Hepatitis B Virus Vaccine for Patients with Hepatitis C Virus Infection

Summary Hepatitis C is a disease with varying rates of progression. The role of hepatitis B virus (HBV) as a cofactor in the development of hepatitis C virus (HCV)-related cirrhosis and hepatocellular carcinoma (HCC) has been suggested and the use of HBV vaccine in all HCV-infected patients has been advocated. This review presents the implications of HBV and HCV coinfection and addresses the issues of HBV vaccine immunogenicity and safety in patients with chronic HCV infection. Received: December, 1999 · Revision accepted: July 1, 2000     

Incorporation of Hepatitis C Virus E1 and E2 Glycoproteins: The Keystones on a Peculiar Virion

Hepatitis C virus (HCV) encodes two envelope glycoproteins, E1 and E2. Their structure and mode of fusion remain unknown, and so does the virion architecture. The organization of the HCV envelope shell in particular is subject to discussion as it incorporates or associates with host-derived lipoproteins, to an extent that the biophysical properties of the virion resemble more very-low-density lipoproteins than of any virus known so far. The recent development of novel cell culture systems for HCV has provided new insights on the assembly of this atypical viral particle. Hence, the extensive E1E2 characterization accomplished for the last two decades in heterologous expression systems can now be brought into the context of a productive HCV infection. This review describes the biogenesis and maturation of HCV envelope glycoproteins, as well as the interplay between viral and host factors required for their incorporation in the viral envelope, in a way that allows efficient entry into target cells and evasion of the host immune response.     

Molecular Signatures of Hepatitis C Virus (HCV)-Induced Type II Mixed Cryoglobulinemia (MCII)

The role of hepatitis C virus (HCV) infection in the induction of type II mixed cryoglobulinemia (MCII) and the possible establishment of related lymphoproliferative disorders, such as B-cell non-Hodgkin lymphoma (B-NHL), is well ascertained. However, the molecular pathways involved and the factors predisposing to the development of these HCV-related extrahepatic complications deserve further consideration and clarification. To date, several host- and virus-related factors have been implicated in the progression to MCII, such as the virus-induced expansion of selected subsets of B-cell clones expressing discrete immunoglobulin variable (IgV) gene subfamilies, the involvement of complement factors and the specific role of some HCV proteins. In this review, we will analyze the host and viral factors taking part in the development of MCII in order to give a general outlook of the molecular mechanisms implicated.     

48例原发性肝癌患者血清丙型肝炎抗体检测

为探讨PHC与丙型肝炎的关系,采用ELISA方法检测48例PHC及106例非肝病患者的扰HCV抗体及HBV-M。结果显示PHC组中抗HCV抗体阳性21例(43.8％),对照组14例(13.2％,P<0.01);HBV-M阳性45例(93.8％),对照组50例(47.2％,P<0.01)。HBV-M阳性PHC病人中,HBsAg、HBeAb及HBcAb三项阳性21例(46.7％),HBsAg、HBeAg及HBcAb三项阳性7例(15.6％),HBsAg及HBcAb二项阳性5例(11.1％)。HBV-M阴性PHC患者中,抗HCV抗体阳性2/3例(66.7％),HBV-M阳性PHC病人中,抗HCV抗体阳性19/45例(42.2％,P<0.05);HBsAg阳性PHC病人中,抗HCV抗体阳性14/38例(36.8％);HBsAg阴性病人中,抗HCV抗体阳性7/10例(70.0％,P<0.05)。在抗HCV抗体阳性PHC患者中,3个月前有明确输血史8例(38.1％)。以上结果提示在我国,PHC与丙型肝炎有关,在HBV-M阳性患者中。HBsAg、HBeAb及HBcAb三项阳性患者发生PHC可能性最大。     

Hepatitis C viral protein translation: mechanisms and implications in developing antivirals

Hepatitis C viral protein translation occurs in a cap‐independent manner through the use of an internal ribosomal entry site (IRES) present within the viral 5′‐untranslated region. The IRES is composed of highly conserved structural domains that directly recruit the 40S ribosomal subunit to the viral genomic RNA. This frees the virus from relying on a large number of translation initiation factors that are required for cap‐dependent translation, conferring a selective advantage to the virus especially in times when the availability of such factors is low. Although the mechanism of translation initiation on the Hepatitis C virus (HCV) IRES is well established, modulation of the HCV IRES activity by both cellular and viral factors is not well understood. As the IRES is essential in the HCV life cycle and as such remains well conserved in an otherwise highly heterogenic virus, the process of HCV protein translation represents an attractive target in the development of novel antivirals. This review will focus on the mechanisms of HCV protein translation and how this process is postulated to be modulated by cis‐acting viral factors, as well as trans‐acting viral and cellular factors. Numerous therapeutic approaches investigated in targeting HCV protein translation for the development of novel antivirals will also be discussed.     

Hepatitis B and C virus infection and risk of haematological malignancies

Hepatitis B virus (HBV) and hepatitis C virus (HCV) are classified as oncogenic human viruses. Chronic HBV and HCV infections are associated with higher risk of haematological malignancy development. Direct and indirect oncogenic mechanisms have been demonstrated for both HBV and HCV in several studies. HCV and overt/occult HBV infections in patients with oncohaematological disease constitute an impediment and a threat during immunosuppressive chemotherapy treatment. We review the HBV and HCV oncogenic mechanisms and the impact and the safety of antiviral treatment in patients with haematological malignancies.     

乙型肝炎病毒C型重组杆状病毒的构建及鉴定

目的构建乙型肝炎病毒（HBV）中国株及其拉米夫定耐药相关变异株的重组杆状病毒.方法将1.2倍HBV基因组（血清adr型、基因C型）连接至杆状病毒的转移载体pFastBacI上,然后转化入DH10Bac菌株中,在细菌内的辅助质粒辅助作用下与杆状病毒基因组Bacmid发生位点特异性转座,形成含有HBV基因组的重组Bacmid,转染昆虫sf9细胞后,包装产生HBV重组杆状病毒vAcHBVc.采用连续聚合酶链反应（PCR）引入方法进行定点突变,构建YVDD变异株质粒,并按照上述方法构建HBV YVDD变异株重组杆状病毒vAcHBVYVDD,扩增并滴定.为便于观察重组杆状病毒的转染和扩增效率及病毒滴度测定,同时构建了含绿色荧光蛋白（GFP）的HBV重组杆状病毒vAcGFPHBVc.结果 HBV野毒株和变异株重组杆状病毒均构建成功,通过免疫空斑及TCID50定量测定病毒滴度为106～108pfu/ml左右.结论应用Bac to Bac杆状病毒表达系统可有效快速地构建HBV C型重组杆状病毒,以用于HBV体外复制系统的建立,为HBV野毒株及变异株生物学特性的研究及抗病毒药物的筛选提供技术平台.     

Effect of Deferiprone on Liver Iron Overload and Fibrosis in Hepatitis C Virus-Infected Thalassemia

To assess the effects of liver iron overload and fibrosis after treatment with a chelating agent in hepatitis C virus (HCV)-infected thalassemia, from April 1999 to July 2004, 45 patients with thalassemia major (age range 9–33 years, mean 19.3) received daily deferiprone (L1) for 23–60 months (75 mg/kg). The patients were divided into two groups on the basis of their hepatitis status (27 with, 18 without). Their serum was analyzed for alanine aminotransferase (GPT), aspartate aminotransferase (GOT), bilirubin (total/direct), r-glutamyl transpeptidase (r-GT), alkaline phosphatase (Alk-P), and ferritin. Liver iron overload and fibrosis were defined by a senior pathologist. No significant differences were demonstrated in serum levels of GPT, GOT, bilirubin, r-GT, Alk-P or ferritin; comparison was made for each group before and after L1 treatment. Iron scores were 2.3 ± 0.9 and 2.8 ± 0.9 for the hepatitis C negative and positive groups, respectively (p = 0.07), with liver fibrosis scores of 1.0 ± 0.5 and 0.4 ± 0.52 (p = 0.56). The two scores were not higher for the positive group. There was no evidence of: 1) greater iron overload and fibrosis in the HCV-infected thalassemic patients; 2) L1 inducing progressive hepatic fibrosis or worsening iron overload in HCV-infected thalassemic patients after long-term therapy; 3) further damage to liver cells associated with L1 treatment.     

Marked increase of serum hepatitis C virus (HCV) RNA titer during treatment with high-dose prednisolone in a case of polymyositis

A 70-year-old Japanese woman with hepatitis C virus (HCV) infection was diagnosed with polymyositis and treated with high-dose prednisolone (PSL). The serum alanine aminotransferase (ALT) level increased from 78 to 345 U/l 1 week after initiating treatment, although the polymyositis settled promptly. Furthermore, the serum HCV RNA level increased markedly from 110 to 850 kIU/ml 3 weeks after starting treatment. Previously, the patient had suffered an occlusion of the left branch of the retinal vein secondary to hyperviscosity syndrome resulting from Sjögrens syndrome and low-dose PSL treatment had been commenced. The serum HCV RNA and transaminase levels had not increased during this low-dose PSL treatment. Although intensive immunosuppression is necessary as an initial treatment of several collagen diseases including polymyositis, high-dose PSL therapy may markedly augment the serum HCV RNA level and therefore careful observation is necessary in HCV-infected patients.     

Impact of Aging on the Development of Hepatocellular Carcinoma in Patients with Hepatitis C Virus Infection in Japan

Background: It is difficult to study the long-term outcome of hepatitis C virus (HCV) infection because chronic infection is often asymptomatic and duration of the disease is prolonged. The clinical outcome of HCV infection remains unclear in patients of advanced age. Methods: Among 575 patients consecutively diagnosed with hepatocellular carcinoma (HCC) from 1988 to 1999 at Hiroshima University, we examined 430 with HCV. We studied the differences between males and females in the following characteristics: age at first diagnosis of HCC, Child grade, various tumour factors, history of blood transfusion, duration to development of HCC, and history of alcohol intake. Results: The incidence of HCC patients with HCV increased in elderly persons, including female patients. Background liver function was significantly better for female patients ( P &#114 < &#114 0.001). In both genders, the duration between blood transfusion and diagnosis of HCC was significantly shorter when the patients received blood transfusion at an older age ( P &#114 < &#114 0.001). In habitual drinkers, the average age at first diagnosis of HCC was significantly younger ( P &#114 < &#114 0.001), and duration to development of HCC significantly shorter ( P &#114 < &#114 0.05). The percentage of atomic bomb survivors among HCV-positive HCC patients was significantly higher than that among HCV-negative HCC patients ( P &#114 < &#114 0.05). Conclusions: Patients with HCV might exhibit slow disease progression and develop HCC finally with aging regardless of gender. Patients of advanced age with HCV, even female patients, should therefore be closely followed.     

Association of the HLA-DRB1*01 allele with spontaneous viral clearance in an Irish cohort infected with hepatitis C virus via contaminated anti-D immunoglobulin

BACKGROUND/AIMS: The host's immune response may influence the course of hepatitis C virus (HCV) infection. The aim of this study was to examine the distribution of HLA Class II DRB1* alleles in a homogeneous cohort of individuals who were infected with HCV-contaminated anti-D immunoglobulin, and to compare frequencies of alleles in individuals with spontaneous viral clearance to those with chronic HCV infection. METHODS: HLA DRB1* typing was performed on whole blood or serum from 157 females. Of these, 73 had spontaneously recovered from infection (persistently HCV RNA negative), while 84 had chronic HCV infection (persistently HCV RNA positive). A group of 5000 healthy bone marrow donors served as a control population. RESULTS: No significant differences were observed between individuals with spontaneous viral clearance or chronic HCV infection for age, sex, alcohol consumption, source or duration of infection. The DRB1*01 allele was found significantly more frequently in individuals with viral clearance compared to those with chronic infection (27.4% vs. 7.1% p = 0.001, odds ratio OR = 4.9, pc = 0.01). No significant association was shown between severity of liver disease and DRB1* alleles. CONCLUSIONS: DRB1*01 is associated with spontaneous viral clearance in an Irish cohort infected with HCV via contaminated anti-D immunoglobulin. HLA-DRB1* genes do not appear to influence severity of liver disease. These results suggest that host HLA-DRB1* alleles are important contributors to disease outcome.     

Binding of Nanoparticles Harboring Recombinant Large Surface Protein of Hepatitis B Virus to Scavenger Receptor Class B Type 1

(1) Background: As nanoparticles containing the hepatitis B virus (HBV) large (L) surface protein produced in yeast are expected to be useful as a carrier for targeting hepatocytes, they are also referred to as bio-nanocapsules (BNCs). However, a definitive cell membrane receptor for BNC binding has not yet been identified. (2) Methods: By utilizing fluorescence-labeled BNCs, we examined BNC binding to the scavenger receptor class B type 1 (SR-B1) expressed in HEK293T cells. (3) Results: Analyses employing SR-B1 siRNA and expression of SR-B1 fused with a green fluorescent protein (SR-B1-GFP) indicated that BNCs bind to SR-B1. As mutagenesis induced in the SR-B1 extracellular domain abrogates or attenuates BNC binding and endocytosis via SR-B1 in HEK293T cells, it was suggested that the ligand-binding site of SR-B1 is similar or close among high-density lipoprotein (HDL), silica, liposomes, and BNCs. On the other hand, L protein was suggested to attenuate an interaction between phospholipids and SR-B1. (4) Conclusions: SR-B1 can function as a receptor for binding and endocytosis of BNCs in HEK293T cells. Being expressed various types of cells, it is suggested that functions as a receptor for BNCs not only in HEK293T cells but also in other types of cells.     

Interaction of Hepatitis B Virus X Protein with the Pregnane X Receptor Enhances the Synergistic Effects of Aflatoxin B1 and Hepatitis B Virus on Promoting Hepatocarcinogenesis

Background and AimsHepatitis B virus (HBV) infection has been found to increase hepatocellular sensitivity to carcinogenic xenobiotics, by unknown mechanisms, in the generation of hepatocellular carcinoma. The pregnane X receptor (PXR) is a key regulator of the body’s defense against xenobiotics, including xenobiotic carcinogens and clinical drugs. In this study, we aimed to investigate the molecular mechanisms of HBV X protein (HBx)-PXR signaling in the synergistic effects of chemical carcinogens in HBV-associated hepatocarcinogenesis.MethodsThe expression profile of PXR-cytochrome p450 3A4 (CYP3A4) signaling was determined by PCR, western blotting, and tissue microarray. Cell viability and aflatoxin B1 (AFB1) cytotoxicity were measured using the cell counting kit-8 assay. Target gene expression was evaluated using transient transfection and real time-PCR. The genotoxicity of AFB1 was assessed in newborn mice with a single dose of AFB1.ResultsHBx enhanced the hepatotoxicity of AFB1 by activating CYP3A4 and reducing glutathione S-transferase Mu 1 (GSTM1) in cell lines. Activation of PXR by pregnenolone 16α-carbonitrile increased AFB1-induced liver tumor incidence by up-regulating oncogenic KRAS to enhance interleukin (IL)-11:IL-11 receptor subunit alpha-1 (IL11RA-1)-mediated inflammation in an HBx transgenic model.ConclusionsOur finding regarding AFB1 toxicity enhancement by an HBx-PXR-CYP3A4/ GSTM1-KRAS-IL11:IL11RA signaling axis provides a rational explanation for the synergistic effects of chemical carcinogens in HBV infection-associated hepatocarcinogenesis.