Sequence variability of hepatitis C virus and its clinical relevance

SUMMARY. Chronic type C hepatitis is a potentially serious disease that can lead to cirrhosis and hepatocelluler carcinoma. This complex disease is caused by the hepatitis C virus (HCV), a positive sense, single-stranded RNA virus. HCV has been assigned to a separate genus within the Flaviviridae, and shares a close relationship to the pestiviruses. Nucleotide sequence variation has been observed in genomes amplified from serum of patients with HCV infection, and cloning of RNA amplified from patients infected with HCV has confirmed the heterogeneity of the agent responsible for post-transfusion and sporadic hepatitis C. The variability of HCV is structured in a way that immediately suggests a two tiered classification: this nomenclature comprises 'types' corresponding to the major branches in a phylogenetic tree of sequences from genomic or subgenomic regions of the genome, and 'subtypes', corresponding to the more closely related sequences within some of the major groups. This genotyping designation has provided an epidemiological tool for studying geographical differences in hepatitis C infection. Clearly discernible patterns of genotype distribution have been found in those countries that have been studied so far. In many European countries genotype distributions vary with the age of patients, reflecting rapid changes in genotype distribution with time within a single geographical area. Unfortunately we know very little about modes of transmission within different communities. There is considerable interest in the clinical significance of different HCV genotypes, and the intriguing question of whether these differences may affect the spectrum of the disease associated with hepatitis C. These data also have implications for diagnosis and treatment of acute and chronic hepatitis C. A uniform typing scheme and nomenclature will facilitate our understanding of the disease caused by this virus worldwide.     

丙型肝炎疫苗研究的新理念、挑战与策略

丙型肝炎病毒（HCV）感染是引起慢性肝病的主要原因之一,严重危害人类健康,目前抗病毒治疗的标准方案为聚乙二醇干扰素α（PEG-IFN-α）联合利巴韦林,其有效率仅为50%70%,且疫苗研究进展缓慢,已成为严峻的公共卫生问题。近10多年来,对HCV感染发病机制、保护性免疫应答和病毒持续感染机制的认识取得了很大进展,中和抗体以及CD4＋和CD8＋T细胞在内的强烈的T细胞免疫应答已被证明与HCV的清除相关,这将是研制丙型肝炎疫苗的希望所在。当前HCV疫苗的研究主要集中在多肽疫苗、核酸疫苗、病毒载体疫苗、重组多表位疫苗、以抗原递呈细胞为载体的树突状细胞（DC）疫苗等,已有多种疫苗正在研制并进行进入临床试验前的测试。我们结合多年来对HCV的研究基础,通过与国内外同行交流,提出变＂单纯预防＂为＂防治结合,以诱导持续免疫应答和维持病毒抑制状态为基本目标＂的HCV疫苗研究新理念,发展以诱导细胞免疫为主的预防和治疗性疫苗,尤其是既能在体内有效激发HCV特异性细胞毒性T淋巴细胞（CTL）反应,又能维持CD4＋记忆T细胞功能的治疗性细胞疫苗。本文综述关于HCV保护性免疫应答及持续感染的机制,HCV疫苗研究新理念,目前面临的挑战以及研究策略。     

microRNA在乙型、丙型肝炎中的作用

近年来,作为基因表达的重要调节因子microRNA(miRNA),以及与这些miRNA关联或调控的各种肝脏疾病,如肝炎、肝纤维化和肝细胞癌(HCC)等方面的研究取得了新进展.许多编码miRNA的基因及其靶标被发现,它们与肝脏疾病的直接或间接的关联性也通过大量的实验研究(包括人体组织)得到确证.病毒性肝炎是由多种不同肝炎病毒引起的一组以肝脏损伤为主的传染病,根据病原学诊断,肝炎病毒至少有5种,但目前最常见的是HBV和HCV感染.本文就miRNA与病毒性肝炎的关系研究进展作一综述.     

PREVALENCE AND CLINICAL SIGNIFICANCE OF HEPATITIS G VIRUS INFECTION IN ADULT BETA-THALASSAEMIA MAJOR PATIENTS

The risk of polytransfused patients for hepatitis C virus (HCV) infection is likely to extend to another recently identified member of the Flaviviridae, hepatitis G virus (HGV). We investigated the prevalence of HGV in 40 adult Italian patients with transfusion-dependent thalassaemia and evaluated the clinical significance of HGV infection. HGV-RNA was detected in 9/40 patients (22.5%). HGV infection was significantly associated with HCV viraemia ( P  =0.0012), with all patients positive for HGV being also viraemic for HCV. Overall, the clinical picture of patients with HCV/HGV co-infection was not different from that of patients with isolated HCV. However, patients co-infected with both viruses had lower values of alanine-transferase ( P  =0035) and a lower titre of HCV viraemia ( P  =0042) in the absence of other evident factors which could influence the clinical expression of HCV infection. In conclusion, HGV is highly prevalent among Italian polytransfused patients. No evidence of a clinically significant pathogenic role for HGV in liver disease could be found in these patients. In a subset of cases a possible interference of HGV with HCV infection was observed.     

健康人群和肝病患者中检测TTV的意义

目的了解新型肝炎病毒－ＴＴＶ的致病性和在健康人群和肝病患者中的流行情况．方法收集１８０份健康体检患者血清和１５６份不同类型肝病患者血清,采用ＰＣＲ方法检测ＴＴＶ的ＤＮＡ．同时检测ＨＡＶ,ＨＢＶ,ＨＣＶ,ＨＥＶ和ＨＧＶ感染标志,比较分析ＴＴＶ在健康人群和不同类型肝病患者中流行情况及其致病性．结果健康体检人群和肝病患者中,ＴＴＶＤＮＡ检出率分别为２２％和４５％,两组间无显著性差异（Ｐ＞００５）．体检人群中,ＡＬＴ正常和升高者的检出率分别为１７％和１４３％．急性肝炎,慢性肝炎和肝硬变者的检出率分别为４８％,４３％和４７％．１１例阳性患者中,３例ＡＬＴ正常,８例ＡＬＴ异常．在８例ＡＬＴ异常患者中,６例为ＨＢＶ现行感染,１例为ＨＣＶ现行感染,仅１例为ＮＡ－Ｇ肝炎患者．结论在中国健康体检人群和肝病患者中能检出低水平的ＴＴＶ现行感染．但似乎仅引起个别患者的转氨酶轻度升高．ＴＴＶ的致病性可能较弱或需要其他因素协同致病．     

血清HBeAg阴性与HBeAg/IC及A1896变异的关系

目的探讨血清ＨＢｅＡｇ阴性（双抗体夹心法）与ＨＢｅＡｇ／ＩＣ形成及ＨＢＶ变异株Ａ１８９６的关系，评价ＨＢｅＡｇ／ＩＣ检测的临床意义．方法单克隆抗ＨＢｅ固相ＥＬＩＳＡ检测血清中ＨＢｅＡｇ／ＩＣ；套式多聚酶链反应检测ＨＢＶＤＮＡ；３＇碱基特异多聚酶链反应判断Ａ１８９６变异；ＥＬＩＳＡ检测ＨＢｅＡｇ、抗ＨＢｅ，研究对象为１１７例慢性ＨＢＶ感染者，２０例健康对照统计处理采用卡方检验．结果ＨＢｅＡｇ／ＩＣ阳性血清中ＨＢＶＤＮＡ检出率明显高于ＨＢｅＡｇ／ＩＣ阴性血清，Ｐ＜０００１（９１３％ｖｓ３６２％）；２９份ＨＢｅＡｇ阴性、ＨＢＶＤＮＡ阳性血清中仅５例（１７２％）检出Ａ１８９６，而且其中２例与野毒株（Ｇ１８９６）混合感染并伴ＨＢｅＡｇ／ＩＣ阳性．２９份中１７份（５８７％）为ＨＢｅＡｇ／ＩＣ阳性的Ｇ１８９６感染；血清抗ＨＢｅ阳性组Ａ１８９６检出率高于抗ＨＢｅ阴性组，Ｐ＜００５（２５％ｖｓ３２％）．结论ＨＢｅＡｇ／ＩＣ为ＨＢＶ活跃复制指标；临床ＨＢｅＡｇ阴性、ＨＢＶＤＮＡ阳性患者仍多数为Ｇ１８９６感染，ＨＢｅＡｇ／ＩＣ形致双抗体夹心法不能检出ＨＢｅＡｇ；抗ＨＢｅ应答可能为促使前Ｃ变异的重要因素     

Human non-A,non-B hepatitis: ultrastructural alterations in hepatocytes

ABSTRACT— Ultrastructural investigation of liver biopsies from two patients with non-A, non-B hepatitis revealed cytoplasmic and nuclear alterations in the hepatocytes. The lesions in both patients, one with acute and one with chronic hepatitis, were similar and distinct from those previously described in other forms of hepatitis. These findings are compared with the reported findings in chimpanzee liver after inoculation with non-A, non-B infective material. The intranuclear findings are similar to the aggregations of 20–27 nm particles described in some infected chimpanzees, and the cytoplasmic alterations seem to be similar to the cytoplasmic structures and tubular arrangements reported in other inoculated chimpanzees. A striking finding of this study is the presence of both alterations together in the same biopsy in two different patients, suggesting that they represent a different stage of viral infection or different parts of the viral agent. It still remains to be proved that the ultrastructural particles indeed contain antigen(s) of the non-A, non-B hepatitis virus. The nuclear and cytoplasmic alterations are, however, characteristic for non-A, non-B hepatitis and are useful as ultrastructural hallmarks of this form of hepatitis.     

Clinical prognostic variables in young patients (under 40 years) with hepatitis B virus-associated hepatocellular carcinoma

OBJECTIVE: The aim of this study was to determine the impact of hepatocelluar carcinoma (HCC) screening in chronic hepatitis B patients who did not meet the current screening recommendations. METHODS: Patients who were admitted to Bellevue Hospital Center with HCC were assessed for risk factors, cirrhosis and tumor‐specific factors. Eligibility for liver transplantation or resection with favorable outcome was determined by applying Milan criteria. RESULTS: In all 93 patients were diagnosed with hepatitis B virus (HBV)‐associated HCC, 18 of whom were under 40 years. Cirrhosis was infrequently associated with HCC in this group, with most cancers occurring in non‐cirrhotic patients (12/18, 66.7%). No patient developed HCC outside the American Association for the Study of Liver Diseases (AASLD) cancer screening recommendations (young age, non‐cirrhotic) were eligible for liver transplantation or resection with favorable outcomes (within Milan criteria). However, HCC patients who were diagnosed within AASLD screening recommendations did meet Milan criteria in 17.3% (14/81) patients. CONCLUSIONS: Current guidelines for HCC screening in patients with HBV may lead to a delay in diagnosis in non‐cirrhotic patients under 40 years. Consideration should be given to modifying current recommendations to advocate entering HBV patients into a cancer‐screening program at young age.     

Experimental non-A,non-B hepatitis in chimpanzees: Light,electron and immune microscopical observations

ABSTRACT— Two chimpanzees (Pan troglodytes) were inoculated and cross-challenged with a fibrinogen and factor VIII preparation, respectively. Successful non-A, non-B (NANB) infection was documented by biphasic elevations of aminotransferases (ALT), concomitant hepatitic reactions and typical electron microscopic alterations, the most consistent being dilatation of the endoplasmic reticulum, as well as tubular and sponge-like cytoplasmic inclusions in the absence of nuclear virus-like particles. An anti-nuclear (anti-DNA) antibody of the IgM class in one of the chimpanzees simulating an antiviral antibody is described.     

Hepatitis C virus vaccines in the era of new direct-acting antivirals

Hepatitis C virus (HCV) infection is a major global health problem as it has a high propensity for establishing chronicity. Chronic HCV carriers are at risk of developing severe liver disease including fibrosis, cirrhosis and liver cancer. While treatment has considerably improved over the years, therapy is still only partially effective, and is plagued by side effects, which contribute to treatment failure and is expensive to manage. The drug development pipeline contains several compounds that hold promise to achieve the goal of a short and more tolerable therapy, and are also likely to improve treatment response rates. It remains to be seen, however, how potent antiviral drug cocktails will affect the hepatitis C burden worldwide. In resource-poor environments, considerable costs, inadequate infrastructure for medical supervision and distribution may diminish the impact of future therapies. Consequently, development of novel therapeutic and prophylactic strategies is imperative to contain HCV infection globally.     

急性乙型病毒性肝炎预后因素分析

探讨急性乙型病毒性肝炎痊愈及慢性化的预测指标。本文对150例急性乙型病毒性肝炎患者就诊时的血清HBV-DNA定量、肝功能及血中淋巴细胞计数情况及预后作一回顾分析。痊愈组的HBV-DNA定量水平,淋巴细胞计数水平较慢性化组低,而转氨酶水平较慢性化组高。联合检测急性乙型病毒性肝炎患者血中HBV水平和转氨酶水平、淋巴细胞计数水平有助于判断患者的预后,血中HBV水平越低,转氨酶水平越高,淋巴细胞计数水平越低乙型病毒性肝炎痊愈的可能性越大。对此类患者以保肝治疗为主;反之慢性化的可能性大。对此类患者以加强抗病毒提高机体免疫能力治疗为主。     

Regulatory T cells in hepatitis C virus infection

Hepatitis C virus (HCV) is a highly mutable RNA virus with a high propensity for chronic infection, affecting over 3% of the world's population. Persistent infection is associated with chronic hepatitis that may progress to cirrhosis and hepatocellular carcinoma over many years of infection. While cellular immune response plays a key role in viral infection, HCV persistence is associated with antiviral effector T-cell dysfunction with increased CD4+ CD25+ Tregs and interleukin-10+ Tr1cells, raising the possibility that the balance between antiviral effector and regulatory T-cell subsets contributes to the outcome of HCV infection.     

血液透析与病毒性肝炎的关系

目的：探讨血液透析与病毒性肝炎的关系。方法：采用酶联免疫法检测每例患者的ＨＡＶ，ＨＣＶ，ＨＤＶ，ＨＥＶ及ＨＢｓＡｇ并对血透各组和非透析组进行对比分析，结果：ＨＡＶ，ＨＤＶ，ＨＥＶ和ＨＢｓＡｇ的阳性率在各组单元差异；ＨＣＶ的阳性率在血透组和非血透组之间差异非常显著，且随着血透时间延长而增加，５年以上组达１００％，ＨＣＶ阳性率与是否输过血无关，结论：血透并不导致增加甲，乙，丁，戊型肝炎的感染，但明显增     

Liver transplantation for acute and chronic viral hepatitis

Summary. Hepatotrophic viruses are responsible for a substantial proportion of cases of both end-stage chronic liver disease and of acute liver failure which are treated by liver transplantation. We review here current practice in transplantation for viral-induced liver disease addressing, in particular, the selection of patients for transplantation and the increasingly recognized problem of recurrent disease in liver grafts.     

重型病毒性肝炎血清甲状腺激素水平检测及临床意义

目的 探讨重型病毒性肝炎患者血清甲状腺激素水平与肝损害程度关系及临床意义.方法 应用放射免疫法测定54例重型病毒性肝炎、41例急性病毒性肝炎患者及30例正常人血清甲状腺激素水平.结果 重型病毒性肝炎T3、T4、TSH水平显著低于急性病毒性肝炎及正常人(P＜0.05);rT3则增高(P＜0.05).T3、T4与血浆Alb呈正相关,L、TSH与PT,rT3与ALT呈负相关.重型病毒性肝炎死亡者T3、T4、TSH显著低于存活者(P＜0.01).rT3则增高(P＜0.01).结论 重型病毒性肝炎患者甲状腺激素水平可作为反映肝功能的敏感指标,对判断疾病严重程度、预后有重大价值.     

血清前白蛋白在肝病中的临床意义

了解病毒性肝炎患者血清前白蛋白 (PA)的变化 ,探讨测定血清前白蛋白对病毒性肝炎患者的诊断价值。采用免疫比浊法检测 2 76例病毒性肝炎患者血清前白蛋白 ,比较不同临床类型的血清PA的水平及同一临床类型间PA与A的异常率。血清PA的水平在急性肝炎与轻度慢性肝炎之间、慢性肝炎轻度与中度、中度与重度之间、肝硬化与慢性重型肝炎之间均有显著性差异 (P <0 0 5 ) ;急性肝炎组PA与白蛋白 (A)两者相比有高度显著性差异 (P <0 0 0 1) ;PA值比A值更灵敏地反映肝功能损害。血清PA的水平持续 <10 0mg/L作为重症肝炎早期诊断指标之一。检测血清PA对病毒性肝炎临床诊断、病情判断和预后估计有一定参考价值     

Report from the International Symposium on viral hepatitis, 24–25 October 1997, Warsaw, Poland

The authors present the results of an International Symposium on 'Viral Hepatitis', held in Warsaw on 24–25 October 1997 and dedicated to the scientific activity of Professor Adam Nowoslawski, the founder of the Polish school of Immunopathology, with many contributions to the viral hepatitis research. The symposium was divided into main sessions and poster reports which covered most of the topics in this field. This successful meeting has gathered many distinguished speakers from different countries and was attended by ca. 350 participants, mainly from Poland, but also from the neighbouring countries.     

Acute viral hepatitis: An aetiological study of 253 patients

Two hundred and fifty-three cases of acute viral hepatitis admitted to Ibn Al-Khateeb Infectious Disease Hospital, Baghdad, were studied prospectively regarding the viral aetiological agent. The most common cause was infection with one of the non-A, non-B viruses (51%). The second most common cause was infection with the hepatitis B virus (32%); two of these patients had hepatitis delta-co-infection. Hepatitis A virus was responsible for 15% of the cases, and hepatitis delta-virus superinfection in 2% of the cases.