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Abdullah MAF, McWhirter SM, Suo Z. Modulation of Kinase Activities In Vitro by Hepatitis C Virus Protease NS3/NS4A Mediated-Cleavage of Key Immune Modulator Kinases. Cells 2023; 12:406. [PMID: 36766748 PMCID: PMC9913602 DOI: 10.3390/cells12030406] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/16/2022] [Revised: 01/09/2023] [Accepted: 01/22/2023] [Indexed: 01/26/2023] Open
Abstract
Hepatitis C Virus NS3/NS4A, a serine protease complex, has been found to interact with many host proteins and cause various adverse effects on cellular function and immune response. For example, the cleavage of important immune factors by NS3/NS4A has been suggested as a mechanism for the hepatitis C virus to evade innate immunity. The spectrum of susceptible substrates for NS3/NS4A cleavage certainly includes important immune modulator kinases such as IKKα, IKKβ, IKKε, and TBK1, as demonstrated in this paper. We show that the kinase activities of these four host kinases were transformed in unexpected ways by NS3/NS4A. Treatment with NS3/NS4A caused a significant reduction in the kinase activities of both IKKα and IKKβ, suggesting that HCV might use its NS3/NS4A protease activity to deactivate the NF-κB-associated innate immune responses. In contrast, the kinase activities of both IKKε and TBK1 were enhanced after NS3/NS4A treatment, and more strikingly, the enhancement was more than 10-fold within 20 min of treatment. Our mass spectroscopic results suggested that the cleavage after Cys89 in the kinase domain of IKKε by NS3/NS4A led to their higher kinase activities, and three potential mechanisms were discussed. The observed kinase activity enhancement might facilitate the activation of both IKKε- and TBK1-dependent cellular antiviral pathways, likely contributing to spontaneous clearance of the virus and observed acute HCV infection. After longer than 20 min cleavage, both IKKε- and TBK1 gradually lost their kinase activities and the relevant antiviral pathways were expected to be inactivated, facilitating the establishment of chronic HCV infection.
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Affiliation(s)
| | - Sarah M. McWhirter
- Department of Molecular and Cellular Biology, Harvard University, Cambridge, MA 02138, USA
| | - Zucai Suo
- Department of Biochemistry, The Ohio State University, Columbus, OH 43210, USA
- Department of Biomedical Sciences, Florida State University College of Medicine, Tallahassee, FL 32306, USA
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Hu X, Li J, Feng X. Threshold dynamics of a HCV model with virus to cell transmission in both liver with CTL immune response and the extrahepatic tissue. JOURNAL OF BIOLOGICAL DYNAMICS 2021; 15:19-34. [PMID: 33357087 DOI: 10.1080/17513758.2020.1859632] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Accepted: 11/16/2020] [Indexed: 06/12/2023]
Abstract
In this paper, a deterministic model characterizing the within-host infection of Hepatitis C virus (HCV) in intrahepatic and extrahepatic tissues is presented. In addition, the model also includes the effect of the cytotoxic T lymphocyte (CTL) immunity described by a linear activation rate by infected cells. Firstly, the non-negativity and boundedness of solutions of the model are established. Secondly, the basic reproduction number R01 and immune reproduction number R02 are calculated, respectively. Three equilibria, namely, infection-free, CTL immune response-free and infected equilibrium with CTL immune response are discussed in terms of these two thresholds. Thirdly, the stability of these three equilibria is investigated theoretically as well as numerically. The results show that when R01<1 , the virus will be cleared out eventually and the CTL immune response will also disappear; when R02<1<R01 , the virus persists within the host, but the CTL immune response disappears eventually; when R02>1 , both of the virus and the CTL immune response persist within the host. Finally, a brief discussion will be given.
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Affiliation(s)
- Xinli Hu
- School of Science, Xi'an Polytechnic University, Xi'an, People's Republic of China
| | - Jianquan Li
- School of Arts and Sciences, Shaanxi University of Science and Technoloty, Xi'an, People's Republic of China
| | - Xiaomei Feng
- School of Mathematics and Informational Sciences, Shaanxi Normal University, Xi'an, People's Republic of China
- School of Mathematics and Informational Technology, Yuncheng University, Yuncheng, People's Republic of China
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Cost-Effectiveness of Hepatitis C Treatment for People Who Inject Drugs and the Impact of the Type of Epidemic; Extrapolating from Amsterdam, the Netherlands. PLoS One 2016. [DOI: 10.1371/journal.pone.0163488 order by 8029-- #] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023] Open
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Cost-Effectiveness of Hepatitis C Treatment for People Who Inject Drugs and the Impact of the Type of Epidemic; Extrapolating from Amsterdam, the Netherlands. PLoS One 2016. [DOI: 10.1371/journal.pone.0163488 order by 8029-- awyx] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023] Open
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Cost-Effectiveness of Hepatitis C Treatment for People Who Inject Drugs and the Impact of the Type of Epidemic; Extrapolating from Amsterdam, the Netherlands. PLoS One 2016. [DOI: 10.1371/journal.pone.0163488 and 1880=1880] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023] Open
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Cost-Effectiveness of Hepatitis C Treatment for People Who Inject Drugs and the Impact of the Type of Epidemic; Extrapolating from Amsterdam, the Netherlands. PLoS One 2016. [DOI: 10.1371/journal.pone.0163488 order by 1-- -] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023] Open
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7
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Cost-Effectiveness of Hepatitis C Treatment for People Who Inject Drugs and the Impact of the Type of Epidemic; Extrapolating from Amsterdam, the Netherlands. PLoS One 2016. [DOI: 10.1371/journal.pone.0163488 order by 1-- #] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023] Open
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8
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Cost-Effectiveness of Hepatitis C Treatment for People Who Inject Drugs and the Impact of the Type of Epidemic; Extrapolating from Amsterdam, the Netherlands. PLoS One 2016. [DOI: 10.1371/journal.pone.0163488 order by 8029-- -] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023] Open
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9
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Cost-Effectiveness of Hepatitis C Treatment for People Who Inject Drugs and the Impact of the Type of Epidemic; Extrapolating from Amsterdam, the Netherlands. PLoS One 2016. [DOI: 10.1371/journal.pone.0163488 order by 1-- gadu] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/10/2023] Open
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Cost-Effectiveness of Hepatitis C Treatment for People Who Inject Drugs and the Impact of the Type of Epidemic; Extrapolating from Amsterdam, the Netherlands. PLoS One 2016; 11:e0163488. [PMID: 27711200 PMCID: PMC5053429 DOI: 10.1371/journal.pone.0163488] [Citation(s) in RCA: 32] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2016] [Accepted: 09/09/2016] [Indexed: 12/17/2022] Open
Abstract
BACKGROUND People who inject drugs (PWID) are disproportionally affected by the hepatitis C virus (HCV) infection. The efficacy of HCV treatment has significantly improved in recent years with the introduction of direct-acting antivirals (DAAs). However, DAAs are more costly than pegylated-interferon and ribavirin (PegIFN/RBV). We aimed to assess the cost-effectiveness of four HCV treatment strategies among PWID and treatment scale-up. METHODS An individual-based model was used describing HIV and HCV transmission and disease progression among PWID. We considered two epidemiological situations. A declining epidemic, based on the situation in Amsterdam, the Netherlands, and a stable HCV epidemic, as observed in other settings. Data on HCV incidence, prevalence, treatment setting and uptake were derived from observed data among PWID in Amsterdam. We assessed the incremental cost-effectiveness ratio (ICER, costs in €/quality-adjusted life year (QALY)) of four treatment strategies: 1) PegIFN/RBV; 2) sofosbuvir/RBV for genotype 2-3 and dual DAA for genotype 1-4; 3) Dual DAA for all genotypes; 4) Dual DAA with 3x treatment uptake. RESULTS In both types of epidemic, dual DAA therapy was most cost-effective strategy. In the declining epidemic, dual DAA yielded an ICER of 344 €/QALY while in the stable epidemic dual DAA led to cost-savings. Scaling-up treatment was also highly cost-effective. Our results were robust over a range of sensitivity analyses. CONCLUSION HCV treatment with DAA-containing regimens is a highly cost-effective intervention among PWID. Based on the economic and population benefits of scaling-up treatment, stronger efforts are needed to achieve higher uptake rates among PWID.
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Attallah AM, El-Far M, Omran MM, Farid K, Attallah AA, Abd-Elaziz D, El-Bendary MS, El-Dosoky I, Ismail H. Levels of Schistosoma mansoni Circulating Antigen in Chronic Hepatitis C Patients with Different Stages of Liver Fibrosis. J Immunoassay Immunochem 2016; 37:316-330. [PMID: 26745203 DOI: 10.1080/15321819.2015.1135163] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
Abstract
The goal of this study was to determine the levels of S. mansoni antigen in different liver fibrosis stages with chronic hepatitis C (CHC) Egyptian patients. A total of 174 CHC patients showing HCV-NS4 antigen and HCV- RNA in their sera were included. S. mansoni antigen was detected in serum using Western blot and ELISA. The levels of interferon-γ (IFN- γ) were determined using ELISA. The 50 kDa S. mansoni antigen discriminated patients infected with S. mansoni from healthy individuals with 0.93 area under curve (AUC), 92% sensitivity, and 97% specificity. The level of S. mansoni antigen (μg/ml) was significantly (P < 0.0001) increased with the progression of liver fibrosis stages (26.9 ± 17.5 in F1, 42.1 ± 25.2 in F2, 49.8 ± 30.3 in F3 and 62.2 ± 26.3 μg/mL in F4 liver cirrhosis), 26.9 ± 17.59 in significant fibrosis (F2-F4); 51.2 ± 27.9 in advanced fibrosis (F3-F4). A significant correlation (r = 0.506; P < 0.0001) was shown between the levels of the S. mansoni antigen and the HCV-NS4 antigen. In conclusion, the presence of S. mansoni antigen in different liver fibrosis stages of CHC patients confirming that concomitant schistosome infection aggravates liver disease.
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Affiliation(s)
| | - Mohamed El-Far
- b Chemistry Department, Faculty of Science , Mansoura University , Mansoura , Egypt
| | - Mohamed M Omran
- c Chemistry Department, Faculty of Science , Helwan University , Cairo , Egypt
| | - Khaled Farid
- d Tropical Medicine Department, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | - Ahmed A Attallah
- a R & D Department, Biotechnology Research Center , New Damietta , Egypt
| | - Dalal Abd-Elaziz
- a R & D Department, Biotechnology Research Center , New Damietta , Egypt
| | | | - Ibrahim El-Dosoky
- e Pathology Department, Faculty of Medicine , Mansoura University , Mansoura , Egypt
| | - Hisham Ismail
- a R & D Department, Biotechnology Research Center , New Damietta , Egypt
- f Biochemistry Division, Chemistry Department, Faculty of Science , Minia University , Minia , Egypt
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Abstract
Liver cancer is the fifth most common cancer, but the second leading cause of cancer death, in the world, with more than 700,000 fatalities annually. The major etiology of liver cancer is infection with an hepatotropic virus such as hepatitis B virus or hepatitis C virus infection. While chronic viral infection remains the main cause of liver disease and risk of hepatocellular carcinoma (HCC), rates of nonviral-associated HCC are occurring at an alarmingly increasing rate. Like many cancers, survival rates are closely associated with time of detection. If HCC is caught early, survival rates can be as high as 50%. Regrettably, most cases of HCC are caught late where survival rates can be as low as 2-7%. Thus, there has been great interest in discovering serum biomarkers that could be used to identify those with HCC. To this end, many groups have examined the N-linked glycans to identify changes that occur with HCC. As the liver secretes the vast majority of proteins into the serum, this has often been a starting point for study. In serum, alterations in core fucosylation, outer-arm fucosylation, increased sialylation, and glycan branching have been observed in patients with HCC. Similar findings have been found directly in HCC tissue suggesting that these glycan changes may play a role in tumor formation and development.
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Affiliation(s)
- Anand Mehta
- Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA
| | - Harmin Herrera
- Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA
| | - Timothy Block
- Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania, USA
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Gao J, Xie L, Yang WS, Zhang W, Gao S, Wang J, Xiang YB. Risk factors of hepatocellular carcinoma--current status and perspectives. Asian Pac J Cancer Prev 2012; 13:743-52. [PMID: 22631642 DOI: 10.7314/apjcp.2012.13.3.743] [Citation(s) in RCA: 107] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2023] Open
Abstract
Hepatocellular carcinoma is a common disorder worldwide which ranks 5th and 7th most common cancer among men and women. In recent years, different incidence trends have been observed in various regions, but the reasons are not completely understood. However, due to the great public efforts in HCC prevention and alternation of lifestyle, the roles of some well documented risk factors played in hepatocarcinogenesis might have changed. This paper summarizes both the environmental and host related risk factors of hepatocellular carcinoma including well established risk factors such as hepatitis virus infection, aflatoxin and alcohol, as well as possible risk factors such as coffee drinking and other dietary agents.
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Affiliation(s)
- Jing Gao
- State Key Laboratory of Oncogene and Related Genes, Shanghai Cancer Institute, Shanghai, China
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El-Kannishy G, Arafa M, Abdelaal I, Elarman M, El-Mahdy R. Persistent oxidative stress in patients with chronic active hepatitis-C infection after antiviral therapy failure. Saudi J Gastroenterol 2012; 18:375-9. [PMID: 23150023 PMCID: PMC3530992 DOI: 10.4103/1319-3767.103429] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/13/2023] Open
Abstract
BACKGROUND/AIMS Oxidative stress and hepatocellular pathological changes are common associations with chronic hepatitis C virus (CHC) disease. The aim of this study was to assess serum antioxidant-oxidant (Redox) balance in patients with CHC infection before and after intake of the traditional antiviral therapy (pegylated interferon α-2b and oral ribavirin). PATIENTS AND METHODS Blood samples from 50 biopsy-proven CHC patients, with no prior anti-viral treatment and persistently elevated serum transaminase levels for 6 months, as well as 15 age- and sex-matched healthy subjects were used for determination of the antioxidants: reduced glutathione (GSH), superoxide dismutase (SOD), α tocopherol and ascorbic acid as well as lipid peroxidation (LPO) index (malondialdehyde [MDA]). The measurements were repeated in the diseased group 25 weeks after pegylated interferon α-2b and ribavirin combination therapy. RESULTS Serum levels of bilirubin, aspartate aminotransferase (AST), and alanine aminotransferase (ALT) were significantly higher in CHC patients than in the control group (P < 0.05). Pretreatment serum MDA values were significantly higher in patients with CHC infection than the control group (P < 0.001), while serum antioxidant levels were significantly lower (P < 0.001). Responders (10 patients) had lower pretreatment serum levels of MDA than non-responders (35 patients) (P < 0.001). Both groups were comparable for the antioxidant serum levels. There was significant negative correlation between serum MDA and serum SOD, GSH, α tocopherol, and ascorbic acid concentrations in CHC patients. On the other hand, there was no correlation between the studied parameters and serum bilirubin, albumin, ALT, and AST. CONCLUSIONS Redox imbalance was detected in patients with CHC. Responders had significantly lower levels of MDA than non-responders. Serum MDA may be used as a pretreatment predictor of response to antiviral treatment in patients with CHC.
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Affiliation(s)
- Ghada El-Kannishy
- Department of Internal Medicine, Faculty of Medicine, Mansoura University, Egypt,Address for correspondence: Dr. Ghada El-Kannishy, Department of Internal Medicine, Faculty of Medicine, Endocrinology Unit, Mansoura University Hospital, Mansoura, Egypt. E-mail:
| | - Mona Arafa
- Department of Tropical Medicine, Faculty of Medicine, Mansoura University, Egypt
| | - Ibrahim Abdelaal
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Egypt
| | - Mohamed Elarman
- Department of Clinical Pathology, Faculty of Medicine, Mansoura University, Egypt
| | - Rasha El-Mahdy
- Department of Medical Microbiology and Immunology, Faculty of Medicine, Mansoura University, Egypt
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Ismail NA, Okasha SH, Dhawan A, Rahman AMOA, Hamid NA, Shaker O. Glutathione peroxidase, superoxide dismutase and catalase activities in children with chronic hepatitis. ACTA ACUST UNITED AC 2012. [DOI: 10.4236/abb.2012.327119] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022]
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Almahdy O, EL-Fakharany EM, EL-Dabaa E, Ng TB, Redwan EM. Examination of the Activity of Camel Milk Casein against Hepatitis C Virus (Genotype-4a) and Its Apoptotic Potential in Hepatoma and HeLa Cell Lines. HEPATITIS MONTHLY 2011; 11:724-730. [DOI: 10.5812/kowsar.1735143x.1367] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2023]
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Liver disorders in the elderly. Best Pract Res Clin Gastroenterol 2009; 23:909-17. [PMID: 19942167 DOI: 10.1016/j.bpg.2009.10.005] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2009] [Revised: 09/24/2009] [Accepted: 10/01/2009] [Indexed: 02/07/2023]
Abstract
Although there are no specific age-related liver diseases, it is increasingly recognized that the percentage and the actual number of elderly will increase substantially over the next twenty years. Moreover, the developments of new emerging conditions (e.g. non-alcoholic steatohepatitis) and novel therapeutic approaches have provoked increasing enthusiasm among hepatologists. Some liver diseases are particularly frequent in the elderly, e.g. chronic hepatitis C and hepatocellular carcinoma. The clinical course and management of liver disease in the elderly may differ in several aspects from those of younger adults. The problem of whether to offer antiviral treatment to a wide range of patients with chronic hepatitis C has arisen over the last eight to ten years, since the reduction in the risk of hepatocellular carcinoma was analyzed. Selected patients aged 65 and older have a chance of treatment with pegylated interferon plus ribavirin, despite a higher likelihood of side effects. The diagnosis of autoimmune hepatitis should be suspected in a patient over 65 years of age in case of 'acute' presentation with 10-fold increase in transaminases, jaundice and hyper-gammaglobulinemia, to avoid any delay in starting immunosuppressive therapy. The age of an end stage liver disease will increase over the next years, thus we will expects an increasing number of decompensated liver disease and hepatocellular carcinomas.
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Comunale MA, Wang M, Hafner J, Krakover J, Rodemich L, Kopenhaver B, Long RE, Junaidi O, Bisceglie AMD, Block TM, Mehta AS. Identification and development of fucosylated glycoproteins as biomarkers of primary hepatocellular carcinoma. J Proteome Res 2009; 8:595-602. [PMID: 19099421 DOI: 10.1021/pr800752c] [Citation(s) in RCA: 118] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Changes in N-linked glycosylation are known to occur during the development of cancer. For example, we have previously reported changes in N-linked glycosylation that occur with the development of hepatocellular carcinoma (HCC) and, through the use of glycoproteomics, identified many of those proteins containing altered glycan structures. To advance these studies and further explore the glycoproteome, we performed N-linked glycan analysis from serum samples depleted of the major acute phase proteins, followed by targeted lectin extraction of those proteins containing changes in glycosylation. Using this method, changes in glycosylation, specifically increased amounts of core and outer arm fucosylation, were observed in the depleted samples. The identities of those proteins containing core and outer arm fucose were identified in the serum of patients with HCC. The usefulness of some of these proteins in the diagnosis of HCC was determined through the analysis of over 300 patient samples using a high-throughput plate based approach. Greatest performance was achieved with fucosylated hemopexin, which had an AUROC of 0.9515 with an optimal sensitivity of 92% and a specificity of 92%.
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Stelzl E, van der Meer C, Gouw R, Beld M, Grahovac M, Marth E, Kessler HH. Determination of the hepatitis C virus subtype: comparison of sequencing and reverse hybridization assays. Clin Chem Lab Med 2007; 45:167-70. [PMID: 17311502 DOI: 10.1515/cclm.2007.043] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Hepatitis C virus (HCV) genotyping and accurate subtyping is becoming increasingly relevant to epidemiological studies, clinical management, pathogenicity, and vaccine development. METHODS The TRUGENE HCV 5'NC Genotyping Kit, the new VERSANT HCV Genotype 2.0 Assay (LiPA), and a new laboratory-developed HCV NS5b sequencing assay designed for automated sequencing of the HCV NS5b region were used. Clinical samples and a molecular diagnostics HCV genotyping proficiency program panel were used to determine accuracy and differentiate performance characteristics of the three methods. RESULTS All amplified samples from among the members of a HCV genotyping proficiency program panel that contained a single HCV genotype were subtyped correctly using all three HCV genotyping assays. With the TRUGENE HCV 5'NC Genotyping Kit, the HCV subtype was determined in 357 of 441 of routine clinical samples. When the 84 samples with only genotype results were retested with the VERSANT HCV Genotype 2.0 Assay (LiPA), 61 could be further subtyped accurately. With the new laboratory-developed HCV NS5b sequencing assay, all 84 could be subtyped accurately. CONCLUSIONS The two new methods show advantages over the routinely used TRUGENE HCV 5'NC Genotyping Kit in terms of genotyping and subtyping accuracy by utilizing part of the HCV core region and NS5b region, respectively.
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Affiliation(s)
- Evelyn Stelzl
- Molecular Diagnostics Laboratory, Institute of Hygiene, Medical University of Graz, Graz, Austria
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20
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Abstract
Although there are no liver diseases specific to advanced age, the clinical course and management of liver diseases in the elderly may differ in several aspects from those of younger adults. During the last decade an explosion of new knowledge in liver disease has provoked increasing enthusiasm among hepatologists. On the other hand, the development of new emerging conditions (e.g. non-alcoholic steatohepatitis) and novel therapeutic approaches has made it increasingly difficult to validate and assimilate information to be applied in clinical practice. Some liver diseases in the elderly need to be revisited, particularly non-alcoholic fatty liver disease, chronic hepatitis C, alcoholic liver disease, and hepatocellular carcinoma. Moreover, some therapeutic approaches, especially antiviral therapy and liver transplantation, should be discussed also in selected groups of elderly patients.
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MESH Headings
- Aged
- Aged, 80 and over
- Aging/physiology
- Fatty Liver/diagnosis
- Fatty Liver/epidemiology
- Fatty Liver/therapy
- Female
- Hepatitis C, Chronic/diagnosis
- Hepatitis C, Chronic/epidemiology
- Hepatitis C, Chronic/therapy
- Hepatitis, Alcoholic/diagnosis
- Hepatitis, Alcoholic/epidemiology
- Hepatitis, Alcoholic/therapy
- Humans
- Incidence
- Liver Diseases/diagnosis
- Liver Diseases/epidemiology
- Liver Diseases/therapy
- Liver Diseases, Alcoholic/diagnosis
- Liver Diseases, Alcoholic/epidemiology
- Liver Diseases, Alcoholic/therapy
- Liver Neoplasms/diagnosis
- Liver Neoplasms/epidemiology
- Liver Neoplasms/therapy
- Male
- Prognosis
- Risk Assessment
- Severity of Illness Index
- Survival Rate
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Affiliation(s)
- Annarosa Floreani
- Department of Surgical and Gastroenterological Sciences, University of Padova, Padova, Italy.
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Mühlbauer M, Fleck M, Schütz C, Weiss T, Froh M, Blank C, Schölmerich J, Hellerbrand C. PD-L1 is induced in hepatocytes by viral infection and by interferon-alpha and -gamma and mediates T cell apoptosis. J Hepatol 2006; 45:520-8. [PMID: 16876901 DOI: 10.1016/j.jhep.2006.05.007] [Citation(s) in RCA: 303] [Impact Index Per Article: 15.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/17/2006] [Revised: 04/26/2006] [Accepted: 05/09/2006] [Indexed: 01/13/2023]
Abstract
BACKGROUND/AIMS B7-H1 (PD-L1) is a B7-family member that binds to programmed death-1 (PD-1). Recently, deficiency of PD-L1 has been demonstrated to result in accelerated hepatocyte damage in experimental autoimmune hepatitis, and PD-L1 was suggested to play a critical role in regulating T cell homeostasis. Absence of PD-1 enhanced proliferation of T cells in adenovirus-infected livers and resulted in a rapid clearance of the virus. Here, we aimed to get more insight into hepatic PD-L1 expression, regulation and function. METHODS PD-L1 expression was analyzed by quantitative PCR and FACS-analysis in primary human liver cells and hepatoma cells. Furthermore, coculture experiments with primary human T cells or Jurkat T cells were established. RESULTS In addition to nonparenchymal liver cells, also hepatocytes constitutively expressed low levels of PD-L1. PD-L1 expression in hepatocytes was strongly enhanced by activated T cells and viral infection, and markedly augmented by further stimulation with type I or type II interferons. Moreover, PD-L1 expression on hepatocytes induced apoptosis in T cells. CONCLUSIONS Our results suggest a novel bidirectional interaction between hepatocytes and lymphocytes modulated by PD-L1 expression in hepatocytes, which may contribute to the unique immunological properties of the liver.
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Affiliation(s)
- Marcus Mühlbauer
- Department of Internal Medicine I, University of Regensburg, D-93042 Regensburg, Germany
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Hwang Y, Chen EY, Gu ZJ, Chuang WL, Yu ML, Lai MY, Chao YC, Lee CM, Wang JH, Dai CY, Shian-Jy Bey M, Liao YT, Chen PJ, Chen DS. Genetic predisposition of responsiveness to therapy for chronic hepatitis C. Pharmacogenomics 2006; 7:697-709. [PMID: 16886895 DOI: 10.2217/14622416.7.5.697] [Citation(s) in RCA: 29] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023] Open
Abstract
BACKGROUND A combination of interferon-alpha (IFN-alpha) and ribavirin has been the choice for treating chronic hepatitis C (CHC) patients. It achieves an overall sustained response rate of approximately 50%; however, the treatment takes 6-12 months and often brings significant adverse reactions to some patients. It would therefore be beneficial to include a pretreatment evaluation in order to maximize the efficacy. In addition to viral genotypes, we hypothesize that patient genotypes might also be useful for the prediction of treatment response. METHODS We retrospectively analyzed the genetic differences of CHC patients that are associated with IFN/ribavirin responses. The DNA polymorphisms among 195 sustained responders and 122 nonresponders of CHC patients of Taiwanese origin were compared. Statistical and algorithmic methods were used to select the genes associated with drug response and single nucleotide polymorphisms (SNPs) that permitted the construction of a predictive model. RESULTS Association studies and haplotype reconstruction revealed selection of seven genes: adenosine deaminase, RNA-specific (ADAR), caspase 5, apoptosis-related cysteine peptidase (CASP5), fibroblast growth factor 1 (FGF1), interferon consensus sequence binding protein 1 (ICSBP1), interferon-induced protein 44 (IFI44), transporter 2, ATP-binding cassette, subfamily B (TAP2) and transforming growth factor, beta receptor associated protein 1 (TGFBRAP1) for the responsiveness trait. Based on confirmed linkage disequilibrium block in the population, a minimal set of 26 SNPs in the seven selected genes was inferred. To predict treatment outcome, a multiple logistic regression model was constructed using susceptible genotypes of SNPs. The performance of the resultant model had a sensitivity of 68.2% and specificity of 60.7% on 317 CHC patients treated with IFN-combined therapy. In addition, a prediction model with both the host genetic and viral genotype information was also constructed which enhanced the performance with a sensitivity of 80.7% and specificity of 67.2%. CONCLUSIONS A genetic model was constructed to predict outcomes of the combination therapy in CHC patients with high sensitivity and specificity. Results also provide a possible process of selecting targets for predicting treatment outcomes and the basis for developing pharmacogenetic tests.
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23
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Comunale MA, Lowman M, Long RE, Krakover J, Philip R, Seeholzer S, Evans AA, Hann HWL, Block TM, Mehta AS. Proteomic analysis of serum associated fucosylated glycoproteins in the development of primary hepatocellular carcinoma. J Proteome Res 2006; 5:308-315. [PMID: 16457596 DOI: 10.1021/pr050328x] [Citation(s) in RCA: 177] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Changes in N-linked glycosylation are known to occur during the development of cancer. For example, increased branching of oligosaccharides has been associated with metastasis and has been correlated to tumor progression in human cancers of the breast, colon and melanomas. Increases in core fucosylation have also been associated with the development of hepatocellular carcinoma (HCC). Chronic infection with the hepatitis B virus is associated with more than 55% of all cases of hepatocellular carcinoma. We show here that increased levels of core fucosylation can be observed via glycan analysis of total serum and are associated with the development of HCC. In a blinded study, the serum glycoproteins derived from people diagnosed with HBV induced liver cancer were found to possess a dramatically higher level of fucosylation. This change occurs on both immunoglobulin molecules and on other serum glycoproteins. Targeted glycoproteomic analysis was used to identify those glycoproteins that are hyperfucosylated in cancer. In total, 19 proteins were found to be hyperfucosylated in cancer. The potential of these proteins as biomarkers of cancer is discussed.
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Affiliation(s)
- Mary Ann Comunale
- Drexel Institute for Biotechnology and Virology Research, Department of Microbiology and Immunology, Drexel University College of Medicine, Doylestown, Pennsylvania 18901, USA
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24
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Gómez CE, Vandermeeren AM, García MA, Domingo-Gil E, Esteban M. Involvement of PKR and RNase L in translational control and induction of apoptosis after Hepatitis C polyprotein expression from a vaccinia virus recombinant. Virol J 2005; 2:81. [PMID: 16156900 PMCID: PMC1242258 DOI: 10.1186/1743-422x-2-81] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/28/2005] [Accepted: 09/12/2005] [Indexed: 12/17/2022] Open
Abstract
Background Hepatitis C virus (HCV) infection is of growing concern in public health with around 350 million chronically infected individuals worldwide. Although the IFN-α/rivabirin is the only approved therapy with 10–30% clinical efficacy, the protective molecular mechanism involved during the treatment is still unknown. To analyze the effect of HCV polyprotein expression on the antiviral response of the host, we developed a novel vaccinia virus (VV)-based delivery system (VT7-HCV7.9) where structural and nonstructural (except part of NS5B) proteins of HCV ORF from genotype 1b are efficiently expressed and produced, and timely regulated in mammalian cell lines. Results Regulated transcript production and viral polypeptide processing was demonstrated in various cell lines infected with the recombinant VT7-HCV7.9, indicating that the cellular and viral proteolytic machineries are functional within these cells. The inducible expression of the HCV polyprotein by VV inhibits the synthesis of both host and viral proteins over the time and also induces apoptosis in HeLa and HepG2-infected cells. These effects occur accompanying with the phosphorylation of the translation initiation factor eIF-2α. In cells co-infected with VT7-HCV7.9 and a recombinant VV expressing the dominant negative eIF-2α-S51A mutant in the presence of the inductor isopropyl-thiogalactoside (IPTG), protein synthesis is rescued. The IFN-inducible protein kinase PKR is responsible for the translational block, as demonstrated with PKR-/- and PKR+/+ cell lines. However, apoptosis induced by VT7-HCV7.9 is mediated by the RNase L pathway, in a PKR-independent manner. Conclusion These findings demonstrate the antiviral relevance of the proteins induced by interferon, PKR and RNase L during expression from a VV recombinant of the HCV polyprotein in human cell lines. HCV polyprotein expression caused a severe cytopathological effect in human cells as a result of inhibition of protein synthesis and apoptosis induction, triggered by the activation of the IFN-induced enzymes PKR and RNase L systems. Thus, the virus-cell system described here highlights the relevance of the IFN system as a protective mechanism against HCV infection.
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Affiliation(s)
- Carmen E Gómez
- Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, CSIC, Campus Universidad Autónoma, 28049 Madrid, Spain
| | - Andrée Marie Vandermeeren
- Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, CSIC, Campus Universidad Autónoma, 28049 Madrid, Spain
| | - María Angel García
- Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, CSIC, Campus Universidad Autónoma, 28049 Madrid, Spain
| | - Elena Domingo-Gil
- Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, CSIC, Campus Universidad Autónoma, 28049 Madrid, Spain
| | - Mariano Esteban
- Department of Molecular and Cellular Biology, Centro Nacional de Biotecnología, CSIC, Campus Universidad Autónoma, 28049 Madrid, Spain
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25
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Ko WS, Guo CH, Yeh MS, Lin LY, Hsu GSW, Chen PC, Luo MC, Lin CY. Blood micronutrient, oxidative stress, and viral load in patients with chronic hepatitis C. World J Gastroenterol 2005; 11:4697-702. [PMID: 16094713 PMCID: PMC4615414 DOI: 10.3748/wjg.v11.i30.4697] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To assess the extent of micronutrient and oxidative stress in blood and to examine their linkages with viral loads in chronic hepatitis C patients.
METHODS: Hepatitis C virus (HCV)-RNA levels were quantified in the serum from 37 previously untreated patients with chronic hepatitis C. The plasma and erythrocyte micronutrients (zinc, selenium, copper, and iron) were estimated, and malondialdehyde (MDA) contents were determined as a marker to detect oxidative stress. Antioxidant enzymes, superoxide dismutase (SOD), glutathione peroxidase (GPX) and glutathione reductase (GR) activities in blood were also measured. The control group contained 31 healthy volunteers.
RESULTS: The contents of zinc (Zn), and selenium (Se) in plasma and erythrocytes were significantly lower in hepatitis C patients than in the controls. On the contrary, copper (Cu) levels were significantly higher. Furthermore, plasma and erythrocyte MDA levels, and the SOD and GR activities in erythrocytes significantly increased in hepatitis C patients compared to the controls. However, the plasma GPX activity in patients was markedly lower. Plasma Se (r = -0.730, P < 0.05), Cu (r = 0.635), and GPX (r = -0.675) demonstrated correlations with HCV-RNA loads. Significant correlation coefficients were also observed between HCV-RNA levels and erythrocyte Zn (r = -0.403), Se (r = -0.544), Cu (r = 0.701) and MDA (r = 0.629) and GR (r = 0.441).
CONCLUSION: The levels of Zn, Se, Cu, and oxidative stress (MDA), as well as related anti-oxidative enzymes (GR and GPX) in blood have important impact on the viral factors in chronic hepatitis C. The distribution of these parameters might be significant biomarkers for HCV.
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Affiliation(s)
- Wang-Sheng Ko
- Department of Food and Nutrition, Hung Kuang University, Taichung, Taiwan, China
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26
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Ko WS, Guo CH, Hsu GSW, Chiou YL, Yeh MS, Yaun SR. The effect of zinc supplementation on the treatment of chronic hepatitis C patients with interferon and ribavirin. Clin Biochem 2005; 38:614-20. [PMID: 15904908 DOI: 10.1016/j.clinbiochem.2005.04.003] [Citation(s) in RCA: 31] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/05/2004] [Revised: 04/07/2005] [Accepted: 04/15/2005] [Indexed: 11/16/2022]
Abstract
OBJECTIVES To evaluate the effects of zinc supplementation on serum zinc and copper levels, and the severity of adverse reactions and virologic responses in chronic hepatitis C patients undergoing interferon (IFN)/ribavirin therapy. DESIGN AND METHODS Forty subjects were randomly assigned to receive IFN-alpha-2a/ribavirin with or without zinc gluconate for 24 weeks, then a period of 6 months for follow-up. Twenty healthy controls were also enrolled in the study. Blood samples were collected at different time points during therapy and at 6 months after the completion of therapy and were analyzed for zinc and copper levels. The adverse reactions and the virologic responses were also examined accordingly. RESULTS Serum zinc levels were significantly lower in chronic hepatitis C patients than in healthy controls and further depressed by IFN/ribavirin treatment. However, serum zinc levels in patients were remediable by zinc supplements. No apparent difference was seen in virologic responses between subjects with or without zinc supplements, but certain adverse side effects associated with the zinc therapy were significantly decreased. CONCLUSIONS Zinc supplementation may be a complementary therapy in chronic hepatitis C patients to increase the tolerance to IFN-alpha-2a and ribavirin.
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Affiliation(s)
- Wang-Sheng Ko
- Department of Food and Nutrition, Hung Kuang University, Taichung 433, Taiwan, Republic of China.
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27
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Aurisicchio L, De Tomassi A, La Monica N, Ciliberto G, Traboni C, Palombo F. Regulated and liver-specific tamarin alpha interferon gene delivery by a helper-dependent adenoviral vector. J Virol 2005; 79:6772-80. [PMID: 15890916 PMCID: PMC1112151 DOI: 10.1128/jvi.79.11.6772-6780.2005] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Gene therapy approaches based on liver-restricted and regulated alpha interferon (IFN-alpha) expression, recently shown to be effective in different murine hepatitis models, appear promising alternatives to inhibit hepatitis C virus (HCV) replication in patients and minimize side effects. Tamarins (Saguinus species) infected by GB virus B (GBV-B) are considered a valid surrogate model for hepatitis C to study the biology of HCV infection and the development of new antiviral drugs. To test the efficacy of local delivery and expression of IFN-alpha in this model, we have developed HD-TET-tIFN, a helper-dependent adenovirus vector expressing tamarin IFN-alpha (tIFN) under the control of the tetracycline-inducible transactivator rtTA2s-S2. Expression of tIFN was successfully induced both in vitro and in vivo in rodents by doxycycline administration with consequent activation of IFN-responsive genes. More importantly, tIFN efficiently inhibited GBV-B replicon in a Huh-7 hepatoma cell line at low HD-TET-tIFN doses. A certain degree of transcriptional control of tIFN was achieved in tamarins injected with HD-TET-tIFN, but under the conditions used in this study, infection and replication of GBV-B were only delayed and not totally abrogated upon virus challenge. Hepatic delivery and regulated expression of IFN-alpha appear to be a possible approach for the cure of hepatitis, but this approach requires more studies to increase its efficacy. To our knowledge, this is the first report showing a regulated gene expression in a nonhuman primate hepatitis model.
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MESH Headings
- Adenoviridae/genetics
- Animals
- Base Sequence
- DNA, Recombinant/genetics
- Disease Models, Animal
- Female
- Flaviviridae Infections/genetics
- Flaviviridae Infections/immunology
- Flaviviridae Infections/therapy
- GB virus B/immunology
- GB virus B/pathogenicity
- Gene Expression
- Genetic Therapy
- Genetic Vectors
- Helper Viruses/genetics
- Hepatitis C/genetics
- Hepatitis C/immunology
- Hepatitis C/therapy
- Hepatitis, Viral, Animal/genetics
- Hepatitis, Viral, Animal/immunology
- Hepatitis, Viral, Animal/therapy
- In Vitro Techniques
- Interferon Type I/genetics
- Liver/immunology
- Liver/virology
- Mice
- Mice, Inbred C57BL
- Rats
- Rats, Sprague-Dawley
- Recombinant Proteins
- Replicon/genetics
- Saguinus/genetics
- Saguinus/immunology
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Affiliation(s)
- Luigi Aurisicchio
- IRBM-Istituto di Ricerche di Biologia Molecolare P. Angeletti, Via Pontina Km 30.6, Pomezia, Italy.
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28
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Pai M, Prabhu R, Panebra A, Nangle S, Haque S, Bastian F, Garry R, Agrawal K, Goodbourn S, Dash S. Activation of Interferon-Stimulated Response Element in Huh-7 Cells Replicating Hepatitis C Virus Subgenomic RNA. Intervirology 2005; 48:301-11. [PMID: 15956798 DOI: 10.1159/000085099] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2004] [Accepted: 11/10/2004] [Indexed: 01/09/2023] Open
Abstract
Interferon-alpha (IFN(alpha)) binds to receptors on the cell surface, which initiate a cascade of signal transduction pathways that leads to transcription of selected genes. This transduction pathway involves binding of transcription factors to a common cis-acting DNA sequence called IFN-stimulated response element (ISRE). To test whether these signaling pathways are functional in hepatitis C virus (HCV)-replicating cells, we studied the regulation of ISRE-mediated transcription of firefly luciferase gene in stable replicon cell lines. A plasmid construct was prepared (pISRELuc) which contains four tandem repeats of 9-27 ISRE sequences positioned directly upstream of the herpes virus 1 thymidine kinase promoter TATA box that drives the expression of firefly luciferase. Regulation of ISRE-mediated expression of firefly luciferase by IFN(alpha) was studied by transfecting this clone into Huh-7 cells replicating HCV subgenomic HCV RNA. The significance of ISRE-mediated transcriptional activation was studied in a replicon cell line by pretreatment of cells with actinomycin D, which inhibits cellular DNA-dependent RNA transcription. IFN treatment activates ISRE-mediated expression of luciferase, indicating that this pathway is functional in Huh-7 cells. Activation of ISRE-mediated transcription of luciferase is relatively high in two Huh-7 stable cell lines replicating HCV subgenomic RNA. Inhibition of ISRE-mediated transcription of luciferase by actinomycin D also makes HCV replication totally resistant to IFN(alpha). These in vitro studies suggest that activation of IFN-inducible genes is important in mounting a successful antiviral response against HCV.
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Affiliation(s)
- Mirabel Pai
- Department of Pathology and Laboratory Medicine, Tulane University Health Sciences Center, New Orleans, LA 70112, USA
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29
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Radaeva S, Jaruga B, Kim WH, Heller T, Liang TJ, Gao B. Interferon-gamma inhibits interferon-alpha signalling in hepatic cells: evidence for the involvement of STAT1 induction and hyperexpression of STAT1 in chronic hepatitis C. Biochem J 2004; 379:199-208. [PMID: 14690454 PMCID: PMC1224051 DOI: 10.1042/bj20031495] [Citation(s) in RCA: 26] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2003] [Revised: 12/15/2003] [Accepted: 12/23/2003] [Indexed: 01/17/2023]
Abstract
IFN-gamma (interferon-gamma) modulates IFN-alpha therapy in chronic hepatitis C infection; however, the underlying mechanism remains unclear. Here we demonstrate that long-term (3-6 days) but not short-term (up to 1 day) IFN-gamma treatment of human hepatoma Hep3B cells attenuates IFN-alpha activation of STAT1 (signal transducers and activators of transcription factor 1), STAT2 and STAT3, but enhances IFN-gamma and interleukin 6 activation of STATs. Prolonged exposure to IFN-gamma also significantly induces STAT1 protein expression without affecting STAT2, STAT3 and ERK (extracellular-signal-regulated kinase) 1/2 protein expression. To determine the role of STAT1 protein overexpression in regulation of IFN-alpha signalling, Hep3B cells were stably transfected with wild-type STAT1. Overexpression of STAT1 via stable transfection enhances IFN-gamma activation of STAT1, but surprisingly attenuates IFN-alpha activation of STAT1, STAT2 and STAT3 without affecting Janus kinase activation. This STAT1-mediated inhibition does not require STAT1 tyrosine phosphorylation because overexpression of dominant-negative STAT1 with a mutation on tyrosine residue 701 also blocks IFN-alpha activation of STAT1, STAT2 and STAT3. Moreover, overexpression of STAT1 blocks IFN-alpha-activated STAT2 translocation from IFN-alpha receptor 2 to IFN-alpha receptor 1, a critical step in IFN-alpha signalling activation. Finally, significantly higher levels of STAT1 protein expression, which is probably induced by IFN-gamma, are detected in the majority of hepatitis C virus-infected livers compared with healthy controls. In conclusion, long-term IFN-gamma treatment inhibits IFN-alpha-activated signals most probably, at least in part, through the induction of STAT1 protein expression, which could partly contribute to IFN-alpha treatment failure in hepatitis C patients.
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Affiliation(s)
- Svetlana Radaeva
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, 12420 Parklawn Drive, MSC 8115, Bethesda, MD 20892, USA
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30
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Wodarz D. Hepatitis C virus dynamics and pathology: the role of CTL and antibody responses. J Gen Virol 2003; 84:1743-1750. [PMID: 12810868 DOI: 10.1099/vir.0.19118-0] [Citation(s) in RCA: 62] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022] Open
Abstract
This paper investigates the role of CTL and antibody responses in hepatitis C virus (HCV) dynamics and pathology. Mathematical models suggest that a strong CTL response is required for resolution of HCV infection and that a weak CTL response can result in persistent infection. According to the model, establishment of persistent infection is accompanied mainly by an ongoing antibody response, while CTLs are not maintained at high levels. In the model, this outcome correlates with absence of pathology. Persistent infection in the face of an ongoing antibody response can result in evolution of antigenic escape. According to the model, evolution towards escape from antibodies can shift the balance of immune responses so that the weak CTL levels become increasingly more dominant relative to antibodies. This shift results in onset of liver pathology as the virus evolves towards increased levels of antigenic escape. Therefore, the relative balance of the immune response can be a decisive factor that determines whether patients are asymptomatic or whether pathology is observed. Virus evolution can shift this balance towards pathology over time. Theoretical results are discussed in the context of published data.
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Affiliation(s)
- Dominik Wodarz
- Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, MP-665, Seattle, WA 98109, USA
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31
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Geiss GK, Carter VS, He Y, Kwieciszewski BK, Holzman T, Korth MJ, Lazaro CA, Fausto N, Bumgarner RE, Katze MG. Gene expression profiling of the cellular transcriptional network regulated by alpha/beta interferon and its partial attenuation by the hepatitis C virus nonstructural 5A protein. J Virol 2003; 77:6367-75. [PMID: 12743294 PMCID: PMC155033 DOI: 10.1128/jvi.77.11.6367-6375.2003] [Citation(s) in RCA: 91] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/01/2023] Open
Abstract
Alpha/beta interferons (IFN-alpha/beta) induce potent antiviral and antiproliferative responses and are used to treat a wide range of human diseases, including chronic hepatitis C virus (HCV) infection. However, for reasons that remain poorly understood, many HCV isolates are resistant to IFN therapy. To better understand the nature of the cellular IFN response, we examined the effects of IFN treatment on global gene expression by using several types of human cells, including HeLa cells, liver cell lines, and primary fetal hepatocytes. In response to IFN, 50 of the approximately 4,600 genes examined were consistently induced in each of these cell types and another 60 were induced in a cell type-specific manner. A search for IFN-stimulated response elements (ISREs) in genomic DNA located upstream of IFN-stimulated genes revealed both previously identified and novel putative ISREs. To determine whether HCV can alter IFN-regulated gene expression, we performed microarray analyses on IFN-treated HeLa cells expressing the HCV nonstructural 5A (NS5A) protein and on IFN-treated Huh7 cells containing an HCV subgenomic replicon. NS5A partially blocked the IFN-mediated induction of 14 IFN-stimulated genes, an effect that may play a role in HCV resistance to IFN. This block may occur through repression of ISRE-mediated transcription, since NS5A also inhibited the IFN-mediated induction of a reporter gene driven from an ISRE-containing promoter. In contrast, the HCV replicon had very little effect on IFN-regulated gene expression. These differences highlight the importance of comparing results from multiple model systems when investigating complex phenomena such as the cellular response to IFN and viral mechanisms of IFN resistance.
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Affiliation(s)
- Gary K Geiss
- Department of Microbiology, School of Medicine, University of Washington, Seattle 98195, USA
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32
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He Y, Yan W, Coito C, Li Y, Gale M, Katze MG. The regulation of hepatitis C virus (HCV) internal ribosome-entry site-mediated translation by HCV replicons and nonstructural proteins. J Gen Virol 2003; 84:535-543. [PMID: 12604803 DOI: 10.1099/vir.0.18658-0] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022] Open
Abstract
Hepatitis C virus (HCV), the global leading cause of chronic liver disease, has a positive-sense, ssRNA genome that encodes a large polyprotein. HCV polyprotein translation is initiated by an internal ribosome-entry site (IRES) located at the 5' end of the viral genome, in a cap-independent manner, but the regulatory mechanism of this process remains poorly understood. In this study, we characterized the effect of HCV nonstructural proteins on HCV IRES-directed translation in both HCV replicon cells and transiently transfected human liver cells expressing HCV nonstructural proteins. Using bicistronic reporter gene constructs carrying either HCV or other viral IRES sequences, we found that the HCV IRES-mediated translation was specifically upregulated in HCV replicon cells. This enhancement of HCV IRES-mediated translation by the replicon cells was inhibited by treatment with either type I interferon or ribavirin, drugs that perturb HCV genome replication, suggesting that the enhancement is probably due to HCV-encoded protein function(s). Reduced phosphorylation levels of both eIF2alpha and eIF4E were observed in the replicon cells, which is consistent with our previous findings and indicates that the NS5A nonstructural protein may be involved in the regulatory mechanism(s). Indeed, transient expression of NS5A or NS4B in human liver cells stimulated HCV IRES activity. Interestingly, mutation in the ISDR of NS5A perturbed this stimulation of HCV IRES activity. All these results suggest, for the first time, that HCV nonstructural proteins preferentially stimulate the viral cap-independent, IRES-mediated translation.
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Affiliation(s)
- Yupeng He
- Department of Microbiology, School of Medicine, University of Washington, Seattle, WA, USA
| | - Wei Yan
- Department of Microbiology, School of Medicine, University of Washington, Seattle, WA, USA
| | - Carlos Coito
- Department of Microbiology, School of Medicine, University of Washington, Seattle, WA, USA
| | - Yu Li
- Department of Microbiology, School of Medicine, University of Washington, Seattle, WA, USA
| | - Michael Gale
- Department of Microbiology, University of Texas Southwestern Medical Center, Dallas, TX, USA
| | - Michael G Katze
- Regional Primate Research Center, University of Washington, Seattle, WA, USA
- Department of Microbiology, School of Medicine, University of Washington, Seattle, WA, USA
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33
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He Y, Katze MG. To interfere and to anti-interfere: the interplay between hepatitis C virus and interferon. Viral Immunol 2002; 15:95-119. [PMID: 11952150 DOI: 10.1089/088282402317340260] [Citation(s) in RCA: 70] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022] Open
Abstract
As popular strategies used by numerous viruses, interception of interferon (IFN) signaling and inhibition of IFN-induced antiviral functions allow viruses to evade the host immune response and set up successful infections. Hepatitis C virus (HCV), the leading cause of chronic liver disease worldwide and a major public health hazard, causes persistent infection in the majority of infected individuals. IFN-based therapies, currently the only ones available for HCV infection, have been unable to eliminate viral infection in the majority of patients, and many studies suggest that HCV possesses mechanisms to antagonize the IFN-induced antiviral response. Multiple viral, host, and IFN-associated factors have been implicated in the interplay between HCV and IFN. Two viral proteins, NS5A and E2, became the focus of much attention and extensive study because of their abilities to inhibit IFN-induced, double-stranded RNA-activated protein kinase (PKR), a major mediator of the IFN-induced biologic response, and to perturb the IFN signaling pathway. In this review, we discuss the significance of the interferon sensitivity determining region (ISDR) within NS5A, which has been the subject of intense debates. In addition, we discuss the potential mechanisms by which NS5A interferes with IFN signaling and the current working models. Further understanding of the molecular mechanisms underlying the interaction between HCV and IFN will likely facilitate improvement of current IFN-based therapies and development of novel treatments for the HCV pandemic. Future HCV research will benefit from both the development of efficient, convenient model systems for viral propagation, and the utilization of high throughput, genomic-scale approaches.
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Affiliation(s)
- Yupeng He
- Department of Microbiology, School of Medicine, University of Washington, 98195, USA
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34
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De Tomassi A, Pizzuti M, Graziani R, Sbardellati A, Altamura S, Paonessa G, Traboni C. Cell clones selected from the Huh7 human hepatoma cell line support efficient replication of a subgenomic GB virus B replicon. J Virol 2002; 76:7736-46. [PMID: 12097587 PMCID: PMC136363 DOI: 10.1128/jvi.76.15.7736-7746.2002] [Citation(s) in RCA: 21] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/20/2022] Open
Abstract
Tamarins (Saguinus species) infected by GB virus B (GBV-B) have recently been proposed as an acceptable surrogate model for hepatitis C virus (HCV) infection. The availability of infectious genomic molecular clones of both viruses will permit chimeric constructs to be tested for viability in animals. Studies in cells with parental and chimeric constructs would also be very useful for both basic research and drug discovery. For this purpose, a convenient host cell type supporting replication of in vitro-transcribed GBV-B RNA should be identified. We constructed a GBV-B subgenomic selectable replicon based on the sequence of a genomic molecular clone proved to sustain infection in tamarins. The corresponding in vitro-transcribed RNA was used to transfect the Huh7 human hepatoma cell line, and intracellular replication of transfected RNA was shown to occur, even though in a small percentage of transfected cells, giving rise to antibiotic-resistant clones. Sequence analysis of GBV-B RNA from some of those clones showed no adaptive mutations with respect to the input sequence, whereas the host cells sustained higher GBV-B RNA replication than the original Huh7 cells. The enhancement of replication depending on host cell was shown to be a feature common to the majority of clones selected. The replication of GBV-B subgenomic RNA was susceptible to inhibition by known inhibitors of HCV to a level similar to that of HCV subgenomic RNA.
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Affiliation(s)
- Amedeo De Tomassi
- Istituto di Ricerche di Biologia Molecolare P. Angeletti, 00040 Pomezia, Rome, Italy
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35
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Moriguchi H, Uemura T, Kobayashi M, Chung RT, Sato C. Management strategies using pharmacogenomics in patients with severe HCV-1b infection: a decision analysis. Hepatology 2002; 36:177-85. [PMID: 12085363 DOI: 10.1053/jhep.2002.33895] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/16/2023]
Abstract
The management of interferon (IFN) therapy for histologically severe chronic hepatitis C virus genotype 1b (HCV-1b [F3]) is controversial. A decision analysis using the Markov decision analysis model was performed for 6 disease management strategies by using clinical data from a Japanese teaching hospital and available published data. The results of base case analyses showed that IFN monotherapy was considered favorable for patients aged 40 to 60 years with HCV-1b (F3). For the sensitivity analyses, to support the results of base case analyses, HCV-1b (F3) patient quality-of-life (QOL) score must be 0.5 or greater for those 40 to 50 years old and 0.4 to 0.5 or greater for those 60 years old. When patients with HCV-1b (F3) were judged as nonresponsive (NR) after IFN monotherapy, the transition probabilities of liver diseases at 40, 50, and 60 years of age had to be such that the progression of liver diseases was controlled at an annual rate of 7.51% to 8.82% or lower, 7.77% to 8.27% or lower, and 6.39% to 6.60% or lower, respectively, and the sustained virologic response (SVR) rate for IFN monotherapy must be 3.0% to 5.51% or greater, 5.57% to 5.93% or greater, and 10.6% to 11.21% or greater, respectively. It is likely that IFN monotherapy could be applied to patients with HCV-1b (F3) aged 40 years at a dose of at least 432 MU. However, IFN monotherapy did not appear useful for patients with HCV-1b (F3) aged 50 and 60 years if they had no amino acid mutation in NS5A 2209 to 2248 and HCV RNA levels exceeded 1.0 mEq/mL. In conclusion, use of decision analysis models can help in therapeutic decisions for patients with HCV-1b.
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Affiliation(s)
- Hisashi Moriguchi
- Division of Advanced Medical Technology and Intellectual Property Policy, Research Center for Advanced Science and Technology, University of Tokyo, 4-6-1 Komaba Meguro-ku, Tokyo, Japan 153-8904.
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36
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Radaeva S, Jaruga B, Hong F, Kim WH, Fan S, Cai H, Strom S, Liu Y, El-Assal O, Gao B. Interferon-alpha activates multiple STAT signals and down-regulates c-Met in primary human hepatocytes. Gastroenterology 2002; 122:1020-1034. [PMID: 11910354 DOI: 10.1053/gast.2002.32388] [Citation(s) in RCA: 104] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/04/2023]
Abstract
BACKGROUND & AIMS Interferon (IFN)-alpha therapy is currently the primary choice for viral hepatitis and a promising treatment for hepatocellular carcinoma (HCC). Primary mouse and rat hepatocytes respond poorly to IFN-alpha stimulation. Thus, it is very important to examine the IFN-alpha signal pathway in primary human hepatocytes. METHODS The IFN-alpha-activated signals and genes in primary human hepatocytes and hepatoma cells were examined by Western blotting and microarray analyses. RESULTS Primary human hepatocytes respond very well to IFN-alpha stimulation as shown by activation of multiple signal transducer and activator of transcription factor (STAT) 1, 2, 3, 5, and multiple genes. The differential response to IFN-alpha stimulation in primary human and mouse hepatocytes may be caused by expression of predominant functional IFN-alpha receptor 2c (IFNAR2c) in primary human hepatocytes vs. expression of predominant inhibitory IFNAR2a in mouse hepatocytes. Microarray analyses of primary human hepatocytes show that IFN-alpha up-regulates about 44 genes by over 2-fold and down-regulates about 9 genes by 50%. The up-regulated genes include a variety of antiviral and tumor suppressors/proapoptotic genes. The down-regulated genes include c-myc and c-Met, the hepatocyte growth factor (HGF) receptor. Down-regulation of c-Met is caused by IFN-alpha suppression of the c-Met promoter through down-regulation of Sp1 binding and results in attenuation of HGF-induced signals and cell proliferation. CONCLUSIONS IFN-alpha directly targets human hepatocytes, followed by activation of multiple STATs and regulation of a wide variety of genes, which may contribute to the antiviral and antitumor activities of IFN-alpha in human liver.
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Affiliation(s)
- Svetlana Radaeva
- Section on Liver Biology, Laboratory of Physiologic Studies, National Institute on Alcohol Abuse and Alcoholism, National Institutes of Health, Bethesda, Maryland 20892, USA
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Abstract
The control of the global expansion and proliferation of the AIDS pandemic has been complicated by the emergence of resistant strains of HIV-1 to the many new antiviral drugs directed to the genes coding for reverse transcriptase and protease enzymes of the virus. Similarly, new drug regimens for the management of chronic hepatitis B and C infections have been complicated by the lack of sustained clinical responses recently associated with either nucleotide mutation (HBV) or specific genotype of the virus (HCV). Commercial systems for performing and interpreting genotypic analysis will facilitate the recognition of informative mutations, standardize results between laboratories, and produce informative and interpretative result formats for optimal treatment of patients. Drug-resistant strains of herpesviruses (HSV, VZV, CMV) are generally associated with prolonged treatment of these infections in immunocompromised patients. Ultimate relevance of genotypic assays for routine clinical practice will require correlation with phenotypic results and the outcomes of long-term studies associating clinical improvement with antiviral drugs with specific mutation patterns of these viruses.
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Affiliation(s)
- T F Smith
- Division of Clinical Microbiology, Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, Minnesota, USA.
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38
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Komurian-Pradel F, Paranhos-Baccalà G, Sodoyer M, Chevallier P, Mandrand B, Lotteau V, André P. Quantitation of HCV RNA using real-time PCR and fluorimetry. J Virol Methods 2001; 95:111-9. [PMID: 11377718 DOI: 10.1016/s0166-0934(01)00300-7] [Citation(s) in RCA: 74] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Real-time PCR technology may provide an accurate and sensitive method to quantify hepatitis C virus (HCV) RNA. So far, studies have been carried out using the Taqman technology with the ABI Prism 7700 sequence detector. An alternative and simple real-time PCR assay is described with no probe requirement, based on the SYBR Green I dye and LightCycler fluorimeter. Amplicon synthesis was monitored continuously by SYBR Green I dye binding to double stranded DNA during PCR of the 5' HCV non-coding (NC) region. Specificity was verified by amplicon melting temperatures. An external standard curve was constructed with serial 10 fold dilutions of a modified synthetic HCV 5' NC RNA. A wide range linear relationship (up to 3.7x10(9) copies/ml) was observed between number of PCR cycle needed to detect a fluorescent signal and number of RNA copy. Intra- and inter-assay coefficients of variation were 0.7 to 2.1 and 3.7% respectively, indicating good reproducibility of the method. Thirty-three HCV positive sera of different genotypes were quantified by this method and gave similar but more sensitive results compared to the branched DNA (bDNA) technology.
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39
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Chung RT, He W, Saquib A, Contreras AM, Xavier RJ, Chawla A, Wang TC, Schmidt EV. Hepatitis C virus replication is directly inhibited by IFN-alpha in a full-length binary expression system. Proc Natl Acad Sci U S A 2001; 98:9847-52. [PMID: 11493707 PMCID: PMC55541 DOI: 10.1073/pnas.171319698] [Citation(s) in RCA: 55] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
Hepatitis C virus (HCV) is a leading cause of chronic hepatitis, cirrhosis, and hepatocellular carcinoma. The absence of culture systems permissive for HCV replication has presented a major bottleneck to antiviral development. We sought to recapitulate the early steps in the life cycle of HCV by means of DNA-based expression of viral genomic sequences. Here we report expression of replicating HCV RNA by using a, to our knowledge, novel binary expression system in which cells were transfected with a T7 polymerase-driven full-length HCV cDNA plasmid containing a cis-acting hepatitis Delta ribozyme to control 3' cleavage, and infected with vaccinia-T7 polymerase. HCV genomic and replicative strand synthesis, in addition to protein synthesis, was detectable and depended on full-length HCV sequences. Moreover, the system was capable of generating HCV RNA quasispecies, consistent with the action of the low-fidelity HCV NS5B RNA polymerase. IFN-alpha, but not ribavirin, directly inhibited the viral replicative cycle in these cells, identifying the virus itself and not solely the immune system as a direct target of IFN action. The availability of a cell-based test for viral replication will facilitate screening of inhibitory compounds, analysis of IFN-resistance mechanisms, and analysis of virus-host cell interactions.
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MESH Headings
- Amantadine/pharmacology
- Animals
- Antiviral Agents/pharmacology
- Bacteriophage T7/genetics
- Carcinoma, Hepatocellular/pathology
- Chlorocebus aethiops
- DNA, Complementary/genetics
- Gene Expression Regulation, Viral/drug effects
- Genes, Synthetic
- Hepacivirus/drug effects
- Hepacivirus/physiology
- Humans
- Interferon-alpha/pharmacology
- Liver Neoplasms/pathology
- Oligodeoxyribonucleotides, Antisense/chemical synthesis
- Oligodeoxyribonucleotides, Antisense/genetics
- Polymerase Chain Reaction
- RNA, Catalytic/genetics
- RNA, Viral/biosynthesis
- Reverse Transcriptase Polymerase Chain Reaction
- Ribavirin/pharmacology
- Terminator Regions, Genetic
- Transfection
- Tumor Cells, Cultured
- Viral Proteins/biosynthesis
- Viral Proteins/genetics
- Virus Replication/drug effects
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Affiliation(s)
- R T Chung
- Gastrointestinal Unit, Cancer Center, and Hospital for Children, Massachusetts General Hospital, Boston, MA 02114, USA.
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40
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Tan SL, Katze MG. How hepatitis C virus counteracts the interferon response: the jury is still out on NS5A. Virology 2001; 284:1-12. [PMID: 11352662 DOI: 10.1006/viro.2001.0885] [Citation(s) in RCA: 153] [Impact Index Per Article: 6.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Interferons (IFNs) induce an antiviral state in the cell through complex and indirect mechanisms, which culminate in a direct inhibition of viral replication and stimulation of the host adaptive responses. Viruses often counteract with elaborate strategies to interfere with the induction as well as action of IFN effector molecules. This evolutionary battle between viruses and IFN components is a subject of intense research aimed at understanding the immunopathogenesis of viruses and the molecular basis of IFN signaling and action. In the case with hepatitis C virus (HCV), this may have profound implications for the therapeutic use of recombinant IFN in treating chronic hepatitis C. Depending on the subtype of HCV, current IFN-based treatment regimens are effective for only a small subset of chronic hepatitis C patients. Thus, one of the Holy Grails in HCV research is to understand the mechanisms by which the virus may evade IFN antiviral surveillance and establish persistent infection, which may eventually provide insights into new avenues for better antiviral therapy. Despite the lack of an efficient tissue culture system and an appropriate animal model for HCV infection, several mechanisms have been proposed based on clinical studies and in vitro experiments. This minireview focuses on the HCV NS5A nonstructural protein, which is implicated in playing a role in HCV tolerance to IFN treatment, possibly in part through its ability to inhibit the cellular IFN-induced PKR protein kinase.
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Affiliation(s)
- S L Tan
- Infectious Diseases Research, Eli Lilly and Company, Indianapolis, Indiana 46285, USA.
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Abstract
With increased recognition of the profound morbidity of sickle cell disease and with growing evidence of the efficacy of transfusion therapy in prevention and treatment of sickle cell complications, most patients now receive intermittent transfusion therapy. The purpose of this report is to review blood component therapy and Its risks for sickle cell patients. Packed red cells are the preferred blood component. Leukocyte-reduced units should be standard because of their beneficial effects in reducing alloimmunization, transfusion reactions, platelet refractoriness, and infection transmission. The use of washed, frozen, or Irradiated units is limited to specific problems. Sickle trait-positive units function normally, but because of difficulties with calculating hemoglobin S percentages and leukocyte filters, they are not routinely used. Transfusion-acquired infections have shown a marked decrease but still present a major risk. Viral hepatitis transmission is currently low, but at least 10% of adult sickle cell patients are hepatitis C positive, and they often have liver damage. Although bacterial infections are rare, they account for 16% of transfusion-related fatalities. Patients who are iron overloaded are particularly vulnerable to Yersina enterocolitica. Red cell alloimmunization is a serious problem that could potentially affect 50% of transfused patients. However, preventive phenotypic matching for common antigens can minimize alloimmunization; limited matching for at least E, C, and K has become the standard of care. Recently, more patients are being identified who have developed red cell autoantibodies, which can mask alloantibodies and occasionally are hemolytic. Careful laboratory evaluation of all cases is essential. Transfusions also may trigger sickle cell events, including pain crises, stroke, and acute pulmonary deterioration. In part, these are induced by blood viscosity and increased blood pressure. Diuretic therapy and close monitoring of transfusion volume and vital signs can minimize these events. In summary, transfusion therapy carries risks, but the routine use of leukocyte-reduced, phenotypically matched units in conjunction with close monitoring of patients can make transfusion therapy safer.
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Affiliation(s)
- E P Vichinsky
- Department of Pediatrics, University of California, San Francisco, USA
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42
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Abstract
Interferon plays a critical role in the host's natural defense against viral infections and in their treatment. It is the only therapy for hepatitis C virus (HCV) infection; however, many virus isolates are resistant. Several HCV proteins have been shown to possess properties that enable the virus to evade the interferon-mediated cellular antiviral responses.
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Affiliation(s)
- D R Taylor
- Department of Molecular Microbiology and Immunology, University of Southern California, School of Medicine, 2011 Zonal Avenue, Los Angeles, CA 90089, USA
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43
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Abstract
Several aspects are revised on the subject related to drugs used, their doses, duration of treatment, different responses obtained, according different types of diseases and patients studied, as the factors able to modify the results obtained.
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Affiliation(s)
- V P Conte
- Departamento de Gastroenterologia da Faculdade de Medicina, Universidade de São Paulo
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