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PubMed2002

Primary hepatocytes of Tupaia belangeri as a potential model for hepatitis C virus infection.

Hepatitis C virus (HCV) is a major cause of chronic hepatitis worldwide, but the study of HCV infection has been hampered by the lack of an in vitro or in vivo small animal model. The tree shrew Tupaia belangeri is susceptible to infection with a variety of human viruses in vivo, including hepatitis viruses. We show that primary Tupaia hepatocytes can be infected with serum- or plasma-derived HCV from infected humans, as measured by de novo synthesis of HCV RNA, analysis of viral quasispecies evolution, and detection of viral proteins. Production of infectious virus could be demonstrated by passage to naive hepatocytes. To assess whether viral entry in Tupaia hepatocytes was dependent on the recently isolated HCV E2 binding protein CD81, we identified and characterized Tupaia CD81. Sequence analysis of cloned Tupaia cDNA revealed a high degree of homology between Tupaia and human CD81 large extracellular loops (LEL). Cellular binding of E2 and HCV infection could not be inhibited by anti-CD81 antibodies or soluble CD81-LEL, suggesting that viral entry can occur through receptors other than CD81. Thus, primary Tupaia hepatocytes provide a potential model for the study of HCV infection of hepatocytes.

Animals↗

PubMed2000

Asian perspectives on viral hepatitis: hepatitis C virus infection.

Hepatitis C virus (HCV) infection is widespread throughout Asia. Unusual features of HCV in Asia include a novel genotype distribution with a significant representation of 3a. This is particularly important as genotype 3 is very sensitive to interferon-based therapies. A major concern in the Asian region is the high prevalence of hepatocellular cancer complicating HCV-associated cirrhosis, particularly in Japan. Finally, liver transplantation for advanced HCV infection with cirrhosis is an option via cadaveric and living donor programmes.

Antiviral Agents↗

PubMed1996

Reciprocal interactions between human immunodeficiency virus and hepatitis C virus infections.

Hepatitis C virus (HCV) and human immunodeficiency virus (HIV) share the same routes of transmission, which explains the high rate of HCV and HIV coinfection (approximately 9%). HIV/HCV coinfection leads to high rates of indeterminate recombinant immunoblot assay patterns and seroreversion; high levels of viral replication; and a more severe histopathologic course. By contrast, HCV infection does not seem to accelerate the progression of HIV infection. Interferon alpha (IFN-alpha) in coinfected patients leads to a similar rate of primary responses, but sustained responses are less frequent. The potential severity of hepatitis C virus infection evidences the need for early diagnosis. Liver biopsy should be performed for all HCV RNA-positive patients in order to evaluate the activity of the liver disease. Given the poor efficiency of IFN-alpha in terms of sustained response in HIV-infected patients, reinforced therapeutic procedures (long-term administration of IFN-alpha or combined ribavirin/IFN-alpha) should be proposed, at least for those patients with severe liver disease.

AIDS-Related Opportunistic Infections↗

PubMed1994

[Summary and evaluation of genome and antibody diagnosis in hepatitis C virus infection].

Hepatitis C virus (HCV) infection can be diagnosed by antibody assay systems using recombinant antigens since the HCV genome has been identified. It is still impossible to detect viral antigens associated with HCV. Therefore, the polymerase chain reaction (PCR) has been widely used in practical laboratory examinations. Because HCV is an RNA virus and the reverse transcription process is required prior to the PCR reaction, the process of HCV RNA detection has a risk of contamination and the detection rate may differ with the PCR condition. There are several genome diagnostic methods for HCV infection; that is, genome detection by nested PCR, HCV subtyping using mixed primer, quantitation of HCV genome using competitive PCR, Quant-Amp and branched DNA probe. To clarify what factors are responsible, the efficacy of interferon therapy against chronic hepatitis C was examined. The normalization rate of serum ALT level and clearance rate of HCV RNA in serum at six months after the end of the treatment were correlated to the titer of HCV RNA genome and the HCV subtype. The patients with HCV RNA titers of less than 10(4) copies/50 microliters and with subtype group III showed a high response to interferon administration. On the other hand, the results of quantitation of the HCV core antibody titer were closely associated with the presence of HCV RNA using core protein with the recombinant vaccinia expression system or recombinant E. coli system (JCC-2). Especially, in the group of high responders to interferon treatment, the antibody titer against core protein was apparently decreased after the end of interferon therapy.(ABSTRACT TRUNCATED AT 250 WORDS)

Genome, Viral↗

PubMed2000

Persistence rate and progression of vertically acquired hepatitis C infection. European Paediatric Hepatitis C Virus Infection.

Data were collected from 104 infected children who were followed up from birth for a mean of 49 (range, 6-153) months in 22 European centers, to outline the natural history of perinatal hepatitis C virus (HCV) infection. Fifty-four children were persistently HCV RNA positive, 44 were occasionally positive, and 6 never had detectable viremia. At least 90% of the children had evidence of ongoing infection at the latest analysis. Eighteen children became HCV RNA negative at their last assessments, but 40% of these had high alanine aminotransferase (ALT) concentrations. Infection was asymptomatic in all but 2 children, who developed hepatomegaly. Mean ALT concentrations decreased substantially after the first 2 years of life; 14 children had persistently normal ALT values. Signs of minimal to moderate inflammation were noted in all 20 patients who underwent liver biopsy. Perinatal HCV infection is usually asymptomatic in the first years of life, but the virus persists in most children, even in the absence of elevated ALT activity.

Adult↗

PubMed2001

Caspase activation correlates with the degree of inflammatory liver injury in chronic hepatitis C virus infection.

Hepatitis C virus (HCV) infection is a major cause of liver disease characterized by inflammation, cell damage, and fibrotic reactions of hepatocytes. Apoptosis has been implicated in the pathogenesis, although it is unclear whether proteases of the caspase family as the central executioners of apoptosis are involved and how caspase activation contributes to liver injury. In the present study, we measured the activation of effector caspases in liver biopsy specimens of patients with chronic HCV infection. The activation of caspase-3, caspase-7, and cleavage of poly(ADP-ribose)polymerase (PARP), a specific caspase substrate, were measured by immunohistochemistry and Western blot analysis by using antibodies that selectively detect the active truncated, but not the inactive precursor forms of the caspases and PARP. We found that caspase activation was considerably elevated in liver lobules of HCV patients in comparison to normal controls. Interestingly, the immunoreactive cells did yet not reveal an overt apoptotic morphology. The extent of caspase activation correlated significantly with the disease grade, i.e., necroinflammatory activity. In contrast, no correlation was observed with other surrogate markers such as serum transaminases and viral load. In biopsy specimens with low activity (grade 0) 7.7% of the hepatocytes revealed caspase-3 activation, whereas 20.9% of the cells stained positively in grade 3. Thus, our results suggest that caspase activation is involved in HCV-associated liver injury. Moreover, measurement of caspase activity may represent a reliable marker for the early detection of liver damage, which may open up new diagnostic and therapeutic strategies in HCV infection.

Adult↗

PubMed2003

Interleukin-1beta gene polymorphisms associated with hepatocellular carcinoma in hepatitis C virus infection.

Hepatitis C virus (HCV) infection is a major risk factor for developing hepatocellular carcinoma (HCC), a life-threatening sequel. However, the factors that affect disease progression to HCC have not been thoroughly elucidated. Genetic polymorphisms in proinflammatory cytokines, the interleukin 1 (IL-1) family (IL-1beta and IL-1ra) and tumor necrosis factor-alpha (TNF-alpha), were studied in 274 Japanese patients with chronic HCV infection and 55 healthy individuals using standard polymerase chain reaction-based genotyping techniques. The association between these polymorphisms and disease status was evaluated while controlling for confounding clinical variables. The proportion of patients with HCC in the IL-1beta-31 T/T (55%, odds ratio to C/C was 2.63, P =.009) genotype was higher than in the T/C (44%, odds ratio to C/C was 1.64, P =.149) and C/C genotypes (35%). The IL-1beta-31 and -511 loci were in near complete linkage disequilibrium, and the IL-1beta-511/-31 haplotype C-T was significantly associated with the presence of HCC (odds ratio of 1.51, P =.02). Polymorphisms in the TNF-alpha gene were not associated with disease. A multivariate analysis revealed that the IL-1beta-31 T/T genotype, alpha-fetoprotein >20 microg/L, presence of cirrhosis, male sex, and age >60 years were associated with the presence of HCC at odds ratios of 3.73 (T/T vs. C/C), 4.12, 4.03, 3.89, and 3.27, respectively. In conclusion, the IL-1beta-31 genotype T/T or the IL-1beta-511/-31 haplotype C-T is associated with the presence of HCC in Japanese patients with chronic HCV infection.

Adult↗

PubMed2001

Sequence evolution and cross-reactive antibody responses to hypervariable region 1 in acute hepatitis C virus infection.

Hepatitis C virus (HCV) infection may result in acute resolving or chronic infection. Patients that clear the infection have a more vigorous cellular immune response and an early humoral response to the hypervariable region 1 (HVR1) of the E2 envelope protein. To analyse further the properties of the early anti-HVR1 response, cross-reactivity of anti-HVR1 responses was assessed in five patients with acute HCV infection, who were infected by the same virus strain during a nosocomial outbreak. The sequence evolution of HVR1 was examined in sequential serum samples up to 37 months post infection. Peptides were synthesised corresponding to the obtained HVR1 sequences and unrelated HVR1 sequences, and antibody reactivity to the peptides in sequential sera was investigated by ELISA. The results suggest an association between specific gaps in humoral immunity and the HVR1 sequence evolution during early infection. Possible interpretations of this phenomenon include immune escape mechanisms or suppression of specific anti-HVR1 antibodies.

Acute Disease↗

PubMed2003

Antiviral treatment down-regulates peripheral B-cell CD81 expression and CD5 expansion in chronic hepatitis C virus infection.

Hepatitis C virus (HCV) infection is associated with immune-mediated abnormalities and B-cell lymphoproliferation. Recently, CD81 was identified as an HCV receptor on B lymphocytes, providing a mechanism by which B cells are infected and activated by the virus. It has recently been shown that peripheral B-cell CD81 overexpression and CD5(+) subpopulation expansion correlate with HCV viral load and are associated with the development of HCV-related autoimmunity. In the present study, we assessed the effects of combination antiviral therapy (alfa interferon and ribavirin) on peripheral B-cell CD81 expression and CD5 expansion and the presence of autoimmune markers. Peripheral B-cell CD5 expression and the mean fluorescence intensity of CD81 were assessed by flow cytometry before and after treatment in 15 HCV-infected patients, in 10 untreated patients, and in 25 healthy controls. A significant posttreatment decrease in peripheral B-cell CD81 expression and disappearance of CD5(+) B-cell expansion were observed in all nine patients in whom a complete and sustained virological response was achieved (P < 0.01) (comparable to those for healthy controls). The decrease in CD81 overexpression and CD5 expansion in these patients was associated with a decrease and/or disappearance of autoimmune markers. In contrast, in nonresponders overexpression of CD81 and expansion of the CD5(+) B-cell subpopulation were not significantly changed and were comparable to those for untreated patients. In conclusion, antiviral therapy down-regulates peripheral B-cell CD81 expression and the CD5(+) population, either directly or by its effect on HCV RNA load. The overexpression of CD81 and the expansion of the population of CD5(+) peripheral B cells in HCV-infected patients may possibly play a role in the development of HCV-associated autoimmunity and lymphoproliferation.

Adult↗

PubMed2005

Wide range of quasispecies diversity during primary hepatitis C virus infection.

Hepatitis C virus (HCV) infections may be initiated by multiple infectious particles, resulting in a genetically heterogeneous viral population, or by a single particle, leading to a clonal population in the initial stage of infection. To determine which of these scenarios is most common, we evaluated the genetic diversity of HCV quasispecies in 12 seronegative subjects with primary infection following community exposures, six acutely infected recipients of HCV-seropositive blood transfusions and six seropositive individuals with infections of undetermined durations. RNA isolated from plasma and a region of the HCV envelope gene including the first hypervariable region (HVR-1) was reverse transcription-PCR amplified and subcloned, and multiple plasmid clones were sequenced. Phylogenetic analysis indicated that all HCV variants clustered by individuals. Genetic distances among HCV variants within recently infected subjects ranged from 1 to 7.8%. On the basis of the estimated mutation rate of HCV in vivo and the Taq polymerase error rate, primary infection viral quasispecies were classified as genetically heterogeneous when the maximum sequence divergence between genetic variants in the same person was >3%. Heterogeneous quasispecies were detected in 4 of 12 preseroconversion subjects, 1 of 6 transfusion recipients, and 4 of 6 seropositive subjects. The high level of viral quasispecies genetic diversity found in at least a third of recently infected individuals is consistent with the transmission of multiple infectious particles. Community-acquired HCV infection, predominantly the result of needle sharing by injection drug users, therefore appears to be frequently initiated by the successful transmission of multiple viral variants.

DNA, Complementary↗

PubMed2002

Diagnosis and management of paediatric hepatitis C virus infection.

Hepatitis C virus (HCV) infection in children is uncommon and there are few guidelines indicating optimal management. It is estimated that 125-250 children are infected vertically with HCV in Australia each year and very few of these children are diagnosed and followed medically. Without accurate diagnosis and follow up, these children cannot be offered optimal care, and are at risk of presenting in adult life with significant liver pathology and long-term sequelae.

Adolescent↗

PubMedDate not supplied

Future directions in the treatment of patients with chronic hepatitis C virus infection.

Hepatitis C virus (HCV) infects over 170 million people worldwide. While interferon is currently the most used single agent therapy, this drug may result in a sustained loss of virus from the blood in only up to 15% of patients; new options for treatment are needed. With the release of ribavirin in North America and Europe, a viral clearance rate or 'cure' may be attained in up to 40% of patients. Developing successful antiviral therapy that prevents or delays the development of cirrhosis, liver failure and liver cancer as well as decreasing the demand for liver transplantation are clearly identified goals. Unfortunately, there is no complete in vitro model of HCV replication or translation. Due to the lack of an animal or cell culture model of HCV infection, in vitro translation screening systems to identify inhibitors of HCV protein translation are being evaluated by a large number of biotechnology companies. With advancing computer technology, high throughput screening processes are now possible and can be joined to specific in vitro model testing systems. Along with examining some of the information known about HCV therapy and the HCV genome, the present review discusses potential targets for new therapies and identifies therapeutic agents that are nearing clinical application.

Antiviral Agents↗

PubMed1996

Incidence, character and clinical relevance of mixed cryoglobulinaemia in patients with chronic hepatitis C virus infection.

Hepatitis C virus (HCV) infection has been implicated in the pathogenesis of mixed cryoglobulinaemia. Several studies have shown the presence of anti-HCV antibodies and HCV-RNA in both sera and cryoglobulins of such patients. However, the prevalence and clinical significance of cryoglobulins remain uncertain in patients with chronic HCV infection. We have studied 113 consecutive patients referred for assessment because of the presence of anti-HCV antibody in serum for the presence of cryoglobulinaemia and ascertained their clinical relevance and immunochemical properties. Twenty-one of 113 (19%) had detectable cryoglobulins with a mean protein concentration of 0.38 g/l (range 0.15-3.34 g/l). Most of these patients were asymptomatic. The cryoglobulins were of type III in 19 (91%) and of type II in two patients (9%). The latter two patients had the highest concentration of cryoglobulins, subnormal C4 and C1q levels suggesting classical pathway activation and vasculitis with renal impairment. The cryoglobulin IgG subclasses were mainly IgG1 and IgG3. HCV-RNA was detected more frequently in the sera of cryoglobulin-positive patients than in cryoglobulin-negative patients. This study showed that mixed cryoglobulinaemia is common in chronic HCV infection, and is predominantly type III. Evidence of systemic or renal disease was rare except in those with type II cryoglobulinaemia, and this may reflect either the concentration of the cryoprecipitate or the presence of a monoclonal complement-activating IgM paraprotein. The detection of HCV-RNA in the majority of the cryoprecipitates further supports the important role of HCV in the etiopathogenesis of essential mixed cryoglobulinaemia, although the mechanism is at present unclear.

Adult↗

PubMed1999

[Cryoglobulinemia following liver transplantation for cirrhosis secondary to hepatitis C virus infection].

Hepatitis C virus (HCV) infection has been linked with some extrahepatic immunologic abnormalities. Cryoglobulinemia is one of the most frequently reported. Nevertheless, there are only a few reports of cryoglobulinemia in the setting of liver transplantation. More studies are needed to clarify the frequency of post-OLT cryoglobulinemia in patients with HCV-related cirrhosis and its impact on OLT outcome. A case of a patient who underwent liver transplantation because of HCV end-stage liver disease and in whom cryoglobulinemia appeared 3 years after transplantation is reported. Treatment with cyclophosphamide and steroids was attempted but patient died of septicemia 3 years after liver transplantation.

Adult↗

PubMed2004

Laboratory approaches to the diagnosis of hepatitis C virus infection.

Hepatitis C virus (HCV) infection is a major and growing health problem worldwide. Laboratory testing plays an important role in the response to the HCV epidemic. Serologic tests for antibody to HCV are useful for screening purposes. The mainstays of laboratory testing for HCV, however, are the molecular approaches. Qualitative molecular tests are useful for confirmation of positive screening tests. Quantitative molecular tests provide prognostic information regarding the likelihood of response to therapy, and allow the monitoring of treatment efficacy. Similarly, genotyping assays predict response to therapy, and allow rational decisions regarding duration of treatment. The combination of continually improving laboratory testing, together with new drugs targeting distinct molecular determinants that are either essential or important in the viral replication cycle, is likely to lead to dramatic improvements in the management of HCV disease.

Genotype↗

PubMed2001

Effect of HLA class II genotype on T helper lymphocyte responses and viral control in hepatitis C virus infection.

Hepatitis C virus (HCV) infection is very common worldwide, but has a broad range of outcomes. A minority of patients are able to clear infection spontaneously, and this is thought to be due to the emergence and maintenance of effective cell-mediated immunity, particularly CD4+ T lymphocyte responses. Furthermore, genetic studies have indicated that HLA class II genotype strongly influences the outcome of infection. We have therefore investigated the influence of the protective HLA class II haplotype (DQB1*0301, which is in tight linkage disequilibrium with DRB1*1101) on the CD4+ T lymphocyte responses to HCV. We observe a strong association between this genotype and maintenance of a multispecific CD4+ T helper response. The effect on T helper responses was also maintained after combination interferon-alpha/ribavirin therapy, although the latter influenced the pattern of viral antigens to which patients responded. This is the first disease in which an association of HLA genotype with clinical outcome has been linked to an alteration of the immunological phenotype. The selection of protective peptides in those with the favourable HLA class II genotype may point in the direction of suitable vaccine candidates.

Adult↗

PubMed2007

Antiviral therapy and resistance with hepatitis B virus infection.

Hepatitis B virus (HBV) infection is still the most common cause of hepatocellular carcinoma and liver cirrhosis world wide. Recently, however, there has been quite dramatic improvement in the understanding of HBV associated liver disease and its treatment. It has become clear that high viral replication is a major risk factor for the development of both cirrhosis and hepatocellular carcinoma. Early studies have shown lamivudine lowers the risk of HBV associated complications. There are currently three nucleos(t)ides licensed, in addition to interferon, and there are more drugs coming to the market soon. Interferon or its pegylated counterpart are still the only options for treatment with defined end points, while nucleos(t)ides therapy is used mostly for long term treatment. Combination therapies have not been shown to be superior to monotherapy in naive patients, however, the outcome depends on how the end point is defined. Interferon plus lamivudine achieves a higher viral suppression than either treatment alone, even though Hbe-seroconversion was not different after a one year treatment. HBV-genotypes emerge as relevant factors, with genotypes "A" and "B" responding relatively well to interferon, achieving up to 20% HBsAg clearance in the case of genotype "A". In addition to having a defined treatment duration, interferon has the advantage of lacking resistance selection, which is a major drawback for lamivudine and the other nucleos(t)ides. The emergence of resistance against adefovir and entecavir is somewhat slower in naive compared to lamivudine resistant patients. Adefovir has a low resistance profile with 3%, 9%, 18%, and 28% after 2, 3, 4, and 5 years, respectively, while entecavir has rarely produced resistance in naive patients for up to 3 years.

Antiviral Agents↗

PubMed2006

Regulation of CXCL-8 (interleukin-8) induction by double-stranded RNA signaling pathways during hepatitis C virus infection.

Hepatitis C virus (HCV) infection induces the alpha-chemokine interleukin-8 (CXCL-8), which is regulated at the levels of transcription and mRNA stability. In the current study, CXCL-8 regulation by double-stranded (ds)RNA pathways was analyzed in the context of HCV infection. A constitutively active mutant of the retinoic acid-inducible gene I (RIG-I), RIG-N, activated CXCL-8 transcription. Promoter mutagenesis experiments indicated that NF-kappaB and interferon (IFN)-stimulated response element (ISRE) binding sites were required for the RIG-N induction of CXCL-8 transcription. IFN-beta promoter stimulator 1 (IPS-1) expression also activated CXCL-8 transcription, and mutations of the ISRE and NF-kappaB binding sites reduced and abrogated CXCL-8 transcription, respectively. In the presence of wild-type RIG-I, transfection of JFH-1 RNA or JFH-1 virus infection of Huh7.5.1 cells activated the CXCL-8 promoter. Expression of IFN regulatory factor 3 (IRF-3) stimulated transcription from both full-length and ISRE-driven CXCL-8 promoters. Chromatin immunoprecipitation assays demonstrated that IRF-3 and NF-kappaB bound directly to the CXCL-8 promoter in response to virus infection and dsRNA transfection. RIG-N stabilized CXCL-8 mRNA via the AU-rich element in the 3' untranslated region of CXCL-8 mRNA, leading to an increase in its half-life following tumor necrosis factor alpha induction. The data indicate that HCV infection triggers dsRNA signaling pathways that induce CXCL-8 via transcriptional activation and mRNA stabilization and define a regulatory link between innate antiviral and inflammatory cellular responses to virus infection.

Cell Line↗