microRNA在HBV感染相关疾病中的作用

microRNA(miRNA)通过调控转录后基因表达在病毒性疾病中发挥重要作用。miRNA可影响HBV在宿主细胞内复制和基因表达,而HBV则可通过调节宿主miRNA的表达为自身存活和复制提供有利的环境。这种miRNA介导的HBV与宿主的相互关系是HBV感染相关疾病发病机制的重要基础。阐述了miRNA在HBV感染相关慢性乙型肝炎﹑肝硬化﹑肝细胞癌中的作用进展。     

microRNA在HBV感染和致病中的作用研究进展

[摘要]?微小RNA （microRNA, miRNA）在宿主-病毒相互作用中起关键调节作用，参与HBV感染、复制和HBV相关疾病的调节。细胞miRNA可以通过直接结合HBV转录物或通过靶向与HBV生命周期相关的细胞因子间接调节HBV转录和复制。反过来，HBV感染也可以影响宿主细胞内的miRNA水平。HBV和miRNA之间的相互作用在HBV复制和HBV相关疾病的发病机制中发挥重要作用。本文对miRNA与HBV的相互关系进行综述，为进一步探讨HBV感染致病的分子机制和开发新的抗HBV治疗策略提供参考。     

表观遗传学对乙型肝炎病毒复制的调节

全球有4亿多人感染了乙型肝炎病毒(HBV),慢性HBV感染仍是造成终末期肝病(肝硬化和肝细胞肝癌)最主要的原因[1-2].一旦形成慢性感染,人体便很难有效清除HBV.HBV在肝细胞内不断利用自身和宿主蛋白酶合成稳定的共价闭合环状DNA(covalently closed circular DNA,cccDNA)寄生于肝细胞核内,使得现有抗病毒药物难以根治HBV感染[3].近年来,研究者们发现HBV复制与许多非免疫调控机制有关,如HBV利用自噬系统促进自身复制[4-5].表观遗传学作为重要的转录后调节机制也受到关注,其中的cccDNA甲基化、miRNA、组蛋白修饰均参与了HBV基因表达的调控[6-13].通过进一步研究表观遗传学对HBV调控的机制,可能为揭示HBV感染慢性化原因、研发新的抗病毒药物治疗靶点提供思路.以下,我们分别就miRNA、cccDNA甲基化、组蛋白乙酰化对HBV调节机制的研究进展进行综述.     

肝脏各段肝细胞内HBV cccDNA和HBV tDNA水平分布

HBV感染宿主肝细胞后,HBV基因组进入肝细胞先生产HBV cccDNA。然后以HBV cccDNA为模板转录装载成HBV rcDNA释放入血,对HBV的复制及感染状态的建立具有十分重要的意义[1]。国内很多文献报道,慢性乙型肝炎病情和乙型肝炎相关性肝癌的发生均与HBV DNA的复制有关,     

microRNA在HBV相关肝病中的研究进展

microRNA是一类内源性染色体上的非编码单链RNA,能够引起靶mRNA降解或者抑制其翻译,对基因进行转录后的表达调控,在体内发挥诸如发育、细胞分化、细胞增殖、细胞死亡、染色体改变、病毒发病机制和癌变等众多重要的生物学功能.乙型肝炎病毒感染宿主后可发生慢性肝炎、肝硬化、肝衰竭、肝癌等病理变化,乙型肝炎病毒和宿主之间通过miRNA进行的相互调节对HBV相关肝病的发生发展很重要,因此miRNA在HBV相关肝病的研究中具有重要的意义.本文对miRNA在HBV相关肝病中的最新研究进展做一综述.     

microRNA在肝癌发生和发展中的作用及其机制

肝细胞肝癌(HCC)是我国常见的恶性肿瘤,其发生、发展是多因素、多基因和多步骤的复杂过程[1].miRNA(microRNA)是一类内源性非编码小分子RNA,可经序列特异性翻译抑制或mRNA裂解来调控基因表达,参与细胞发育、增殖、分化、凋亡等,约有1/3以上基因在转录后受其调控[2].新近研究结果表明,多种miRNA通过调节其靶基因参与HCC的细胞生物程序调控,间接发挥癌基因和抑癌基因的功能[3].了解miRNA的调控机制,可为肝细胞恶性转化及HCC的诊治提供理论依据.本文综述了miRNA在肝癌发生、发展中作用与机制的研究进展.     

HBV感染恢复期血清标志物与肝细胞HBV cccDNA检测对照

目的:了解肝组织乙肝病毒共价闭合环状脱氧核糖核酸(HBV cccDNA)与血清HBV复制指标的关系,以探索判定抗HBV的疗程终结点的观察方法。方法:既往HBV感染者、乙型肝炎肝硬化肝癌及慢性乙型肝炎(CHB)患者各13例,将血清HBV DNA、HBV-M及肝组织HBV cccDNA检测结果进行对照。结果:肝硬化肝癌及CHB患者抗-HBe阳性分别为12例和9例,血HBV DNA阳性分别为6例和8例,肝细胞HBV cccDNA均阳性;既往HBV感染13例中,HBsAg阴性,抗-HBs和/或抗HBc阳性各7和6例,有3例肝细胞中HBV cccDNA阳性。抗-HBs阳性的7例肝细胞HBV cccDNA阴性,抗-HBe阳性及抗HBs合并抗-HBe阳性者,肝细胞HBV cccDNA分别为105拷贝/ml和103拷贝/ml,与抗-HBs阳性组对照,t=4.5、4.0(P均<0.01),差异有非常显著性意义。CHB患者核苷类治疗后全应答,肝组织HBV cccDNA仍均为阳性。结论:抗-HBs阳性HBV感染后恢复期血清,肝组织HBV cccDNA阳性比率明显低于CHB抗HBe阳性HBV DNA阴性病例。抗病毒治疗CHB的终点,应是血清抗-HBs阳性的出现。     

蛋白质精氨酸甲基转移酶5表观调控cccDNA抑制HBV复制

正【据《Hepatology》2017年6月报道】题:蛋白质精氨酸甲基转移酶5通过表观调控cccDNA转录及干扰pgRNA包装抑制HBV复制(作者Zhang W等)目前认为,慢性HBV感染难以治愈的根本原因之一在于HBV感染肝细胞后会在细胞核内形成共价闭合环状DNA(cccDNA),并以微小染色体结构形式稳定存在,是病毒持续转录复制及停药复发的源头。已有证据表明组蛋白乙酰化修饰有助于cccDNA转录,但对组蛋白甲基化是否影响cccDNA转录活性及相关宿主因子尚不明确。     

白细胞介素10水平与HBV感染转归及预后的关系

HBV感染过程受多种因素的综合调控。白细胞介素(IL)10是免疫调节的必需因子,IL-10基因启动子多态性影响IL-10 mRNA的转录,从而影响血清IL-10水平。IL-10与HBV感染转归、预后有关联。简述了IL-10基因多态性与血清IL-10的关系和IL-10基因多态性与HBV感染转归的联系,对IL-10作为炎症反应抑制因子,在机体免疫功能、HBV感染转归、HBV发展及其相关并发症的发生发展方面的作用进行了综述。认为IL-10基因多态性及血清IL-10与HBV感染后炎症反应关系密切,影响机体清除HBV,并与HBV感染肝损害程度、HBV感染肝硬化、HBV相关肝细胞癌有关。检测IL-10基因及血清水平对预测HBV感染转归有一定的指导意义。     

HBV动物模型研究进展

HBV感染动物模型是研究HBV致病机制、筛选新型有效抗HBV药物和治疗方法的重要工具,然而HBV感染具有高度组织特异性以及种属特异性,这给HBV感染动物模型的建立带来了困难。近年来,随着分子生物学、实验动物学、病毒学及免疫学等相关学科技术的进步,HBV感染或复制动物模型取得了明显进展。目前应用于HBV(包括与HBV具有相似特性的动物肝炎病毒)研究的动物模型主要包括黑猩猩、树鼩、土拨鼠及鸭HBV感染模型,HBV转基因小鼠、高压水动力注射介导的小鼠HBV复制模型和重组腺相关病毒载体介导的小鼠HBV复制模型,以及人源化人-鼠嵌合肝脏HBV感染模型,此外,钠离子-牛磺胆酸共转运蛋白转基因小鼠感染模型是近年的研究热点。本文就上述HBV动物模型的研究进展进行综述。     

Hepatitis B virus taxonomy and hepatitis B virus genotypes

Hepatitis B virus (HBV) is a member of the hepadnavirus family. Hepadnaviruses can be found in both mammals (orthohepadnaviruses) and birds (avihepadnaviruses).The genetic variability of HBV is very high. There are eight genotypes of HBV and three clades of HBV isolates from apes that appear to be additional genotypes of HBV. Most genotypes are now divided into subgenotypes with distinct virological and epidemiological properties. In addition, recombination among HBV genotypes increases the variability of HBV. This review summarises current knowledge of the epidemiology of genetic variability in hepadnaviruses and, due to rapid progress in the field,updates several recent reviews on HBV genotypes and subgenotypes.     

Dual chronic hepatitis B virus and hepatitis C virus infection

Dual hepatitis B virus (HBV) and hepatitis C virus (HCV) infection are common in HBV or HCV endemic areas. However, several clinical and pathogenetic issues remain unresolved. First, clinical and in vitro studies suggest the interactions between two viruses. The dynamics of the interaction in untreated setting versus treated setting and its influence on the long-term outcomes await further studies. A key issue regarding viral interactions is whether modulation of infection occurs in the same dually infected individual hepatocyte of the liver. Clarifying this issue may help to understand the reciprocal interference between HCV and HBV and provide clues for future immunopathogenetic studies. Second, the prevalence and clinical significance of coexisting occult HBV infection in patients with chronic HCV infection need further investigations. Third, combination therapy of peginterferon alfa-2a and ribavirin appears to be just as effective and safe for the treatment of hepatitis B surface antigen (HBsAg)-positive patients chronically infected with active chronic hepatitis C as it is in patients with HCV monoinfection. Nevertheless, one-third of dually infected patients with nondetectable serum HBV DNA-level pretreatment developed HBV reactivation posttreatment. How to prevent and treat this reactivation should be clarified. Furthermore, about 10% of the dually infected patients lost HBsAg. Underlying mechanisms await further investigations. Finally, the optimal treatment strategies for dually infected patients with hepatitis B e antigen-positive chronic hepatitis B should be identified in future clinical trials.     

Myocarditis and hepatitis B virus

Two patients with hepatitis B virus infection and myocarditis are reported. The implicated pathogenesis was an immune complex mechanism in one patient. Both patients presented with heart failure and arrhythmia which were controlled with conventional medical therapy. Echocardiography played an important role for early detection of left ventricular dysfunction. The efficacy and safety of corticosteroid therapy is still conjectural. Acute hepatitis B infection should be a differential diagnostic consideration in the etiology of acute myocarditis.     

HBV/HCV重叠感染的抗病毒治疗

从全球范围看,乙型肝炎病毒(hepatitis B virus,HBV)和丙型肝炎病毒(hepatitis C virus,HCV)重叠感染估计约有700-2000万人口感染.重叠感染和单一HBV或HCV感染比较,更易发展为肝硬化、肝细胞癌甚至肝衰竭的比例也高,HBV和HCV重叠感染可有四种不同的临床模式,即HCV活动...     

Hepatitis B virus genotypes and hepatitis B surface antigen mutations in family contacts of hepatitis B virus infected patients with occult hepatitis B virus infection

Background:  The association and profile of surface gene mutations with viral genotypes have been studied in patients with chronic hepatitis B virus (HBV) but not in subjects with occult HBV infection.
Aim:  This study aimed to investigate the association of surface gene mutations with viral genotypes in occult HBV infection.
Materials & Methods:  Of 293 family contacts of 90 chronic HBV index patients, 110 consented for the study. Of 110 subjects, 97 were hepatitis B surface antigen (HBsAg) negative. HBV genotyping was done using direct DNA sequencing. The S-gene was also sequenced in 13 chronic hepatitis B patients to serve as controls.
Results:  Twenty-eight (28.8%) of the 97 subjects had occult HBV infection. Bidirectional sequencing of partial S-gene was successful in 13 of them. Seven (53.8%) of the viral sequences are genotype A1, two (15.3%) each having genotypes D5&D2 and one each (7.6%) having D1&G genotypes. Seven (53.8%) of the 13 HBsAg positive patients, had genotype D&6 (46.1%) genotype A. A128V & T143M mutations were observed in 5 of 13 (38.4%) subjects and A128V & P127S in 2 of 13 (15.3%) patients ( P  = 0.385). A128V mutation was seen in two (15.3%) subjects with D2 genotype, while T143M mutation was seen in three (23.07%) subjects with A1genotype. At aa125, three (23.07%) subjects with D5 genotype had methionine instead of threonine. There were wild type sequences in five (38.4%) subjects, one each of D1, G genotypes (20%) and four A1 (80%) genotypes. None of the subjects had G145R mutation.
Conclusions:  Occult HBV infection may be common in household contacts of chronic HBV infected patients. Equal prevalence of A&D sub-genotypes was present in occult HBV subjects and in chronic HBV patients. Mutations of the S-gene are genotype specific in both occult as well as chronic HBV infection.     

Vietnamese community screening for hepatitis B virus and hepatitis C virus

Summary. Asian Americans represent an important cohort at high risk for viral hepatitis. To determine the prevalence of Hepatitis B virus (HBV) and Hepatitis C virus (HCV) infection and HBV vaccination in a Vietnamese community, a total of 322 Vietnamese subjects from a local doctor’s office and annual Vietnamese Health Fair were included in this study. Demographic and clinical data were collected. 2.2% of the screened cohort tested positive for anti‐HCV and 9.3% tested positive for HBsAg. Unlike HBV‐positive subjects, HCV‐positive subjects had significantly higher liver enzymes (P = 0.0045 and P = 0.0332, respectively). The HBV‐positive group was more likely to report jaundice (P = 0.0138) and a family history of HBV (P = 0.0115) compared to HBV‐negative subjects. Forty‐eight patients (15.5%) reported a family history of liver disease (HBV, HCV, HCC, cirrhosis, other). Of this 48, 68.8% reported no personal history of HBV vaccination and 77.1% reported no family history of vaccination for HBV. Among the 183 subjects without a family history of liver disease, 156 (85.2%) reported no personal history of vaccination and 168 (91.8%) reported no family history of vaccination. HBV vaccination rates in those reporting a family history of liver disease were significantly higher (P = 0.020). There was a high prevalence of HBV infection in this community screening. Nevertheless, the rate for HBV vaccination was low. The low prevalence of abnormal liver enzymes in HBV‐positive subjects emphasizes the need for screening to be triggered by risk factors and not by abnormal liver enzymes.     

The hepatitis B virus

Of all the hepatotropic viruses, HBV is associated with the greatest worldwide morbidity and mortality. This is because of the ease of transmission and the potential for progression to a chronic infective carrier state, with the complications of cirrhosis and hepatocellular carcinoma. The use of PCR has shown that some of the earlier concepts concerning the interpretation of serological data were inaccurate. Many patients with anti-HBe and anti-HBs have viral DNA detectable by PCR, and some hepatocellular carcinoma patients have detectable HBV DNA in their livers in the absence of all serological markers of HBV disease. The clearance of HBV infected cells from the liver is dependent on the interplay between the interferon system and the cellular limb of the host immune response. The importance of the nucleocapsid proteins as targets for sensitized cytotoxic T cells has been established for chronic HBV infection. The importance of pre-S sequences as inducers and targets of the virus-neutralizing humoral immune response is becoming established, but their precise role must await the development of in vitro models of hepadnavirus infection and a greater understanding of the mechanisms of viral uptake. The epidemiology and clinical course of the disease can be modified by immunization, immune stimulation and antiviral chemotherapy. For the developing world, a programme of immunization at birth would be the most effective way of eliminating this disease, but at present the cost is prohibitive. For the developed world, immunization is realistic for the at-risk population, and anti-viral and immunostimulatory therapy available for those already infected. In adult acquired chronic HBV infection alpha-interferon produces HBe antigen clearance in 40-60% of cases and is followed by resolution of the hepatic inflammation. Results in neonatally acquired infection are less impressive and prednisolone priming followed by interferon may be needed. The presence of a mutation in the pre-core region of some virus isolates has recently been described. Hepatocytes infected with this virus cannot produce HBe antigen and the course of the liver disease is fairly rapid. Whether this mutant causes liver damage in the same way as the wild virus or is directly cytopathic remains unclear, and its relationship to fulminant hepatitis is under investigation.     

Comparable ten-year outcome in hemodialysis patients with hepatitis C virus and hepatitis B virus coinfection and single hepatitis B virus infection

Hepatitis B virus (HBV) and hepatitis C virus (HCV) coinfection in comparison with single HBV infection causes more severe liver disease in nonuremic population. The long-term impact of HBV/HCV coinfection on severity of liver diseases and patient survival in hemodialysis patients is unclear. Forty-eight HBV-positive patients and 19 HBV/HCV-positive patients were followed up from February 1996 to September 2006. During 10-year follow-up, there was no difference in acute hepatitis episodes, abnormal serum alanine aminotransferase period, occurrence of cirrhosis and hepatocellular carcinoma, and patient survival between the two groups. The serum HBV DNA levels in HBV/HCV-positive patients were significantly lower than those in HBV-positive patients during the first 27-month follow-up. In conclusion, HCV infection suppresses the serum HBV DNA level in hemodialysis patients. Nevertheless, HBV/HCV coinfection in comparison with single HBV infection does not cause more severe liver diseases or reduce patient survival in hemodialysis patients during 10-year follow-up.     

乙型肝炎病毒和丙型肝炎病毒在肝癌发生中的作用研究进展

肝细胞癌(hepatocellular carcinoma,HCC)是世界上最常见的十大恶性肿瘤之一,目前全世界每年新增5.O×10~6～1.0×11~6病例。在我国,HCC已占恶性肿瘤死亡的第三位。目前对乙型肝炎病毒(hepatitis B Virus,HBV)和丙型肝炎病毒(hepatitis C virus,HCV)感染与HCC发生的关系最为重视。研究表明,全世界现有4亿慢性HBV携带者,80％以上的HCC患者伴有HBV感染,持续HBV感染者发生HCC的机率比正常人高100～200倍;60％～80％HCV感染者将转为慢性,最终将有20％发展为HCC,而HCV相关肝硬化患者15年