Hepatitis B virus and hepatitis C virus dual infection

Hepatitis B virus (HBV) and hepatitis C virus (HCV) share common mode of transmission and both are able to induce a chronic infection. Dual HBV/HCV chronic coinfection is a fairly frequent occurrence, especially in high endemic areas and among individuals at high risk of parenterally transmitted infections. The intracellular interplay between HBV and HCV has not yet been sufficiently clarified, also due to the lack of a proper in vitro cellular model. Longitudinal evaluation of serum HBV DNA and HCV RNA amounts has revealed that complex virological profiles may be present in coinfected patients. Dual HBV/HCV infection has been associated to a severe course of the liver disease and to a high risk of developing hepatocellular carcinoma. Despite the clinical importance, solid evidence and clear guidelines for treatment of this special population are still lacking. This review summarizes the available data on the virological and clinical features as well as the therapeutic options of the dual HBV/HCV infection, and highlights the aspects that need to be better clarified.     

Hepatitis B virus and hepatitis C virus infection in healthcare workers

Approximately 3 million healthcare workers per year receive an injury with an occupational instrument, with around 2000000 exposures to hepatitis B virus(HBV) and 1000000 to hepatitis C virus(HCV). Although an effective HBV vaccine has been available since the early eighties, and despite the worldwide application of universal vaccination programs started in the early nineties, HBV still remains a prominent agent of morbidity and mortality. There is no vaccine to limit the diffusion of HCV infection, which progresses to chronicity in the majority of cases and is a major cause of morbidity and mortality worldwide due to a chronic liver disease. Healthcare workers are frequently exposed by a mucosal-cutaneous or percutaneous route to accidental contact with human blood and other potentially infectious biological materials while carrying out their occupational duties. Mucosal-cutaneous exposure occurs when the biological material of a potentially infected patient accidentally comes in contact with the mucous membranes of the eyes or mouth or with the skin of a healthcare worker. Percutaneous exposure occurs when an operator accidentally injures himself with a sharp contaminated object, like a needle, blade or other sharp medical instrument. About 75% of the total occupational exposure is percutaneous and 25% mucosal-cutaneous, the risk of infecting a healthcare worker being higher in percutaneous than in mucosal-cutaneous exposure. All healthcare workers should be considered for HBV vaccination and should meticulously apply the universal prophylactic measures to prevent exposure to HBV and HCV.     

Animal models for the study of hepatitis C virus infection and replication

Hepatitis C virus (HCV) hepatitis, initially termed non-A, non-B hepatitis, has become one of the leading causes of cirrhosis and hepatocellular carcinoma worldwide. With the help of animal models, our understanding of the virus has grown substantially from the time of initial discovery. There is a paucity of available animal models for the study of HCV, mainly because of the selective susceptibility limited to humans and primates. Recent work has focused modification of animals to permit HCV entry, replication and transmission. In this review, we highlight the currently available models for the study of HCV including chimpanzees, tupaia, mouse and rat models. Discussion will include methods of model design as well as the advantages and disadvantages of each model. Particular focus is dedicated to knowledge of pathophysiologic mechanisms of HCV infection that have been elucidated through animal studies. Research within animal models is critically important to establish a complete understanding of HCV infection, which will ultimately form the basis for future treatments and prevention of disease.     

Neutralizing antibodies in hepatitis C virus infection

Hepatitis C virus (HCV) is a major cause of hepatitis world-wide. The majority of infected individuals develop chronic hepatitis which can then progress to liver cirrhosis and hepatocellular carcinoma. Spontaneous viral clearance occurs in about 20%-30% of acutely infected individuals and results in resolution of infection without sequaelae. Both viral and host factors appear to play an important role for resolution of acute infection. A large body of evidence suggests that a strong, multispecific and long-lasting cellular immune response appears to be important for control of viral infection in acute hepatitis C. Due too the lack of convenient neutralization assays, the impact of neutralizing responses for control of viral infection had been less defined. In recent years, the development of robust tissue culture model systems for HCV entry and infection has finally allowed study of antibody-mediated neutralization and to gain further insights into viral targets of host neutralizing responses. In addition, detailed analysis of antibody-mediated neutralization in individual patients as well as cohorts with well defined viral isolates has enabled the study of neutralizing responses in the course of HCV infection and characterization of the impact of neutralizing antibodies for control of viral infection. This review will summarize recent progress in the understanding of the molecular mechanisms of antibody-mediated neutralization and its impact for HCV pathogenesis.     

MiR-122 in hepatitis B virus and hepatitis C virus dual infection

Hepatitis B virus (HBV) and hepatitis C virus (HCV) infections are the most common causes of chronic liver diseases and hepatocelluar carcinomas. Over the past few years, the liver-enriched microRNA-122 (miR-122) has been shown to differentially regulate viral replication of HBV and HCV. It is notable that the level of miR-122 is positively and negatively regulated by HCV and HBV, respectively. Consistent with the well-documented phenomenon that miR-122 promotes HCV accumulation, inhibition of miR-122 has been shown as an effective therapy for the treatment of HCV infection in both chimpanzees and humans. On the other hand, miR-122 is also known to block HBV replication, and HBV has recently been shown to inhibit miR-122 expression; such a reciprocal inhibition between miR-122 and HBV suggests an intriguing possibility that miR-122 replacement may represent a potential therapy for treatment of HBV infection. As HBV and HCV have shared transmission routes, dual infection is not an uncommon scenario, which is associated with more advanced liver disease than either HBV or HCV mono-infection. Thus, there is a clear need to further understand the interaction between HBV and HCV and to delineate the role of miR-122 in HBV/HCV dual infection in order to devise effective therapy. This review summarizes the current understanding of HBV/HCV dual infection, focusing on the pathobiological role and therapeutic potential of miR-122.     

Chaperones in hepatitis C virus infection

The hepatitis C virus(HCV) infects approximately 3% of the world population or more than 185 million people worldwide. Each year, an estimated 350000-500000 deaths occur worldwide due to HCV-associated diseases including cirrhosis and hepatocellular carcinoma. HCV is the most common indication for liver transplantation in patients with cirrhosis worldwide. HCV is an enveloped RNA virus classified in the genus Hepacivirus in the Flaviviridae family. The HCV viral life cycle in a cell can be divided into six phases:(1) binding and internalization;(2) cytoplasmic release and uncoating;(3) viral polyprotein translation and processing;(4) RNA genome replication;(5) encapsidation(packaging) and assembly; and(6) virus morphogenesis(maturation) and secretion. Many host factors are involved in the HCV life cycle. Chaperones are an important group of host cytoprotective molecules that coordinate numerous cellular processes including protein folding, multimeric protein assembly, protein trafficking, and protein degradation. All phases of the viral life cycle require chaperone activity and the interaction of viral proteins with chaperones. This review will present our current knowledge and understanding of the role of chaperones in the HCV life cycle. Analysis of chaperones in HCV infection will provide further insights into viral/host interactions and potential therapeutic targets for both HCV and other viruses.     

Fibromyalgia syndrome in chronic hepatitis C virus (HCV) infection patients: A potential association and pathogenic role

BackgroundHigher prevalence of fibromyalgia (FM) among chronic hepatitis-C virus (HCV) suspects virally-mediated pathway.Aim of the workTo determine the frequency and clinical characteristics of FM in Egyptian patients with chronic HCV and to evaluate its relationship to viral load.Patients and methods150 Egyptian patients with chronic HCV and 150 controls were included. Liver function tests, thyroid stimulating hormone (TSH), HCV antibodies, HCV-ribonucleic acid (RNA) and abdominal ultrasonography were done. FM was diagnosed according to 2010 American College of Rheumatology (ACR) classification criteria.ResultsThe mean age of the patients was 54.1 ± 8.4 years and they were 94 females: 56 males; and the mean duration of HCV was 6.9 ± 3.2 years. Fatigue, arthralgia, arthritis, morning stiffness, weakness, sicca-like symptoms, depression, cognitive, sleep disturbances and irritable bowel syndrome (IBS) were significantly more frequent in HCV patients. Twenty six patients with HCV (17.3%) and 4 (2.7%) of the controls had FM. HCV patients with FM had significantly higher widespread pain index, symptom severity score, visual analogue scale (VAS), tender points count and stiffness than controls with FM. HCV patients with FM had significant higher VAS score, fatigue and depression than without FM. Rates of hematological features, autoantibodies, liver enzymes, abdominal US findings, patients with viral load > 800,000 IU/L were comparable.ConclusionThere is increased rate of fibromyalgia in chronic HCV patients and is associated with higher pain intensity, tender point count, symptom severity and fatigue. FM in patients with HCV infection is not related to viral load of HCV.     

Hepatitis C virus inhibitor synergism suggests multistep interactions between heat-shock protein 90 and hepatitis C virus replication

AIM: To address the effect of heat-shock protein 90(HSP90) inhibitors on the release of the hepatitis C virus(HCV), a cell culture-derived HCV(JFH1/HCVcc) from Huh-7 cells was examined.METHODS: We quantified both the intracellular and extracellular(culture medium) levels of the components(RNA and core) of JFH-1/HCVcc. The intracellular HCV RNA and core levels were determined after the JFH1/HCVcc-infected Huh-7 cells were treated with radicicol for 36 h. The extracellular HCV RNA and core protein levels were determined from the medium of the last 24 h of radicicol treatment. To determine the possible role of the HSP90 inhibitor in HCV release, we examined the effect of a combined application of low doses of the HSP90 inhibitor radicicol and the RNA replication inhibitors cyclosporin A(Cs A) or interferon. Finally, we statistically examined the combined effect of radicicoland Cs A using the combination index(CI) and graphical representation proposed by Chou and Talalay.RESULTS: We found that the HSP90 inhibitors had greater inhibitory effects on the HCV RNA and core protein levels measured in the medium than inside the cells. This inhibitory effect was observed in the presence of a low level of a known RNA replication inhibitor(Cs A or interferon-α). Treating the cells with a combination of radicicol and cyclosporin A for 24 h resulted in significant synergy(CI 1) that affected the release of both the viral RNA and the core protein. CONCLUSION: In addition to having an inhibitory effect on RNA replication, HSP90 inhibitors may interfere with an HCV replication step that occurs after the synthesis of viral RNA, such as assembly and release.     

Hepatitis C virus (HCV) genotypes in Spanish patients with HCV infection: relationship between HCV genotype 1b, cirrhosis and hepatocellular carcinoma

Background/Aims: The influence of the infecting virus genotype on the progression of the underlying liver disease in patients with chronic hepatitis C virus (HCV) infection remains controversial. The aim of this study was to investigate the prevalence of HCV genotypes in Spanish patients with chronic HCV infection and to elucidate the relationship between the infecting genotype and severity of the disease.Methods: A cross-sectional, retrospective analysis of frequency distribution of HCV genotypes was carried out in 414 Spanish patients with chronic HCV infection, including 243 patients with asymptomatic or minimally symptomatic chronic hepatitis, 112 patients with cirrhosis and hepatocellular carcinoma and 59 patients with decompensated cirrhosis. HCV genotype was determined by restriction fragment length polymorphisms of the 5′ non-coding region.Results: Infection with HCV genotype 1b was found in 72% of patients with chronic hepatitis and in more than 90% of patients with cirrhosis, with or without hepatocellular carcinoma. Older age, infection with genotype 1b and absence of overt parenteral exposure as a possible source of infection were associated with cirrhosis and hepatocellular carcinoma by univariate analysis and this association was confirmed by regression analysis.Conclusions: HCV genotype 1b is associated with advanced liver disease in our geographical area. However, this may be related to a cohort-effect caused by over-representation of genotype 1b in older patients with more advanced disease, because, in our country, this HCV genotype appeared earlier in time and is therefore associated with more prolonged periods of infection.     

Hepatitis C virus proteins

Hepatitis C virus (HCV) encodes a single polyprotein, which is processed by cellular and viral proteases to generate 10 polypeptides. The HCV genome also contains an overlapping +1 reading frame that may lead to the synthesis of an additional protein. Until recently, studies of HCV have been hampered by the lack of a productive cell culture system. Since the identification of HCV genome approximately 17 years ago, structural, biochemical and biological information on HCV proteins has mainly been obtained with proteins produced by heterologous expression systems. In addition, some functional studies have also been confirmed with replicon systems or with retroviral particles pseudotyped with HCV envelope glycoproteins. The data that have accumulated on HCV proteins begin to provide a framework for understanding the molecular mechanisms involved in the major steps of HCV life cycle. Moreover, the knowledge accumulated on HCV proteins is also leading to the development of antiviral drugs among which some are showing promising results in early- phase clinical trials. This review summarizes the current knowledge on the functions and biochemical features of HCV proteins.     

Alcoholic liver disease and hepatitis C virus infection

Alcohol consumption and hepatitis C virus(HCV) infection have a synergic hepatotoxic effect, and the coexistence of these factors increases the risk of advanced liver disease. The main mechanisms of this effect are increased viral replication and altered immune response, although genetic predisposition may also play an important role. Traditionally, HCV prevalence has been considered to be higher(up to 50%) in alcoholic patients than in the general po pulation. However, the presence of advanc e d alcoholic liver disease(ALD) or intravenous drug use(IDU) may have confounded the results of previous studies, and the real prevalence of HCV infection in alcoholic patients without ALD or prior IDU has been shown to be lower. Due to the toxic combined effect of HCV and alcohol, patients with HCV infection should be screened for excessive ethanol intake. Patients starting treatment for HCV infection should be specifically advised to stop or reduce alcohol consumption because of its potential impact on treatment efficacy and adherence and may benefi t from addi tionalsupport during antiviral therapy. This recommendation might be extended to all currently recommended drugs for HCV treatment. Patients with alcohol dependence and HCV infection, can be treated with acamprosate, nalmefene, topiramate, and disulfiram, although baclofen is the only drug specifically tested for this purpose in patients with ALD and/or HCV infection.     

Hepatitis C virus infection in the human immunodeficiency virus infected patient

Human immunodeficiency virus(HIV)and hepatitis C virus(HCV)share the same transmission routes;therefore,coinfection is frequent.An estimated 5-10 million individuals alone in the western world are infected with both viruses.The majority of people acquire HCV by injection drug use and,to a lesser extent,through blood transfusion and blood products.Recently,there has been an increase in HCV infections among men who have sex with men.In the context of effective antiretroviral treatment,liver-related deaths are now more common than Acquired Immune Deficiency Syndromerelated deaths among HIV-HCV coinfected individuals.Morbidity and mortality rates from chronic HCV infection will increase because the infection incidence peaked in the mid-1980s and because liver disease progresses slowly and is clinically silent to cirrhosis and end-stage-liver disease over a 15-20 year time period for 15%-20%of chronically infected individuals.HCV treatment has rapidly changed with the development of new direct-acting antiviral agents;therefore,cure rates have greatly improved because the new treatment regimens target different parts of the HCV life cycle.In this review,we focus on the epidemiology,diagnosis and the natural course of HCV as well as current and future strategies for HCV therapy in the context of HIV-HCV coinfection in the western world.     

Hepatitis C virus (HCV) NS5A protein: role in HCV replication and resistance to interferon-alpha

The hepatitis C virus (HCV) non-structural (NS) 5A protein appears to play an important regulatory role on viral replication and could also be involved in viral pathogenesis. HCV resistance to interferon is a complex mechanism involving multiple causes, among which certain NS5A functions could play a role.     

乙型和丙型肝炎病毒感染与肝细胞癌

为探讨乙型和丙型肝炎病毒（ＨＢＶ和ＨＣＶ）感染与肝细胞癌（肝癌）发生的关系，采用ＥＬＩＳＡ和聚合酶链反应（ＰＣＲ）对沈阳地区１１７例肝癌、１０７例肝硬化和４５例血液透析患者血清进行了ＨＢＶ和ＨＣＶ血清标志及ＨＢＶＤＮＡ和ＨＣＶＲＮＡ检测，并采用限制性片段长度多态性对其中７３例ＨＣＶＲＮＡ阳性血清进行了ＨＣＶ基因分型。结果，肝癌组ＨＢＶ感染率（６０７％）显著高于ＨＣＶ感染率（３３３％，Ｐ＜００１），肝硬化组ＨＢＶ感染率（４３９％）明显高于ＨＣＶ感染率（２９０％，Ｐ＜００５）；血液透析组ＨＢＶ和ＨＣＶ重叠感染率（２６７％）明显高于肝硬化组（１０３％，Ｐ＜００５）；各组均以ＨＣＶⅡ型为主（６５２％～８００％），ＨＣＶⅢ型次之（２００％～３１４％）。结果提示：沈阳地区肝癌的诱发因素仍以ＨＢＶ为主，血液透析患者ＨＢＶ和ＨＣＶ重叠感染的机会更大，ＨＣＶⅡ型感染在本地区ＨＣＶ相关性肝癌和肝硬化的发生中可能起主要作用。     

Hepatitis B and C virus co-infections in human immunodeficiency virus positive North Indian patients

INTRODUCTION Diseases of the hepatobiliary system are a major problem in patients with human immunodeficiency virus (HIV) infection. An estimated one-third of deaths in HIV patients are directly or indirectly related to liver disease. Liver diseases in HI…     

肝特异性自身抗体与丙型肝炎病毒感染的关系

本研究探讨了HCV感染时体内产生免疫应答并出现多种自身抗体的特点,试图通过检测分析HCV感染与自身抗体的相关性,对丙型肝炎的诊断及治疗提供一些实验数据.     

Progress in the development of vaccines for hepatitis C virus infection

The hepatitis C virus(HCV), first described in 1989, is now a leading cause of liver cirrhosis and hepatocellular carcinoma. With more than 170 million people infected globally, this virus is a major public health issue. The current standard therapy is based on interferon in combination with ribavirin. This costly therapy often fails to completely clear the infection and is associated with adverse side effects. Recent anti-HCV therapies are interferon-free direct-acting antiviral(DAA) regimens for HCV, including simeprevir, sofosbuvir, and ledipasvir, which have effects on non-structural proteins. DAA regimens have several advantages, such as specifically targeting HCV viral replication, accompanied by very high sustained virological response rates and lower side effects like flu-like syndrome. These facts plus the fact that most HCV cases progress to chronic infection suggest the potential need for an efficient HCV vaccine. Different innovative methods, including methods based on peptide, recombinant protein, DNA, vector-based, and virus-like particles, have been introduced for the development of HCV vaccines. An extensive number of studies have been published on these vaccines, and some vaccines were even tested in clinical trials. In the current review, progress in the development of preventive and therapeutic vaccines against the HCV is reviewed in the context of peptide vaccines, recombinant protein vaccines, HCV-like particle, DNA vaccines and viral vectors expressing HCV genes.     

New animal models for hepatitis C viral infection and pathogenesis studies

Hepatitis C virus (HCV) is a major cause of chronic live disease, cirrhosis and hepatocellular carcinoma (HCC) In man, the pathobiological changes associated wit HCV infection have been attributed to both the immun system and direct viral cytopathic effects. Until now, th lack of simple culture systems to infect and propagat the virus has hampered progress in understandin the viral life cycle and pathogenesis of HCV infection including the molecular mechanisms implicated in HCV induced HCC. This clearly demonstrates the need t develop small animal models for the study of HCV associated pathogenesis. This review describes an discusses the development of new HCV animal models t study viral infection and investigate the direct effects o viral protein expression on liver disease.