aiming to prevent loss of the body protein pool, such as total parenteral nutrition, enteral nutrition designed to provide excessive calories as a form

of energy substrate, and protein itself, Gemcitabine the loss of body protein cannot be prevented by any of these. Loss of the boyd protein store occurs as a consequence of the alteration of the intermediate metabolism that works for the production of energy substrate. This alteration of substrate metabolism may be linked to the alteration of protein metabolism. However, no specific factors regulating amino acid and protein metabolism have been identified. Thus, further investigations evaluating amino acid and protein metabolism are required to obtain better understanding of metabolic regulation in the body, which may lead to the development of novel and more effective therapeutic modalities for nutrition in the future.

10 The objectives of this article are (1) to provide a description of all adult patients enrolled in NASH CRN studies; (2) to determine the associations of basic clinical variables with the diagnosis of definite NASH, stage of fibrosis, grade of inflammation and presence of hepatocellular ballooning injury; and (3) to determine the overall accuracy of models using only demographic and basic clinical variables to predict the presence LY2109761 purchase of NASH,

and the activity grade and fibrosis stage of NASH. A similar analysis of the clinical and histological features of NAFLD in children enrolled in the NASH CRN studies has been published.11 ANA, antinuclear antibody; ASMA, anti-smooth muscle antibody; ANA, antimitochondrial antibody; ALT, alanine aminotransferase; AST, aspartate aminotransferase; AUROC, area under the receiver operator characteristic curve; BMI, body mass index; CI, confidence interval; GGT, gamma glutamyl transpeptidase; HDL, high-density lipoprotein; HOMA-IR, homeostasis model of assessment of insulin resistance; LDL, low-density lipoprotein; NAFLD, nonalcoholic fatty

liver disease; NASH, nonalcoholic steatohepatitis; NASH CRN, NASH Clinical Research Network; NAS, NAFLD activity score; NCEP, National Cholesterol selleck compound Education Program; NIDDK, National Institute of Diabetes and Digestive and Kidney Diseases. Patients with suspected or histologically proven NAFLD were enrolled into the Database observational study at nine U.S. medical centers: Case Western Reserve (Cleveland, OH); Duke University (Durham, NC); Indiana University (Indianapolis, IN); Johns Hopkins University (Baltimore, MD); Saint

Louis University (St. Louis, MO); University of California, San Diego (San Diego, CA); University of California, San Francisco (San Francisco, CA); University of Washington (Seattle, WA); and Virginia Commonwealth University (Richmond, VA). The data were stored, monitored, Gefitinib chemical structure and analyzed at the Data Coordinating Center at the Johns Hopkins Bloomberg School of Public Health. The NASH CRN enrolled into the Database patients who were at least 2 years of age who met any one of the following criteria: (1) a histologic diagnosis of NAFLD; (2) a histologic diagnosis of cryptogenic cirrhosis; (3) suspected NAFLD based on imaging studies; (4) clinical evidence of cryptogenic cirrhosis. Patients were excluded if they had clinical or histological evidence of alcoholic liver disease or alcohol consumption during the 2 years before entry of more than 20 g daily for men and 10 g daily for women.

20 In the majority of other human cancers, such as prostate,21–23 breast,24–26 lung,27 bladder28 and colon29 cancers, however, upregulated expression of clusterin was frequently detected. In HCC, it was reported that 89% of HCC cases exhibited clusterin overexpression in neoplastic BYL719 molecular weight cells as detected by immunohistochemical staining,30 and recently, we have found that an increased expression of clusterin in metastatic HCC tissues when compared with that in primary HCC tissues of the same patients.31 These data suggested that changed expression (upregulated or downregulated) of clusterin may play

an important role in the tumorigenesis of several types of human cancer, including HCC. In view of the possible diagnostic role of clusterin in the development and/or progression of HCC, in the

present study, we developed a sandwich enzyme-linked immunosorbent assay (ELISA) to determine the serum clusterin concentrations in a cohort of HCC patients and control subjects (i.e, Wnt cancer healthy subjects, HBV carriers, chronic hepatitis B and liver cirrhosis patients) and thus, to evaluate the correlation and potential usefulness of this marker in screening patients at risk of HCC. A total of 184 adults at the Cancer Center and the First Affiliated Hospital, Sun Yat-Sen University, China between November 2002 and September 2007 were enrolled in this study. All subjects gave their informed consent to the study, which was approved by the local ethics committee. These subjects were set into five groups according to different clinical characteristics (Table 1). Group 1(G1): Healthy subjects. This group included 22 healthy blood donors with no history of liver disease. All subjects had a normal liver biochemistry. Group 2(G2): HBV carriers. This group included 31 patients with HBV infection. With regard to etiology, HBV was diagnosed

by positive serum surface antigen for HBV. Group 3(G3): Patients with chronic hepatitis B. This group included 26 patients with mild to severe chronic hepatitis B. These patients had no sign of liver cirrhosis or any tumors according to clinical, biochemical new and imaging criteria. Group 4(G4): Patients with liver cirrhosis. This group included 29 patients with HBV-related liver cirrhosis. The diagnosis of liver cirrhosis was established on the basis of clinical, biochemical, imaging (US and computed tomography [CT]) and histological examinations. All patients underwent clinical evaluation, routine laboratory investigation, assessment of circulating levels of AFP and liver US. Group 5(G5): HCC patients. This group included 76 HCC patients with HBV-related liver cirrhosis. HCC was diagnosed histologically when the surgical liver specimens were available.

[31] In these mice, hepatic expression of OPN protein was markedly increased at 1 day after the beginning of MCD diet and persisted

Lumacaftor datasheet up to 8 weeks, whereas OPN mRNA expression was increased at 4 weeks.[31] OPN protein expression was predominantly localized to hepatocytes, not inflammatory cells, assessed by immunohistochemistry at 3 days and at 8 weeks. Moreover, hepatic inflammation induced by MCD diet was markedly reduced in OPN–/– mice compared with OPN+/+ mice, while histological steatosis and liver triglyceride levels were similar among these mice.[31] This may be because mice fed MCD diet lose weight and do not show insulin resistance, unlike human or other diet-induced rodent models of NAFLD. Osteopontin mRNA was increased during culture-related activation of rat quiescent hepatic stellate cells to myofibroblastic stellate cells.[32] Furthermore, incubation of hepatic stellate cells with OPN induced their collagen production, transforming growth factor-β receptor upregulation, proliferation and migration.[32] These results suggested a potential role for OPN in the progression of hepatic fibrosis. Hepatic fibrosis induced by MCD diet was Navitoclax supplier attenuated in OPN–/–

mice compared with OPN+/+ mice.[31, 33] Moreover, hepatic OPN mRNA and protein levels were not affected by feeding an MCD diet in genetically leptin-deficient, obese and diabetic ob/ob mice, which developed steatohepatitis but not liver fibrosis after the feeding.[34] In contrast, the diet had a stimulatory effect on OPN mRNA and protein levels in hyperleptinemic, obese and diabetic db/db mice, which exhibited a lesser degree of steatosis, but greater histological inflammation and marked pericellular fibrosis by the diet.[34]

Recently, it was reported that OPN was induced by Hedgehog signaling and directly promoted profibrogenic responses in steatohepatitis (Fig. 2). Hedgehog pathway can promote activation of quiescent hepatic stellate cells to myofibroblastic stellate cells.[35] In patients with NAFLD, accumulation of Hedgehog ligands and expression of Hedgehog-target genes were significantly correlated with Org 27569 hepatic fibrosis stage.[36] Furthermore, Hedgehog-mediated accumulation of natural killer T (NKT) cells contributed to fibrosis progression of NASH in mice and humans.[37] As shown in Figure 3, after the binding of the Hedgehog ligand to the Patched (Ptc) receptor, glioma-associated oncogene (Gli) is activated by release from a large protein complex and translocated to the nucleus to function as a transcriptional activator. The consensus DNA-binding sequences of Gli-1 were indentified in the 5′ regions of OPN, and gel shift analysis confirmed Gli-1 protein could bind to the oligonucleotides of OPN promoter region.[38] Syn et al. analyzed hepatic OPN expression and fibrosis grade, using Ptc-deficient (Ptc+/−) mice with haploinsufficiency of Ptc, which exhibit overly active Hedgehog signaling.

The low fitness cost for these mutations observed in culture implies that a minimal genetic barrier to their selection would exist in vivo, explaining the perceived lack of efficacy for p7 inhibitors in clinical trials. HCV IFN/Rib resistance is a multifactorial phenomenon, involving virus and host-associated factors. This is distinct to resistance against direct-acting STAT-C antivirals, which are host-independent and mediated through single HCV point mutations. According to quasispecies theory, all possible single variants exist within learn more an HCV-infected individual,

with selection dependent on fitness. Generation of dual, triple, and further variants becomes exponentially less RXDX-106 likely and forms the basis for the successful application of combination therapies. Combination of IFN/Rib with single STAT-C molecules targeting replication therefore suppresses HCV replication through distinct mechanisms. As such, IFN/Rib-resistant HCV will rapidly become resistant to a third STAT-C drug,

depending on fitness cost and drug potency, because it is essentially a monotherapy. For virus assembly inhibitors, resistance would be expected to arise all the more rapidly in IFN/Rib-resistant viruses as no suppression of genome replication occurs. Combinations of assembly inhibitors, however, can suppress RNA virus resistance.37 Our demonstration of distinct, specific antiviral effects for two classes of p7 inhibitor therefore

supports that combination with STAT-C therapies, rather than IFN/Rib, may enhance patient responses, because the genetic barrier to dual resistance would be significantly raised. Given that prototype p7 inhibitors have been trialed in patients (amantadine, rimantadine, UT-231b [IS] and BIT225 [amiloride]), these could be rapidly deployed alongside other STAT-C compounds. Our approach was necessarily Thymidylate synthase based on molecular modeling of p7 ion channel complexes. Models comprised a lumenal N-terminal helix with a conserved His17 proton sensor, analogous to M2 His37. Cu2+-mediated inhibition confirms His17 as lumenal,35 and lowered pH activates GT1b p7.33 Accordingly, modeling p7 under acidic conditions where His17 is protonated induced an opening of the structure (Fig. 1A). We recently showed that p7 induces vesicle alkalinization, protecting intracellular virions from reduced pH.19 Because low pH induces the fusogenic action of HCV glycoproteins,38 p7 may act analogously to M2 from certain influenza A virus strains, where it prevents such change in hemagglutinin.39 Interestingly, secreted HCV virions are acid resistant,19, 40 meaning that an as-yet unidentified maturation event occurs at a late stage of virion production where particles are acid-stabilized. Accordingly, p7 inhibitors do not reduce intracellular infectivity (Fig. 2D), supporting a post-assembly role for p7 proton channel function.

The low fitness cost for these mutations observed in culture implies that a minimal genetic barrier to their selection would exist in vivo, explaining the perceived lack of efficacy for p7 inhibitors in clinical trials. HCV IFN/Rib resistance is a multifactorial phenomenon, involving virus and host-associated factors. This is distinct to resistance against direct-acting STAT-C antivirals, which are host-independent and mediated through single HCV point mutations. According to quasispecies theory, all possible single variants exist within Staurosporine ic50 an HCV-infected individual,

with selection dependent on fitness. Generation of dual, triple, and further variants becomes exponentially less Saracatinib molecular weight likely and forms the basis for the successful application of combination therapies. Combination of IFN/Rib with single STAT-C molecules targeting replication therefore suppresses HCV replication through distinct mechanisms. As such, IFN/Rib-resistant HCV will rapidly become resistant to a third STAT-C drug,

depending on fitness cost and drug potency, because it is essentially a monotherapy. For virus assembly inhibitors, resistance would be expected to arise all the more rapidly in IFN/Rib-resistant viruses as no suppression of genome replication occurs. Combinations of assembly inhibitors, however, can suppress RNA virus resistance.37 Our demonstration of distinct, specific antiviral effects for two classes of p7 inhibitor therefore

supports that combination with STAT-C therapies, rather than IFN/Rib, may enhance patient responses, because the genetic barrier to dual resistance would be significantly raised. Given that prototype p7 inhibitors have been trialed in patients (amantadine, rimantadine, UT-231b [IS] and BIT225 [amiloride]), these could be rapidly deployed alongside other STAT-C compounds. Our approach was necessarily Dipeptidyl peptidase based on molecular modeling of p7 ion channel complexes. Models comprised a lumenal N-terminal helix with a conserved His17 proton sensor, analogous to M2 His37. Cu2+-mediated inhibition confirms His17 as lumenal,35 and lowered pH activates GT1b p7.33 Accordingly, modeling p7 under acidic conditions where His17 is protonated induced an opening of the structure (Fig. 1A). We recently showed that p7 induces vesicle alkalinization, protecting intracellular virions from reduced pH.19 Because low pH induces the fusogenic action of HCV glycoproteins,38 p7 may act analogously to M2 from certain influenza A virus strains, where it prevents such change in hemagglutinin.39 Interestingly, secreted HCV virions are acid resistant,19, 40 meaning that an as-yet unidentified maturation event occurs at a late stage of virion production where particles are acid-stabilized. Accordingly, p7 inhibitors do not reduce intracellular infectivity (Fig. 2D), supporting a post-assembly role for p7 proton channel function.