HCV-related Diseases Research Articles

HMGB1 Promotes Hepatitis C Virus Replication by Interaction with Stem-Loop 4 in the Viral 5' Untranslated Region.

High-mobility group box 1 (HMGB1) protein is a highly conserved nuclear protein involved in multiple human diseases, including infectious diseases, immune disorders, metabolic disorders, and cancer. HMGB1 is comprised of two tandem HMG boxes (the A box and the B box) containing DNA-binding domains and an acidic C-terminal peptide. It has been reported that HMGB1 enhances viral replication by binding to viral proteins. However, its role in hepatitis C virus (HCV) replication is unknown. Here, we show that HMGB1 promoted HCV replication but had no effect on HCV translation. RNA immunoprecipitation experiments indicated that the positive strand, not the negative strand, of HCV RNA interacted with HMGB1. HCV infection triggered HMGB1 protein translocation from the nucleus to the cytoplasm, in which it interacted with the HCV genome. Moreover, the A box of HMGB1 is the pivotal domain to interact with stem-loop 4 (SL4) of the HCV 5' untranslated region. Deletion of the HMGB1 A box abrogated the enhancement of HCV replication by HMGB1. Our data suggested that HMGB1 serves as a proviral factor of HCV to facilitate viral replication in hepatocytes by interaction with the HCV genome. Hepatitis C virus (HCV) is a major global health threat, affecting more than 170 million people infection worldwide. These patients are at high risk of developing severe liver diseases such as chronic hepatitis, cirrhosis, and hepatocellular carcinoma. Currently, no vaccine is available. Many host factors may be implicated in the pathogenesis of HCV-related diseases. In this study, we found a novel HCV RNA-binding protein, HMGB1, that promotes HCV RNA replication. Moreover, SL4 in the 5' untranslated region of the HCV genome is the key region for HMGB1 binding, and the A box of HMGB1 protein is the functional domain to interact with HCV RNA and enhance viral replication. HMGB1 appears to play an important role in HCV-related diseases, and further investigation is warranted to elucidate the specific actions of HMGB1 in HCV pathogenesis.

The role of HCV proteins on treatment outcomes.

For many years, the standard of treatment for hepatitis C virus (HCV) infection was a combination of pegylated interferon alpha (Peg-IFN-α) and ribavirin for 24–48 weeks. This treatment regimen results in a sustained virologic response (SVR) rate in about 50 % of cases. The failure of IFN-α-based therapy to eliminate HCV is a result of multiple factors including a suboptimal treatment regimen, severity of HCV-related diseases, host factors and viral factors. In recent years, advances in HCV cell culture have contributed to a better understanding of the viral life cycle, which has led to the development of a number of direct-acting antiviral agents (DAAs) that target specific key components of viral replication, such as HCV NS3/4A, HCV NS5A, and HCV NS5B proteins. To date, several new drugs have been approved for the treatment of HCV infection. Application of DAAs with IFN-based or IFN-free regimens has increased the SVR rate up to >90 % and has allowed treatment duration to be shortened to 12–24 weeks. The impact of HCV proteins in response to IFN-based and IFN-free therapies has been described in many reports. This review summarizes and updates knowledge on molecular mechanisms of HCV proteins involved in anti-IFN activity as well as examining amino acid variations and mutations in several regions of HCV proteins associated with the response to IFN-based therapy and pattern of resistance associated amino acid variants (RAV) to antiviral agents.

Anti-HCV effect of Lentinula edodes mycelia solid culture extracts and low-molecular-weight lignin

Lentinula edodes mycelia solid culture extract (MSCE) contains several bioactive molecules, including some polyphenolic compounds, which exert immunomodulatory, antitumor, and hepatoprotective effects. In this study, we examined the anti-hepatitis C virus (HCV) activity of MSCE and low-molecular-weight lignin (LM-lignin), which is the active component responsible for the hepatoprotective effect of MSCE. Both MSCE and LM-lignin inhibited the entry of two HCV pseudovirus (HCVpv) types into Huh7.5.1 cells. LM-lignin inhibited HCVpv entry at a lower concentration than MSCE and inhibited the entry of HCV particles in cell culture (HCVcc). MSCE also inhibited HCV subgenome replication. LM-lignin had no effect on HCV replication, suggesting that MSCE contains additional active substances. We demonstrate here for the first time the anti-HCV effects of plant-derived LM-lignin and MSCE. The hepatoprotective effect of LM-lignin suggests that lignin derivatives, which can be produced in abundance from existing plant resources, may be effective in the treatment of HCV-related diseases.

P0752 : NOTCH4 and MHC class II polymorphisms contibute to HCV-related benign and malignant lymphoproliferative diseases

P0752 : NOTCH4 and MHC class II polymorphisms contibute to HCV-related benign and malignant lymphoproliferative diseases

Genetic diversity of the KIR/HLA system and susceptibility to hepatitis C virus-related diseases.

BackgroundThe variability in the association of host innate immune response to Hepatitis C virus (HCV) infection requires ruling out the possible role of host KIR and HLA genotypes in HCV-related disorders: therefore, we therefore explored the relationships between KIR/HLA genotypes and chronic HCV infection (CHC) as they relate to the risk of HCV-related hepatocarcinoma (HCC) or lymphoproliferative disease progression.Methods and FindingsWe analyzed data from 396 HCV-positive patients with CHC (n = 125), HCC (118), and lymphoproliferative diseases (153), and 501 HCV-negative patients. All were HIV and HBV negative. KIR-SSO was used to determine the KIR typing. KIR2DL5 and KIR2DS4 variants were performed using PCR and GeneScan analysis. HLA/class-I genotyping was performed using PCR-sequence-based typing. The interaction between the KIR gene and ligand HLA molecules was investigated. Differences in frequencies were estimated using Fisher’s exact test, and Cochran-Armitage trend test. The non-random association of KIR alleles was estimated using the linkage disequilibrium test. We found an association of KIR2DS2/KIR2DL2 genes, with the HCV-related lymphoproliferative disorders. Furthermore, individuals with a HLA-Bw6 KIR3DL1+ combination of genes showed higher risk of developing lymphoma than cryoglobulinemia. KIR2DS3 gene was found to be the principal gene associated with chronic HCV infection, while a reduction of HLA-Bw4 + KIR3DS1+ was associated with an increased risk of developing HCC.ConclusionsOur data highlight a role of the innate-system in developing HCV-related disorders and specifically KIR2DS3 and KIR2D genes demonstrated an ability to direct HCV disease progression, and mainly towards lymphoproliferative disorders. Moreover the determination of KIR3D/HLA combination of genes direct the HCV progression towards a lymphoma rather than an hepatic disease. In this contest IFN-α therapy, a standard therapy for HCV-infection and lymphoproliferative diseases, known to be able to transiently enhance the cytotoxicity of NK-cells support the role of NK cells to counterstain HCV-related and lymphoproliferative diseases.

Epidemiology of Hepatitis B and C Virus Infections and Liver Cancer in Vietnam.

Vietnam has been a highly endemic country of hepatitis B virus (HBV) and hepatitis C virus (HCV) infections with high hepatitis B surface antigen (HBsAg) rate (8.8-19.0%) and high anti-HCV rate (1.0-3.3%) among general population. High mortality rates of liver cancer were also estimated from 14.8 to 23.7 per 100,000. Recently, the coverage of universal HB vaccination for infants has not been high as expected while there have been no other national programs against HBV and HCV infections yet. The burden of HBV and HCV-related diseases is predicted to remain a significant health problem in next decade.How to cite this articleDo SH. Epidemiology of Hepatitis B and C Virus Infections and Liver Cancer in Vietnam. Euroasian J Hepato-Gastroenterol 2015;5(1):49-51.

Hepatitis C virus syndrome: A constellation of organ- and non-organ specific autoimmune disorders, B-cell non-Hodgkin's lymphoma, and cancer.

The clinical course of chronic hepatitis C virus (HCV) infection is characterized by possible development of both liver and extrahepatic disorders. The tropism of HCV for the lymphoid tissue is responsible for several immune-mediated disorders; a poly-oligoclonal B-lymphocyte expansion, commonly observed in a high proportion of patients with HCV infection, are responsible for the production of different autoantibodies and immune-complexes, such as mixed cryoglobulins. These serological alterations may characterize a variety of autoimmune or neoplastic diseases. Cryoglobulinemic vasculitis due to small-vessel deposition of circulating mixed cryoglobulins is the prototype of HCV-driven immune-mediated and lymphoproliferative disorders; interestingly, in some cases the disease may evolve to frank malignant lymphoma. In addition, HCV shows an oncogenic potential as suggested by several clinico-epidemiological and laboratory studies; in addition to hepatocellular carcinoma that represents the most frequent HCV-related malignancy, a causative role of HCV has been largely demonstrated in a significant percentage of patients with isolated B-cells non-Hodgkin's lymphomas. The same virus may be also involved in the pathogenesis of papillary thyroid cancer, a rare neoplastic condition that may complicate HCV-related thyroid involvement. Patients with HCV infection are frequently asymptomatic or may develop only hepatic alteration, while a limited but clinically relevant number can develop one or more autoimmune and/or neoplastic disorders. Given the large variability of their prevalence among patients' populations from different countries, it is possible to hypothesize a potential role of other co-factors, i.e., genetic and/or environmental, in the pathogenesis of HCV-related extra-hepatic diseases.

PIN45 - Direct and Indirect Cost of HCV-Related Diseases in Italy: An Incidence-Based Probabilistic Approach

PIN45 - Direct and Indirect Cost of HCV-Related Diseases in Italy: An Incidence-Based Probabilistic Approach

Impact of Immunogenetic IL28B Polymorphism on Natural Outcome of HCV Infection

With the aim of investigating whether interleukin 28B gene (IL28B) rs1297860 polymorphism is associated with different hepatitis C (HCV) infection statuses, we compared IL28B allelic distribution in an Italian case series of 1050 patients with chronic infection and different outcomes, 47 individuals who spontaneously cleared HCV, and 178 blood donors. Furthermore, we compared IL28B variants among 3882 Caucasian patients with chronic infection, 397 with spontaneous clearance, and 1366 blood donors reported in PubMed. Overall data confirmed a relation between IL28B C allele and HCV spontaneous clearance. Furthermore, we found that IL28B T allele had a weak relation with chronic HCV progression to hepatocellular carcinoma. Study findings are in accordance with the hepatocellular carcinogenic model where IL28B TT genotype, by promoting a persistent chronic hepatitis which leads to both hepatocyte injury and chronic inflammation, could facilitate HCC development. Conversely, patients with lymphoproliferative disorders had not any significantly different IL28B rs1297860 allelic distribution than those with chronic HCV, but, like all chronic HCV-related diseases, they showed a lower CC frequency than patients who spontaneously cleared HCV. Study results confirmed the model of persistent HCV infection as a risk factor for the pathogenesis of both liver and lymphoproliferative disorders.

PIN7 - Epidemiology, Treatment Outcomes and Costs of Treating Hepatitis C in Routine Care – Results from a Large Multicenter Trial

Estimates assume that 400,000 to 500,000 people are chronically infected with Hepatitis C in Germany. About 27% of end-stage liver cirrhosis and 25% of hepatocellular carcinoma are associated with HCV. The economic relevance of hepatitis C results from high costs for antiviral treatment as well as accompanying and secondary diseases. The aim of the study was to gain information on epidemiological characteristics, treatment outcomes and costs. Underlying data were collected in a non-interventional trial between 2008 and 2011. Inclusion criteria were a confirmed HCV diagnosis and need for antiviral treatment. Besides sociodemographic and clinical parameters, HCV related resource utilization was gathered for a subgroup of patients. Data presented are mean values. Data on 7,637 patients receiving antiviral treatment with peginterferon-α-2a and ribavirin were collected. This analysis relates on 3,708 patients without HIV coinfection and/or drug substitution treatment. Mean age was 43.7 years, 60.3% were male. Most patients had a genotype-1 (61.3%) or genotype-3 infection (28.5%). The majority of patients was treatment-naïve (86.5%), 7.3% were relapser and 5.6% non-responder. Main sources of infection were injection drug use (34.8%) and blood products (14.2%). Mean duration of infection was 13.6 years. In average 48.9% of treatment-naïve GT-1(4-6) and 63.0% of GT-2/3 patients achieved SVR. For prior relapse patients and non-responder SVR-rates were: GT-1(4-6): 35.4%; GT-2/3: 58.5 and GT-1(4-6): 23.3% GT-2/3: 37.9%, respectively. Costs for antiviral treatment amount for €20,889 in GT-1(4-6) patients and €13,610 in GT-2/3 patients. Costs for the management of adverse events or HCV-related diseases sum up for €11.70. Ambulatory care, diagnostics procedures and hospital care amount for a small proportion of total costs. This study provides an overview on epidemiologic characteristics, treatment outcomes and treating costs in routine care. Treatment of HCV is costly and mainly affected by length of antiviral therapy.

Functional Attributes of Responding T Cells in HCV Infection: The Recent Advances in Engineering Functional Antiviral T Cells

Hepatitis C virus (HCV) is one of the major causes of hepatocellular carcinoma (HCC) around the world. HCV promotes characteristics of cancer stem cells and the infected cells are insensitive to apoptotic signals, which lead to persistent antigen stimulation and T cell exhaustion in the host. In spite of new effective antiviral drugs, new challenges are around the corner as drug-resistant viral strains and drug-drug interactions have already been reported. Considering that there are few effective treatments available for HCC, novel immunotherapies to prevent HCC and late stage HCV-related liver diseases should be considered. Given that adoptive immunotherapy with antigen-specific T lymphocytes has emerged as an effective therapeutic strategy for combating cancer, there is, therefore, reason to examine the possibility of using highly functional HCV-reactive T cells in immunotherapy. This review aims to provide the current understanding of natural HCV responding T cells in HCV infection and to give an update on the novel approaches that have the capacity to ex vivo generate functional T cells for potential adoptive cell therapy. Approaches based on the pMHC tetramer-associated magnetic enrichment, exogenous HCV T cell receptor transfer, and induced pluripotent stem cell technologies are described herein. Their potentials as immunotherapeutic against HCV-related diseases are discussed.

Hepatitis C Virus Infection Induces Inflammatory Cytokines and Chemokines Mediated by the Cross Talk between Hepatocytes and Stellate Cells

Inflammatory cytokines and chemokines play important roles in inflammation during viral infection. Hepatitis C virus (HCV) is a hepatotropic RNA virus that is closely associated with chronic liver inflammation, fibrosis, and hepatocellular carcinoma. During the progression of HCV-related diseases, hepatic stellate cells (HSCs) contribute to the inflammatory response triggered by HCV infection. However, the underlying molecular mechanisms that mediate HSC-induced chronic inflammation during HCV infection are not fully understood. By coculturing HSCs with HCV-infected hepatocytes in vitro, we found that HSCs stimulated HCV-infected hepatocytes, leading to the expression of proinflammatory cytokines and chemokines such as interleukin-6 (IL-6), IL-8, macrophage inflammatory protein 1α (MIP-1α), and MIP-1β. Moreover, we found that this effect was mediated by IL-1α, which was secreted by HSCs. HCV infection enhanced production of CCAAT/enhancer binding protein (C/EBP) β mRNA, and HSC-dependent IL-1α production contributed to the stimulation of C/EBPβ target cytokines and chemokines in HCV-infected hepatocytes. Consistent with this result, knockdown of mRNA for C/EBPβ in HCV-infected hepatocytes resulted in decreased production of cytokines and chemokines after the addition of HSC conditioned medium. Induction of cytokines and chemokines in hepatocytes by the HSC conditioned medium required a yet to be identified postentry event during productive HCV infection. The cross talk between HSCs and HCV-infected hepatocytes is a key feature of inflammation-mediated, HCV-related diseases.

Abstract LB-235: Functional SNP in MICA binding to SP1 is associated with HCV-induced hepatocellular carcinoma.

Abstract Hepatitis C virus (HCV) infection is the major cause of hepatocellular carcinoma (HCC) in Japan. To understand the genetic basis of HCV related diseases, identification of the susceptibility gene involving HCV-induced HCC is important. We previously identified the association of SNP rs2596542 in the 5′ flanking region of the MHC class I polypeptide-related sequence A (MICA) gene with the risk of HCV-induced HCC. In the current study, we performed detailed functional analysis of 12 candidate SNPs in the promoter region. A SNP rs2596538 located at 2.8 kb upstream of the MICA gene affected the binding of a nuclear protein(s) to the genomic segment including this SNP. By electrophoretic mobility shift assay (EMSA) and chromatin immunoprecipitation (ChIP) assay, we identified that transcription factor Specificity Protein 1 (SP1) can bind to the protective G allele, but not to the risk A allele. In addition, reporter construct containing the G allele exhibited higher transcriptional activity than that containing the A allele. SNP rs2596538 exhibited the stronger association with HCV-induced HCC (P = 1.82 x10−5 and OR = 1.34) than the marker SNP rs2596542. We also found significantly higher serum level of soluble MICA (sMICA) in HCV-induced HCC patients carrying the G allele than those carrying the A allele (P = 0.00616). In summary, we have identified a functional SNP that is associated with expression of MICA and risk for HCV-induced HCC. Citation Format: Paulisally H. Lo, Chizu Tanikawa, Yusuke Nakamura, Koichi Matsuda. Functional SNP in MICA binding to SP1 is associated with HCV-induced hepatocellular carcinoma. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr LB-235. doi:10.1158/1538-7445.AM2013-LB-235

Discovery of Cellular Proteins Required for the Early Steps of HCV Infection Using Integrative Genomics

Successful viral infection requires intimate communication between virus and host cell, a process that absolutely requires various host proteins. However, current efforts to discover novel host proteins as therapeutic targets for viral infection are difficult. Here, we developed an integrative-genomics approach to predict human genes involved in the early steps of hepatitis C virus (HCV) infection. By integrating HCV and human protein associations, co-expression data, and tight junction-tetraspanin web specific networks, we identified host proteins required for the early steps in HCV infection. Moreover, we validated the roles of newly identified proteins in HCV infection by knocking down their expression using small interfering RNAs. Specifically, a novel host factor CD63 was shown to directly interact with HCV E2 protein. We further demonstrated that an antibody against CD63 blocked HCV infection, indicating that CD63 may serve as a new therapeutic target for HCV-related diseases. The candidate gene list provides a source for identification of new therapeutic targets.

Green Tea Phenolic Epicatechins Inhibit Hepatitis C Virus Replication via Cycloxygenase-2 and Attenuate Virus-Induced Inflammation

Chronic hepatitis C virus (HCV) infection is the leading risk factor for hepatocellular carcinoma (HCC) and chronic liver disease worldwide. Green tea, in addition to being consumed as a healthy beverage, contains phenolic catechins that have been used as medicinal substances. In the present study, we illustrated that the epicatechin isomers (+)-epicatechin and (−)-epicatechin concentration-dependently inhibited HCV replication at nontoxic concentrations by using in vitro cell-based HCV replicon and JFH-1 infectious systems. In addition to significantly suppressing virus-induced cyclooxygenase-2 (COX-2) expression, our results revealed that the anti-HCV activity of the epicatechin isomers occurred through the down-regulation of COX-2. Furthermore, both the epicatechin isomers additively inhibited HCV replication in combination with either interferon-α or viral enzyme inhibitors [2′-C-methylcytidine (NM-107) or telaprevir]. They also had prominent anti-inflammatory effects by inhibiting the gene expression of tumor necrosis factor (TNF)-α, interleukin (IL)-1β, and inducible nitrite oxide synthase as well as the COX-2 in viral protein-expressing hepatoma Huh-7 cells. Collectively, (+)-epicatechin and (−)-epicatechin may serve as therapeutic supplements for treating HCV-related diseases.

Chronic HCV infection and inflammation: Clinical impact on hepatic and extra-hepatic manifestations

The liver has a central role in regulating inflammation by its capacity to secrete a number of proteins that control both local and systemic inflammatory responses. Chronic inflammation or an exaggerated inflammatory response can produce detrimental effects on target organs. Chronic hepatitis C virus (HCV) infection causes liver inflammation by complex and not yet well-understood molecular pathways, including direct viral effects and indirect mechanisms involving cytokine pathways, oxidative stress and steatosis induction. An increasing body of evidence recognizes the inflammatory response in chronic hepatitis C as pathogenically linked to the development of both liver-limited injury (fibrosis, cirrhosis and hepatocellular carcinoma) and extrahepatic HCV-related diseases (lymphoproliferative disease, atherosclerosis, cardiovascular and brain disease). Defining the complex mechanisms of HCV-induced inflammation could be crucial to determine the global impact of infection, to estimate progression of the disease, and to explore novel therapeutic approaches to avert HCV-related diseases. This review focuses on HCV-related clinical conditions as a result of chronic liver and systemic inflammatory states.

Is there a True Link between HCV and Pathogenesis of RCC?

Is there a True Link between HCV and Pathogenesis of RCC? It is estimated that approximately 3% (130-200 million) of the world population are infected with chronic hepatitis C virus (HCV). 130–200 million people, or ~3% of the world’s population, are living with chronic hepatitis C. Approximately, 350,000 deaths and 4 million new cases are confirmed annually from HCV-related diseases. In the United States, 35,000-185,000 new cases are reported with an estimated death 8,000-10,000 annually.

Molecular Epidemiology and Genetic History of Hepatitis C Virus Subtype 3a Infection in Thailand

Objective: Among all hepatitis C virus (HCV) infections, subtype 3a is the most common genotype in Thailand. This study investigates the molecular epidemiology and epidemic history of HCV subtype 3a in Thailand. Methods: Three hundred and fifty-six serum samples were collected from HCV-infected Thai patients. The virus was isolated, after which the core and NS5B regions were sequenced. Subsequently, the HCV genotype was classified by phylogenetic analysis based on the core and NS5B regions. Molecular evolution analysis of HCV subtype 3a was estimated using BEAST (Bayesian Evolutionary Analysis by Sampling Trees) v.1.5.4. Results: Based on our phylogenetic analyses, subtype 3a (38.5%) was the most prevalent, followed by 1a (21%), 1b (13.8%), genotype 6 (19.9%) [comprised of subtypes 6e (0.3%), 6f (11%), 6i (1.9%), 6j (1.9%) and 6n (4.8%)] and 3b (5.6%). Our phylogenetic tree indicates the existence of a specific group of HCV subtype 3a strains in the Thai population. Molecular evolutionary analysis dated the most recent common ancestor of the Thai HCV subtype 3a strains as existing approximately 200 ago, and a Bayesian skyline plot showed that this particular strain spread to Thailand during the mid-1970s and early 1980s. This period overlaps with the Vietnam War (1955-1975) and the widespread use of injection stimulants introduced by the US Army during this time. Conclusion: The estimated history of HCV subtype 3a infection in Thailand may help to predict the future burden of HCV-related diseases and facilitate better public health control and surveillance.

Living donor vs. deceased donor liver transplantation for patients with hepatitis C virus-related diseases

Living donor liver transplantation (LDLT) provides a timely alternative to deceased donor liver transplantation (DDLT) for patients with hepatitis C virus-related (HCV-related) diseases in the circumstances of severe organ dearth. However, the patient and graft outcomes, and recurrence of HCV after LDLT remain controversial. Here we sought to compare the post-transplant outcomes after LDLT and DDLT. A systematic review and meta-analysis were performed. PubMed/MEDLINE, EMBASE, and the Cochrane database were searched for eligible literatures. The major end points were patient survival, graft survival, recurrence rate, and acute rejection. The pooled odds ratio (OR) was calculated using random-effects model to synthesize the results. Heterogeneity and publication bias were quantitatively evaluated. Fourteen studies with a total of 2024 participants were included in this analysis. We found comparable patient survival between groups (1-year: OR, 0.78, 95% CI, 0.48-1.26, p=0.31; 2-year: OR, 0.71, 95% CI, 0.41-1.23, p=0.23; 3-year: OR, 0.79, 95% CI, 0.5-1.12, p=0.18; 4-year: OR, 0.92, 95% CI, 0.43-1.95, p=0.83; 5-year: OR, 1.06, 95% CI, 0.53-2.14, p=0.86, respectively). Although 1- and 3-year graft survivals were inferior in LDLT, 2-, 4- and 5-year graft survivals were similar. HCV recurrence rates and acute rejection rates were equivalent. LDLT was equivalent to DDLT in terms of patient survival, long-term graft survival, HCV recurrence, and acute rejection rates, with potentially lower short-term patient and graft survival.

Cytokines and HCV-Related Disorders

Cytokines are intercellular mediators involved in viral control and liver damage being induced by infection with hepatitis C virus (HCV). The complex cytokine network operating during initial infection allows a coordinated, effective development of both innate and adaptive immune responses. However, HCV interferes with cytokines at various levels and escapes immune response by inducing a T-helper (Th)2/T cytotoxic 2 cytokine profile. Inability to control infection leads to the recruitment of inflammatory infiltrates into the liver parenchyma by interferon (IFN)-gamma-inducible CXC chemokine ligand (CXCL)-9, -10, and -11 chemokines, which results in sustained liver damage and eventually in liver cirrhosis. The most important systemic HCV-related extrahepatic diseases—mixed cryoglobulinemia, lymphoproliferative disorders, thyroid autoimmune disorders, and type 2 diabetes—are associated with a complex dysregulation of the cytokine/chemokine network, involving proinflammatory and Th1 chemokines. The therapeutical administration of cytokines such as IFN-alpha may result in viral clearance during persistent infection and reverts this process.