Intrahepatic hepatitis C virus replication correlates with chronic hepatitis C disease severity in vivo

The role of viral factors in the pathogenesis of chronic hepatitis C is unknown. The objective of the present study was to characterize markers of hepatitis C virus (HCV) infection and replication in liver biopsy specimens obtained from 65 genotype 1-infected subjects, including 31 who were coinfected with human immunodeficiency virus (HIV), and to analyze associations between intrahepatic viral markers and hepatitis C disease severity. The percentages of liver cells harboring HCV genomes (%G) and replicative-intermediate RNAs (%RI) were evaluated using strand-specific in situ hybridization, while HCV core and NS3 antigens were assessed by immunocytochemistry. HIV-positive and HIV-negative subjects had similar mean grades and stages of liver disease and had similar indices of HCV infection and replication in liver, even though coinfected subjects had significantly shorter mean disease duration (P = 0.0003). Multivariate analysis showed that %G was not associated with grade or stage of liver disease (P = 0.5 and 0.4, respectively), while %RI was strongly associated with liver inflammation (P < 0.001), liver fibrosis (P < 0.001), and serum alanine aminotransferase levels (P = 0.01). NS3 antigen (but not core) was more frequently detected in HCV RI-positive versus RI-negative specimens (P = 0.028). These findings demonstrate a link between HCV proliferation and hepatitis C disease severity and suggest similar pathogenic mechanisms in HIV-positive and HIV-negative individuals.     

Human immunodeficiency virus seroconversion and evolution of the hepatitis C virus quasispecies

When chronic hepatitis C virus (HCV) infections are complicated by acquisition of human immunodeficiency virus (HIV), liver disease appears to accelerate and serum levels of HCV RNA may rise. We hypothesized that HIV might affect the HCV quasispecies by decreasing both complexity (if HIV-induced immunosuppression lessens pressure for selecting HCV substitutions) and the ratio of nonsynonymous (d(N)) to synonymous (d(S)) substitutions, because d(N) may be lower (if there is less selective pressure). To test this hypothesis, we studied the evolution of HCV sequences in 10 persons with chronic HCV infection who seroconverted to HIV and, over the next 3 years, had slow or rapid progression of HIV-associated disease. From each subject, four serum specimens were selected with reference to HIV seroconversion: (i) more than 2 years prior, (ii) less than 2 years prior, (iii) less than 2 years after, and (iv) more than 2 years after. The HCV quasispecies in these specimens was characterized by generating clones containing 1 kb of cDNA that spanned the E1 gene and the E2 hypervariable region 1 (HVR1), followed by analysis of clonal frequencies (via electrophoretic migration) and nucleotide sequences. We examined 1,320 cDNA clones (33 per time point) and 287 sequences (median of 7 per time point). We observed a trend toward lower d(N)/d(S) after HIV seroconversion in 7 of 10 subjects and lower d(N)/d(S) in those with rapid HIV disease progression. However, the magnitude of these differences was small. These results are consistent with the hypothesis that HIV infection alters the HCV quasispecies, but the number of subjects and observation time may be too low to characterize the full effect.     

Progression of fibrosis during chronic hepatitis C is associated with rapid virus evolution

Hepatic fibrosis is the primary mediator of disease due to chronic infection with hepatitis C virus (HCV). HCV exists as a quasispecies in each infected individual, and longitudinal viral sequence changes may reveal viral dynamics and the selection pressures applied by the host immune system. Thus, we hypothesized that patterns of sequence change might reveal the immunopathogenesis of fibrosis progression. We tested this hypothesis by studying individuals enrolled in a prospective study of chronic HCV-related hepatic fibrosis with little or no fibrosis at first biopsy (stage 0 or 1) and a second planned liver biopsy sample obtained 4 years later. Serum was obtained from five individuals with fast progression (FP; defined as a >2-stage change between visits) and 10 carefully matched individuals with slow progression (SP; defined as a <2-stage change between visits). We sequenced multiple cloned hemigenomic cDNAs from each person spanning six genes (core through NS3). Phylogenetic analysis revealed temporal shifts in phylogenetic clustering over time, suggesting frequent quasispecies replacement rather than simple diversification. In addition, mixed infections were detected in three subjects, with coexistence in two subjects (one FP, one SP) of subtypes 1a and 1b throughout the 4-year biopsy interval. Subjects with FP had a higher rate of evolution than subjects with SP, with a preponderance of synonymous changes, suggesting purifying selection, except in hypervariable region 1, where positive selection pressure is frequently detected. Thus, in a small but carefully matched cohort we found evidence for rapid neutral evolution of HCV in persons with rapid progression of hepatic fibrosis, suggesting higher turnover of infected cells.     

Lymphotoxin Signaling Is Initiated by the Viral Polymerase in HCV-linked Tumorigenesis

Exposure to hepatitis C virus (HCV) typically results in chronic infection that leads to progressive liver disease ranging from mild inflammation to severe fibrosis and cirrhosis as well as primary liver cancer. HCV triggers innate immune signaling within the infected hepatocyte, a first step in mounting of the adaptive response against HCV infection. Persistent inflammation is strongly associated with liver tumorigenesis. The goal of our work was to investigate the initiation of the inflammatory processes triggered by HCV viral proteins in their host cell and their possible link with HCV-related liver cancer. We report a dramatic upregulation of the lymphotoxin signaling pathway and more specifically of lymphotoxin-β in tumors of the FL-N/35 HCV-transgenic mice. Lymphotoxin expression is accompanied by activation of NF-κB, neosynthesis of chemokines and intra-tumoral recruitment of mononuclear cells. Spectacularly, IKKβ inactivation in FL-N/35 mice drastically reduces tumor incidence. Activation of lymphotoxin-β pathway can be reproduced in several cellular models, including the full length replicon and HCV-infected primary human hepatocytes. We have identified NS5B, the HCV RNA dependent RNA polymerase, as the viral protein responsible for this phenotype and shown that pharmacological inhibition of its activity alleviates activation of the pro-inflammatory pathway. These results open new perspectives in understanding the inflammatory mechanisms linked to HCV infection and tumorigenesis.     

Hepatitis C Virus Nonstructural 3/4A Protein Dampens Inflammation and Contributes to Slow Fibrosis Progression during Chronic Fibrosis In Vivo

HCV infection typically induces liver injury and inflammation, which appears to be responsible for the associated fibrogenesis. To date, the mechanism underlying the different rates of disease progression remains unclear. The aim of the study is to understand the possible role of the HCV non-structural (NS) 3/4A protein in the fibrosis progression. We used NS3/4A-expressing transgenic mice (NS3/4A-Tg) to accomplish the goals of the study. Different stages of liver fibrosis were induced in wild-type and NS3/4A-Tg mice by single carbon tetrachloride (acute) or multiple injections for 4 (intermediate) or 8 (chronic) weeks. Fibrotic parameters, inflammatory responses and hepatocyte turnover were extensively examined. Hepatic expression of HCV NS3/4A did not induce spontaneous liver damage. However, NS3/4A expression exerted contrasting effects during acute and chronic liver damage. During early fibrogenesis and intermediate fibrosis (4 weeks), NS3/4A-Tg mice exhibited enhanced liver damage whereas reduced fibrosis was observed in NS3/4A-Tg during chronic liver fibrosis (8 weeks). Furthermore, attenuated inflammation was observed in NS3/4A-Tg during chronic fibrosis with increase in M2 macrophages, hepatocyte proliferation, decreased hepatocyte apoptosis and decreased ductular reaction. In conclusion, during early fibrogenesis, HCV NS3/4A contributes to liver damage. While, during chronic liver fibrosis, NS3/4A dampens inflammation and induces hepatocyte regeneration thereby contributing to slow fibrosis progression to promote its survival or persistence.     

Expression and purification of E2/NS1 protein of hepatitis C virus and detection of anti-E2/NS1 antibodies in chronic liver disease patients

Glycoproteins on the surface of viral particles present the main target of neutralizing antibodies. The structural proteins of most Flaviviruses are known to elicit neutralizing antibodies and, thus, to help in both the natural resolution of the infection and the protection from challenge with homologous hepatitis C virus (HCV). Because such antigens are associated with the viral clearance in both humans and chimpanzees, we aimed to express the E2/NS1 protein of HCV and to study the role of anti-E2/NS1 antibodies in the natural resolution of HCV infection. The prevalence of anti-E2/NS1 antibodies to recombinant E2/NS1 protein was seen by Western blot in chronic liver disease patients (15 chronic hepatitis and 12 cirrhotic patients), who were positive for anti-HCV and negative for HBV infection. The study also included 2 negative controls (positive for HBV infection and negative for anti-HCV antibodies) and 2 healthy controls (negative for both HBV and HCV infection). Anti-E2/NS1 was present in 20% of the chronic hepatitis and 16% of the cirrhosis patients. None of the controls were positive for anti-E2/NS1 antibodies. Serum samples positive for anti-E2/NS1 antibodies were also positive for HCV RNA by RT/PCR. Accordingly, the presence of anti-E2/NS1 may have very little or no role in the natural resolution of HCV infection.     

Multigene Tracking of Hepatitis C Virus Quasispecies after Liver Transplantation: Correlation of Genetic Diversification in the Envelope Region with Asymptomatic or Mild Disease Patterns

To investigate the role of hepatitis C virus (HCV) quasispecies mutation in the pathogenesis of HCV infection, we analyzed changes in the genetic diversity of HCV genomes in 22 patients before and after liver transplantation by using heteroduplex mobility assay (HMA) technology. All patients were infected with HCV genotype 1 and developed high-titer posttransplant viremia. Each patient was classified according to the severity of posttransplant hepatitis, as assessed by standard biochemical and histological criteria. HCV quasispecies were characterized by HMA analysis of eight separate subgenomic regions of HCV, which collectively comprise 44% of the entire genome. The glycoprotein genes E1 and E2, as well as the nonstructural protein genes NS2 and NS3, had the greatest genetic divergence after liver transplantation (the change in the heteroduplex mobility ratio [HMR] ranged from 2.5 to 7.0%). In contrast, genes encoding the core, NS4, and NS5b proteins had the least amount of genetic divergence after liver transplantation (range, 0.3 to 1.2%). The E1/E2 region showed the greatest change in genetic diversity after liver transplantation, and the change in HMRs was 2.5- to 3.3-fold greater in patients with asymptomatic or moderate disease than in those with severe disease. The E1-5′ region of HCV quasispecies isolated from patients in the asymptomatic group had a significantly greater degree of diversification after liver transplantation than the same regions of HCV quasispecies isolated from patients in the severe disease group (P = 0.05). While changes in the genetic diversity of some nonstructural genes were also greater in asymptomatic patients or in patients with mild disease than in patients with severe disease, the results were not significant. Data from this cohort demonstrate that greater rates of HCV quasispecies diversification are associated with mild or moderate liver disease activity in this immunosuppressed population.

Hepatitis C virus (HCV), a member of the Flaviviridae family, is known to be a major causative agent of chronic liver diseases, including chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma (27). Chronic hepatitis C is now recognized as the leading indication for orthotopic liver transplantation in the United States, with nearly 100% of HCV-infected liver transplant recipients developing recurrent viremia after transplantation (4, 17, 22, 32, 44).The HCV genome is a single-stranded, positive-sense RNA of about 9.5 kb, which exists as a viral quasispecies in infected humans (6, 25, 31, 41). HCV quasispecies are characterized by extensive genetic mutation in the hypervariable region 1 (HVR1) of the second envelope glycoprotein gene (E2) (25, 41). Mutation of this region of the genome is believed to be associated with viral persistence via immune escape mechanisms (15, 16, 29, 42). The role of evolution of HCV quasispecies in the development of chronic hepatitis C is currently unknown.HCV-infected liver transplant recipients offer an opportunity to study the evolution of HCV quasispecies in a new host tissue and to assess the role of quasispecies diversification in the development of posttransplant hepatitis. In a previous study (23) of HCV-infected liver transplant recipients, we found that in the three patients who developed severe, recurrent hepatitis, quasispecies major variants present in pretransplant serum samples were efficiently propagated after liver transplantation and during acute and chronic posttransplant hepatitis. In contrast, in the two asymptomatic cases, we observed rapid depletion of pretransplant quasispecies major variants from posttransplant serum samples, followed by the emergence of quasispecies minor variants. These data suggested that the evolution of HCV quasispecies after liver transplantation may be related to posttransplant disease severity.In order to extend our previous findings and to address the hypothesis that mutation of other HCV genes also correlates with severity of posttransplant hepatitis C, we analyzed the pre- and posttransplant HCV quasispecies in 22 HCV-infected liver transplant recipients. The 22 patients were selected based on two virological criteria: all patients were infected with HCV genotype 1 before and after liver transplantation, and all patients developed recurrent, high-titer HCV viremia within 30 days posttransplant. Additionally, at least five posttransplant liver biopsies were available in each case to evaluate the histopathologic course of posttransplant hepatitis C. Pre- and posttransplant HCV quasispecies were characterized by using the heteroduplex mobility assay (HMA) to analyze eight different regions of the viral genome.     

Hepatitis C virus-associated mixed cryoglobulinemia. Clinical manifestations, histopathological changes, mechanisms of cryoprecipitation and options of treatment

Chronic hepatitis C virus (HCV) infection is frequently associated with a variety of autoimmune phenomenons. Mixed cryoglobulinemia (MC) appears in up to 50% of chronic HCV-infected patients. Cryoglobulins consist of immunoglobulin complexes precipitating in vitro when cooled below body temperature. In most cases IgM with rheumatoid factor activity is found in cryoprecipitates which could lead to vasculitis induced by the deposition of immnuocomplexes in small vessels. This vasculitis is thought to cause clinical symptoms called Meltzer's triad. This triad is represented by purpura, arthralgia and weakness. One third of patients suffering from HCV-associated mixed cryoglobulinemia are developing typical symptoms during their course of disease. The striking association between HCV infection and MC has conduced to the hypothesis that HCV is of major importance in the production of MC with followed vasculitis. Both hepatrophism and lymphotrophism have been reported for the hepatitis C virus. Infection of B-cells by HCV could probably lead to a bcl-2 translocation and immunoglobulin gene rearrangement which results in clonal lymphoproliferation and in synthesis of monoclonal IgM with rheumatoid factor activity. These IgM form immunocomplexes with IgG in the cold, which are finally responsible for the described vasculitis. Histopathological changes of the liver are dominated by chronic HCV infection. The majority of times mild activity of hepatitis or mild fibrosis could be found. Nevertheless, cirrhosis is more often found in HCV-infected patients suffering from MC compared to patients without MC. Conventional treatment of MC is aimed to reduce circulating immune complexes by immunosupression and plasmapheresis. With the emerging concept of a viral pathogenesis the therapeutic approach has changed during the last decade. Interferon treatment of MC, particularly of HCV-associated MC is well established nowadays.     

Intracellular expression of the proliferative marker Ki-67 and viral proteins (NS3, NS5A and C) in chronic, long lasting hepatitis C virus (HCV) infection

Hepatitis C virus (HCV) continues to represent the main causative agent of the hepatitis, which leads to chronic transformation of the process in 60-80% individuals. It remains unclear how far cellular expression of HCV proteins in vivo may represent an index of progression of the disease and of proliferative activity in the liver in chronic hepatitis C. Aim of the studies included detection and subcellular localization of three HCV proteins (NS3, NS5A and C) in liver biopsies from adults (n=19) with chronic, long lasting hepatitis C as related to hepatocyte proliferative activity. The immunocytochemical ABC (avidin biotin-peroxidase complex) technique was applied, alone or associated with the ImmunoMax technique. Results of the immunocytochemical tests were compared to histological alterations in liver biopsies, proliferation index and with selected clinical data. A significantly higher expression of NS3 protein was noted, as compared to expressions of NS5A and C proteins. In all the patients, cytoplasmic localization of all proteins dominated over nuclear localization (p0.05). At the level of electron microscopy, protein localization in endoplasmic reticulum (ER) membranes, mitochondria, perinuclear region and/or in hepatocyte cell nucleus was observed. No direct relationships could be demonstrated between expressions of HCV proteins and of Ki-67 antigen. No correlations could also be demonstrated between cellular expression of any HCV protein on one hand and grading or staging, alanine transaminase (ALT), serum level of HCV RNA or alpha-fetoprotein (AFP) on the other. However, positive correlations were disclosed between proliferative activity of hepatocytes on one hand and patient's age, grading and staging on the other. Advanced hepatic fibrosis correlated also with serum levels of AFP. The studies were supplemented with data on subcellular localization of HCV proteins. Moreover, they indicated that in HCV infection grading and staging, proliferative activity of hepatocytes and serum AFP level represent more valuable indices of the disease progress than those provided by cellular expression of three potentially oncogenic HCV proteins in vivo.     

Novel 5-arylthio-5H-chromenopyridines as a new class of anti-fibrotic agents

Liver fibrosis is a critical wound healing response to chronic liver injury such as hepatitis C virus (HCV) infection. If persistent, liver fibrosis can lead to cirrhosis and hepatocellular carcinoma (HCC). The development of new therapies for preventing liver fibrosis and its progression to cancer associated with HCV infection remains a critical challenge. Identification of novel anti-fibrotic compounds will provide opportunities for innovative therapeutic intervention of HCV-mediated liver fibrosis. We designed and synthesized a focused set of 5-arylthio-5H-chromenopyridines as a new class of anti-fibrotic agents. Liver fibrosis assays demonstrated that the compounds 3a and 3c show inhibitory activity towards human hepatic stellate cells (LX2) activation at 10 μM. The HCV NS3 and NS5A proteins in HCV subgenome-expressing cells were also significantly reduced in cells treated with 3a and 3c, suggesting the possible inhibitory role of the compounds in HCV translation/replication activities. We have also examined the reactivity of these compounds with medicinally-relevant metal compounds such as platinum and gold. The reactivity of these complexes with metals and during Mass Spectrometry suggests that CS bond cleavage is relatively facile.     

Sequence Variation in the Gene Encoding the Nonstructural 3 Protein of Hepatitis C Virus: Evidence for Immune Selection

To determine whether the persistent nature of hepatitis C infection is related to the emergence of antigenic variants driven by immune selection, we examined the sequence heterogeneity in a portion of the hepatitis C virus (HCV) nonstructural 3 (NS3) gene of a patient infected over the course of more than 2 years. By PCR amplification, cloning, and sequencing, we observed several variable and conserved regions in the NS3 segment of the HCV genome. All variable regions had higher ratios of nonsynonymous/synonymous mutations and encompassed immunodominant epitopes, and their locations were not essential to maintain the known function of HCV RNA helicase. In contrast, the regions that are critical for HCV RNA helicase activity were found to be conserved with lower heterogeneity or lower ratios of nonsynonymous/synonymous mutations, and none except one of these regions was encoded within immunodominant epitopes. Our results are consistent with immune selection of viral variants at the epitope and molecular levels that may enable HCV to evade host defenses over time. Plotting the relatedness of sequence variants revealed a star topology suggesting that a wild-type HCV sequence is maintained, unlike HIV. Received: 2 November 2000 / Accepted: 1 October 2001     

肝组织弥散度成像在慢性肝损伤诊断中的临床研究

目的:探讨Strain Histogram组织弥散度成像技术在慢性肝损伤程度无创诊断中的临床价值。方法:应用Strain Histogram组织弥散度成像技术定量检测180例慢性肝炎(病毒性肝炎105例,非病毒性肝炎75例)患者肝脏弹性特征值,对照病理,分析肝脏弹性特征值与肝纤维化及肝脏炎症程度的相关性。结果:180例慢性肝炎患者LF指数用于判断轻度与中重度纤维化的诊断界值为2.785,LF指数越大,纤维化程度越重,灵敏度76.6%,特异度48.9%;LF指数用于判断轻度与中重度炎症的诊断界值为2.925,LF指数越大,炎症程度越重,灵敏度73.2%,特异度56.8%。105例病毒性肝炎患者LF指数用于判断轻度与中重度纤维化的诊断界值为2.975,LF指数越大,纤维化程度越重,灵敏度69.2%,特异度67.1%;LF指数用于判断轻度与中重度炎症的诊断界值为2.915,LF指数越大,炎症程度越重,灵敏度80.0%,特异度57.8%。75例非病毒性肝炎患者LF指数与肝纤维化和炎症程度不具有相关性。结论:LF指数可以反映肝脏纤维化及炎症程度,诊断灵敏度高,LF指数越大,肝纤维化及炎症程度越重。     

Recruitment and activation of a lipid kinase by hepatitis C virus NS5A is essential for integrity of the membranous replication compartment

Hepatitis C virus (HCV) is a major causative agent of chronic liver disease in humans. To gain insight into host factor requirements for HCV replication, we performed a siRNA screen of the human kinome and identified 13 different kinases, including phosphatidylinositol-4 kinase III alpha (PI4KIIIα), as being required for HCV replication. Consistent with elevated levels of the PI4KIIIα product phosphatidylinositol-4-phosphate (PI4P) detected in HCV-infected cultured hepatocytes and liver tissue from chronic hepatitis C patients, the enzymatic activity of PI4KIIIα was critical for HCV replication. Viral nonstructural protein 5A (NS5A) was found to interact with PI4KIIIα and stimulate its kinase activity. The absence of PI4KIIIα activity induced a dramatic change in the ultrastructural morphology of the membranous HCV replication complex. Our analysis suggests that the direct activation of a lipid kinase by HCV NS5A contributes critically to the integrity of the membranous viral replication complex.     

Endogenous Hepatitis C Virus Homolog Fragments in European Rabbit and Hare Genomes Replicate in Cell Culture

Endogenous retroviruses, non-retroviral RNA viruses and DNA viruses have been found in the mammalian genomes. The origin of Hepatitis C virus (HCV), the major cause of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma in humans, remains unclear since its discovery. Here we show that fragments homologous to HCV structural and non-structural (NS) proteins present in the European rabbit (Oryctolagus cuniculus) and hare (Lepus europaeus) genomes replicate in bovine cell cultures. The HCV genomic homolog fragments were demonstrated by RT-PCR, PCR, mass spectrometry, and replication in bovine cell cultures by immunofluorescence assay (IFA) and immunogold electron microscopy (IEM) using specific MAbs for HCV NS3, NS4A, and NS5 proteins. These findings may lead to novel research approaches on the HCV origin, genesis, evolution and diversity.     

Genetic Clustering of Hepatitis C Virus Strains and Severity of Recurrent Hepatitis after Liver Transplantation

The influence of viral factors on the severity of hepatitis C virus (HCV)-related liver disease is controversial. We studied 68 liver transplant patients with recurrent hepatitis C, of whom 53 were infected by genotype 1 strains. Relationships between core sequences, serum HCV RNA levels, and fibrosis scores for each patient were analyzed in pairwise fashion 5 years after transplantation. We used Mantel's test, a matrix correlation method, to evaluate the correspondence between measured genetic distances and observed phenotypic differences. No clear relationship was found when all 68 patients were analyzed. In contrast, when the 53 patients infected by genotype 1 strains were analyzed, a strong positive relationship was found between genetic distance and differences in 5-year fibrosis scores (P = 0.001) and differences in virus load (P = 0.009). In other words, the smaller the genetic distance between two patients' viral core sequences, the smaller the difference between the two patients' fibrosis scores and viral replication levels. No relationship was found between genetic distance and differences in age, sex, or immunosuppression. In multivariate analysis, the degree of fibrosis was negatively related to the virus load (r = -0.68; P = 0.003). In the particular setting of liver transplantation, and among strains with closely related phylogenetic backgrounds (genotype 1), this study points to a correlation between the HCV genetic sequence and the variability of disease expression.     

四环素诱导的丙型肝炎病毒非结构蛋白5B稳定细胞株的构建和检测

丙型肝炎病毒(HCV)感染个体后在宿主细胞内长时间保持低水平复制,与慢性肝炎、肝硬化及肝细胞肝癌的发生密切相关.目前,HCV感染后肝细胞发生转化的具体机制还不清楚.非结构蛋白5B(NS5B)是HCV编码的非结构蛋白之一,具有RNA依赖的RNA聚合酶活性(RdRp),是病毒复制所需的关键酶.除参与病毒复制外,NS5B通过...     

Is interleukin-10 gene polymorphism a predictive marker in HCV infection?

The clinical outcome of hepatitis C virus (HCV) infection varies between individuals - from spontaneous viral clearance and persistence without complication, to chronic hepatitis, cirrhosis and hepatocellular carcinoma. Also patterns of response to interferon-based anti-HCV therapy are different from person to person. This diversity may be affected by host genetic factors, including alterations in genes encoding cytokines. Interleukin-10, as an anti-inflammatory cytokine and immune response modulator, may influence on HCV infection susceptibility as well as spontaneous and treatment-induced HCV eradication. Moreover, it is stated that IL-10 has antifibrotic properties and play a role in progression of liver disease. This review summarized studies on interleukin-10 gene polymorphisms (mainly promoter SNPs at positions -1082(G/A), -819(C/T) and -592(C/A)), which may determine IL-10 production, regarding susceptibility to HCV infection, course of HCV-related liver disease (fibrosis, cirrhosis, hepatocellular carcinoma, ALT abnormalities), spontaneous viral elimination as well as hepatitis C treatment outcomes. Analysis of hereby summarized studies shows that it is difficult to unambiguously determine the importance of IL-10 polymorphism as a predictor of clinical outcome of hepatitis C and response to anti-HCV therapy before its beginning. Thus, future larger studies need to address these issues. Continuation of studies on interleukin-10 polymorphisms as well as identification of other candidate predictive markers in HCV infection has important practical implications and there is a chance that may contribute to reduce the scale of hepatitis C problem.     

Viral interference: A potential therapeutic method for chronic viral hepatitis?

Viral interference exists between different viral hepatitis. Acute Hepatitis C virus (HCV) super-infection on Hepatitis B virus (HBV) chronic carriers showed an inhibition of the HBV genome. And acute HBV super-infection on HCV chronic carriers indicated a similar interaction. In these cases, if the acute liver viral super-infection presents a self-limited course, the patients may be free from both viral infections or at least with undetectable underlying chronic viremia. The mechanism of viral interference is still undefined. Anyway this still leads to the hypothesis of using one hepatitis virus (live attenuated vaccine) to treat another hepatitis virus.