战略来消除乙肝病毒感染

StephenW

Recently, two American scinetists have published an article:
http://www.medscape.com/viewarticle/829588?src=wnl_edit_tpal&uac=41936DY
Strategies to Eliminate HBV Infection

Rama Kapoor, Shyam Kottilil
Disclosures

Future Virology. 2014;9(6):565-585.
Rama Kapoor1,2 & Shyam Kottilil*,2

1Clinical Research Directorate/Clinical Monitoring Research Program, Leidos Biomedical Research Inc., (formerly SAIC-Frederick, Inc.) Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA

2Laboratory of Immunoregulation, National Institute of Allergy & Infectious Diseases, NIH, Department of Health & Human Services, Bethesda, MD 20892, USA

*Author for correspondence

Tel.: +1 301 435 036; Fax: +1 301 435 3339; [email protected]

Content is very similar to [新药汇总]. I will select and post extracts.

近日，两名美国科学家发表了一篇文章：

  http://www.medscape.com/viewarticle/829588?src=wnl_edit_tpal&uac=41936DY  
战略来消除乙肝病毒感染

拉玛·卡普尔，希亚姆Kottilil
披露

未来病毒。 2014年，9（6）：565-585。
拉玛Kapoor1,2和希亚姆Kottilil*2

1Clinical研究处/临床监测研究计划，Leidos生物医学研究公司（前身为上汽，冯检基公司）弗雷德里克国家癌症研究实验室，冯医师21702，USA

过敏与传染病，美国国立卫生研究院，卫生与人类服务部，马里兰州贝塞斯达20892，美国国立2Laboratory免疫调节的，

*作者为通信

电话：+1301435036;传真：+13014353339; [email protected]

内容很相似[新药汇总]。http://www.hbvhbv.info/forum/thread-1236082-1-1.html我会选择和发帖提取。

StephenW

Introduction

Approximately 240 million people worldwide have chronic HBV (CHB).[1] Current therapy for HBV is aimed at achieving suppression of HBV replication at levels below detection. Although this can be accomplished in almost all patients, long-term management of CHB remains a challenge. Failure to achieve sustained response and HBV persistence is related to the viral factors and inadequate induction of immune response that are seen in acute HBV patients, which naturally clears the infection. HLA polymorphisms also determine the variability in host immune response by influencing host susceptibility to HBV infection.

Advancement in the understanding of the basis of HBV persistence has guided the development of strategies that could lead to a functional cure for HBV infection. We discuss the potential strategies under development to achieve a functional cure of hepatitis B by targeting the virus, host or both. Some of these interventions are currently experimental and some have attained preclinical validation, whereas few have reached active clinical trials at this time.

简介

约240万人在全球有慢性乙肝（CHB）。[1]目前治疗乙肝的目的是实现抑制乙肝病毒的复制，在低于检测水平。虽然这可以在几乎所有的患者来完成，慢性乙肝的长期管理仍然是一个挑战。未能达到持续应答和HBV的持久性是相关的病毒因子并诱导免疫应答的那些见于急性HBV的病人，这自然会清除感染不足。人类白细胞抗原基因多态性还通过影响宿主易感性HBV感染确定宿主免疫反应的可变性。

提高乙肝病毒的持久性的基础上的认识有了指导策略，可能会导致功能性治愈乙肝病毒感染的发展。我们讨论下发展潜力的战略由针对病毒，主机或两者来实现乙肝的功能治愈。一些干预措施，目前的实验和一些已获得临床验证，但是很少有人在这个时候达到了积极的临床试验。

StephenW

Pitfalls of Current Therapy
Chronic Suppression Without Sustained Cure

Current antiviral therapies are aimed towards inhibition of viral replication. Sustained viral suppression is associated with improved outcomes and it has been shown that elevated HBV DNA level is a strong predictor of increased risk of cirrhosis[13] and HCC[14,15] in CHB. None of the current therapies lead to HBsAg loss or seroconversion in the majority of patients. In addition, current antiviral therapies do not target defective immune response and persistence of covalently closed circular DNA (cccDNA) in the infected hepatocytes. Thus, the goal of current treatment is to achieve long-term virologic control since elimination or 'cure' is not possible.

目前的治疗误区
慢性抑制无持续治疗

当前的抗病毒治疗的目的是对抑制病毒复制。持续的病毒抑制和改善结果有关，它已经表明，升高血清HBV DNA水平是肝硬化[13]和HCC[14,15]慢性乙型肝炎的风险增加了一个强有力的预测。没有当前疗法导致的HBsAg在大多数患者损失或血清转化。此外，目前的抗病毒治疗不达标，在感染的肝细胞有缺陷的免疫反应，共价闭合环状DNA的持久性（cccDNA的）。因此，目前的治疗的目标是实现长期病毒学控制自消或“治愈”是不可能的。

What Does the Elimination or Sustained Cure Mean?

Despite the tremendous improvement in CHB therapy with new antivirals, viral replication typically rebounds after the treatment is stopped. Therefore, complete elimination or cure is still not possible with current treatment. The plausible explanation is the persistence of cccDNA, which plays a vital role in persistence and reactivation. Nucleoside analog therapy prevents further formation of cccDNA, but has no effect on existing cccDNA. Ideally, elimination of HBV can be defined by loss of HBsAg and seroconversion to anti-HBs antibody and sustained suppression of HBV DNA. This may also result in depletion or inactivation of cccDNA. Until we reach the point when elimination/eradication of cccDNA can be achieved, HBsAg can be used as a marker of surrogate for the level of transcriptionally active cccDNA. Several studies have shown a positive correlation between transcriptionally active cccDNA and HBsAg levels in CHB patients.[24,25]


   什么是消除或持续治疗是什么意思？

尽管慢性乙型肝炎治疗的巨大进步与新的抗病毒药物，病毒的复制通常篮板治疗停止后。因此，完全消除或治愈，仍然不能与当前治疗。对合理的解释是cccDNA的，它在持久性和激活了至关重要的作用的持久性。核苷类似物治疗防止进一步形成的cccDNA的，但对现有的cccDNA没有影响。理想情况下，消除HBV可通过损失的HBsAg和血清转换被定义为抗HBs抗体和持续抑制HBV DNA的。这也可能导致耗尽或cccDNA的失活。直到到达该点时，可以实现消除/根除的cccDNA的，乙肝表面抗原，可作为替代的转录活性的cccDNA的水平的标志物。一些研究表明，转录活性的cccDNA与HBsAg水平在慢性乙型肝炎患者之间存在正相关关系[24,25]

StephenW

Basis of HBV Persistence

Understanding the basis for HBV persistence is critical in designing therapeutic strategies to eradicate HBV. Chronic HBV infection is characterized by an evolving interplay between viral replication and host immune responses. Both viral and host factors contribute to persistence of HBV. Highly efficient and unique replication mechanism of the virus uses a transcriptional template, cccDNA that is sequestered inside the nucleus, and escapes detection by innate DNA sensing cellular machinery. Another factor is the production of viral proteins (HBsAg, HBeAg), which function as a tolerogen and leads to T-cell exhaustion.[26] Advancement in the understanding of the mechanisms involved in HBV persistence has helped to develop strategies that overcome these factors and could result in sustained virologic remission.
乙肝病毒持续性的基础

了解基础乙肝病毒的持久性是在设计治疗方案，以消除乙肝的关键。慢性HBV感染的特征在于病毒复制和宿主的免疫反应之间的不断变化的相互影响。这两种病毒与宿主因素造成乙肝病毒的持久性。该病毒的高效和独特的复制机制使用的转录模板，cccDNA的被隔离的细胞核内，并通过感测细胞机器固有的DNA逃脱检测。另一个因素是生产病毒蛋白（乙肝表面抗原，e抗原），它充当耐受原，并导致T细胞耗竭。[26]进步涉及乙肝病毒的持久性机制的了解有助于开发出克服这些因素的策略和可能导致的持续病毒学缓解。

肝肠欲断

最喜欢看你的帖子，你总给我们带来希望！

肝肠欲断

StephenW

Viral Factors病毒因素

Error Prone Replication. HBV is a small, enveloped DNA virus with a very unique genomic organization and replication mechanism. Genome length of HBV is only 3200 bp compared with 10,000 bp for HIV and that multiple overlapping open reading frames (ORFs) may impose more constraints against variation on HBV than HIV. Despite the constraint imposed by ORFs, HBV replication is error prone due to lack of proofreading activity of HBV polymerase (error rate of 10−4 to 10−5), which leads to an accumulation of a pool of genomic sequences with heterogeneous viral population, also called quasispecies.[17,27] These viral variants have a robust survival advantage in particular, when exposed to multiple selection pressures such as immunological pressure from hepatitis B immunoglobulin, NAs and/or vaccination.
容易出错的复制。乙肝病毒是一种体积小，包膜DNA病毒，具有非常独特的基因组结构和复制的机制。 10,000 bp的艾滋病毒和多个重叠的开放阅读框（ORF），可并处更多的约束对变异的乙肝病毒比乙肝病毒相比，基因组的长度只有3200个基点。尽管通过的ORF所施加的约束，HBV复制是容易出错的，由于缺乏HBV聚合酶的校对活性的（10-4〜10-5的误码率），这导致了与异构病毒种群的基因组序列的池的积累，也称为准种[17,27]，这些病毒变异体具有坚固的生存优势，特别是当暴露于多个选择压力，例如从B型肝炎免疫球蛋白，NAS和/或疫苗接种的免疫压力。

Precore/Core Mutants. The viral core mRNA encodes a core protein (major nucleocapsid protein), DNA polymerase (which reverse transcribes RNA pregenome), and serves as pregenomic RNA, which acts as a template for reverse transcription. Precore mRNA encodes the precore protein, which is processed in the endoplasmic reticulum (ER) to produce HBeAg; the basal core promoter (BCP), nucleotide 1744–1804, resides in X ORF, and controls transcription of both precore and core regions.[28] A variety of precore and core mutants have been reported. There are two well-studied precore mutations: stop codon mutation at nt 1896, which results in cessation of HBeAg expression, and a mutation in BCP at nt 1762 and nt 1764, which results in diminished production of HBeAg and a resulting increased host immune response.[28] These mutations lead to the development of HBeAg-negative CHB. Associations of precore mutants and increased pathogenicity have been described. Earlier studies have demonstrated that precore mutants might be associated with severe chronic liver disease and with acute liver failure. It has been shown that patients with detectable precore and/or BCP mutants have a lower probability of response and are less optimal candidates for PEG-IFN therapy.[29] Double mutations in BCP at nt 1762 and nt 1764 are reported to be associated with severe liver disease,[30] fulminant hepatitis,[31] cirrhosis and HCC.[32,33]
前C区/核心突变体。病毒核心基因编码核心蛋白（主要衣壳蛋白），DNA聚合酶（其中反向转录的RNA前基因组），并作为前基因组RNA，其作为用于反转录的模板。前C区基因编码的前核心蛋白，其在内质网（ER），以产生HBeAg的处理;基底核心启动子（BCP），核苷酸1744年至1804年，位于X中的ORF，并控制这两个前C区和芯区的转录。[28]各种前C区和核心突变体已有报道。有两个充分研究前C区突变：终止密码突变新台币1896年，这将导致停止HBeAg的表达，而在BCP突变，至新台币1762 NT1764年，这将导致生产减少的e抗原和由此增加的宿主免疫反应[28]这些突变导致HBeAg阴性慢性乙型肝炎的发展。前C区突变体，增加致病的关联已被描述。早先的研究已经表明，前C区突变体可能具有严重的慢性肝脏疾病和​​急性肝衰竭有关。它已经表明，患者检测前C区和/或BCP变异有反应的机率较低，而且不太理想人选PEG-IFN治疗。[29]双突变的BCP，至新台币1762和NT1764顷报道与相关严重的肝脏疾病，[30]暴发性肝炎，[31]肝硬化和肝癌。[32,33]

HBV Genotypes. HBV genotypes account for the heterogeneity in clinical manifestations and treatment response among patients with chronic hepatitis B in different parts of the world; several studies reported correlation of HBV genotype with clinical outcomes and response to treatment, especially IFN treatment.[34] To date, ten HBV genotypes (A–J) and several subtypes have been identified, defined by divergence in the entire HBV genomic sequences and distinct geographic distribution. Genotype A is found as an independent risk factor for progression to chronic infection and persistence following acute hepatitis B infection.[35] Acute infection with genotypes A and D results in higher rates of chronicity than genotypes B and C. Patients with genotypes C and D have lower rates of spontaneous HBeAg seroconversion as compared with genotype A and B. There is also a clear association between HBV genotypes, and precore and BCP mutations. Genotype C has a higher frequency of double mutation in BCP A1762T/G1764A, pre-S deletion and is associated with higher viral load than genotype B. Similarly, genotype D has a higher prevalence of BCP A1762T/G1764A mutation than genotype A. Genotype C and D are associated with more severe liver disease, including cirrhosis and HCC. Genotype A and B shows better responses to IFN-based therapy than genotypes C and D, but there are few consistent differences for NAs.[36]
HBV基因型。 HBV基因型占在临床表现和患者中，在世界不同地区慢性乙型肝炎治疗反应的异质性;几项研究HBV基因型与临床结果和对治疗的反应，特别是IFN治疗的报道的相关性。[34]迄今，10 HBV基因型（A-J）和几种亚型已经确定，由发散在整个HBV基因组序列的定义和独特的地理分布。 A基因型发现，作为发展为慢性感染和持续性急性乙型肝炎感染的独立危险因素[35]。急性感染基因型A和D会导致慢性化率高于基因型B和C患者基因型C和D与A基因型比较，二也有HBV基因型之间有明显的联系，和前C区和BCP变异有自发性HBeAg血清学转换率较低。 C基因型在BCP A1762T/ G1764A，前S缺失双突变频率较高，并具有较高的病毒载量高于基因型B.同样相关，基因型D是BCP A1762T/ G1764A突变的发病率较高，比基因型A. C基因型和D是更严重的肝脏疾病，包括肝硬化和肝癌有关。基因型A和B具有更好的响应干扰素为基础的治疗比基因型C和D，但也有NAS的一些一致的差异。[36]

cccDNA. A major determinant in the slow kinetics of HBV clearance from infected cells and persistence is the presence of cccDNA. The HBV genome assumes a supercoiled configuration of cccDNA and exists in association with histones and DNA chaperone proteins as a minichromosome. This form allows HBV to persist inside the nucleus by avoiding host innate immune responses. Furthermore, infected hepatocytes have a long half-life, which allows the maintenance of cccDNA in the nuclei of infected cells indefinitely[37] and acts as reservoir for reactivation of viral genome replication. Studies have shown that drug-resistant mutations are archived in the cccDNA and can be rapidly selected out with the use of drugs that exhibits crossresistance.[38–40] The estimated 15–50 copies/cell of cccDNA in the nucleus serve as a store of viral escape variants generated by the error-prone viral polymerase.[41] Antiviral therapies with the currently approved antiviral agents suppress viral replication but do not directly target cccDNA. Thus, inactivation or elimination of cccDNA is one of the potential novel strategies for eradication of HBV.
cccDNA的。在清除乙肝病毒，从病毒感染的细胞和持久性慢反应动力学的主要决定因素是cccDNA的存在。 HBV基因组假设的cccDNA的超螺旋结构和存在于与组蛋白和DNA的分子伴侣蛋白的微染色体的关联。这种形式可以让乙肝病毒，避免宿主天然免疫应答坚持的细胞核内。此外，感染的肝细胞具有较长的半衰期，这允许cccDNA的在感染细胞的细胞核的保养无限期[37]，并作为贮存于病毒基因组复制的再活化。研究表明，药物抗性突变被存档在cccDNA的，并且可以迅速地筛选出与使用的药物表现出交叉耐受[38-40]估计15-50个拷贝/ cccDNA的在核细胞用作存储病毒逃避变体由易错的病毒聚合酶产生的。[41]抗病毒疗法与目前批准的抗病毒药物抑制病毒的复制，但不直接针对的cccDNA。因此，灭活的cccDNA或消除是消除HBV的潜在的新的策略之一。

StephenW

Host Factors宿主因素

Host Genetics. Persistence of HBV and variability in disease outcome also depends on the multiple host factors. HLA type of an individual is an important factor that determines the variability in host immune response to HBV. Evidence from genome-wide association studies has shown that the HLA DRB locus alleles DRref-1*1301/2 are consistently associated with spontaneous resolution of infection,[42] whereas HLA-DR7 (DRref-1*07) and HLA-DR3 (DRref-1*0301) were found to be associated with increased susceptibility to chronic HBV.[43–47] Other HLA types associated with risk of chronic infection were HLA-DPA1(*)0202-DPref-1(*)0501 and HLA-DPA1(*)0202-DPref-1(*)0301.[48] HLA-DRref-1*0701 and DRref-1*0301 have not only been associated with increased susceptibility to chronic infection but also with failure to respond to HBsAg-based vaccine.[49,50] Other alleles strongly associated with no/poor response are DRref-1*03, DRref-1*07, DQref-1*02 and DPref-1*1101.[51] HLA- DRref-1*0901, DQA1*0301, DQA1*0501 and DQref-1*0301 are found to be consistently associated with persistent HBV infection in different ethnic groups[52–56] Conceivably, this genotype influences host response by allowing more promiscuous binding of peptides to this allele than others, resulting in a broader T-cell response in subjects with the favorable allele and hence self-limiting infection.[57]
宿主遗传。乙肝病毒的持久性和变异性疾病的结果还取决于多种宿主因素。
个体
的HLA型，是决定在对HBV的宿主免疫反应的变异性的重要因素。从全基因组关联研究的证据表明，HLA DRB等位基因DRref-1 *二分之一千三百零一始终与感染的自发分辨率有关，[42]而HLA-DR7（DRref-1 *07）和HLA-DR3（ DRref-1 *0301）被发现与增加的易感性的慢性HBV相关[43-47]对慢性感染的风险相关联的其他HLA型为HLA-DPA1（*）0202-DPref-1（*）0501和HLA -DPA1（*）0202-DPref-1（*），0301[48] HLA-DRref-1 *0701和DRref-1 *0301不仅具有增加的易感性的慢性感染被关联而且还与未能对HBsAg回应为基础的疫苗。无/低反应密切相关[49,50]的其他等位基因是DRref-1*03，DRref-1*07，DQref-1*02和DPref-1* 1101。[51] HLA-DRref- 1* 0901，DQA1 *0301，DQA1 *0501和DQref-1*0301顷发现是始终与HBV持续感染有关不同族群[52-56]可以想象，这种基因型的影响，允许肽更加淫乱的结合宿主反应该等位基因比其他，导致在受试者的有利等位基因，因而自限感染更广的T细胞应答。[57]

Another genome-wide linkage study in siblings with CHB found that a region of linkage on chromosome 21 with single nucleotide polymorphisms spanning the IFN-α receptor II and IL-10 receptor II was associated with chronicity.[57,58]
在兄弟姐妹慢性乙型肝炎的另一个全基因组关联研究发现，联动与跨越IFN-α受体II和IL-10受体II的单核苷酸多态性21号染色体的一个区域与慢性关联[57,58]

Host–Viral Interactions. Adaptive immune responses to HBV are blunted in CHB subjects when compared with those who have resolved acute infection. Studies have demonstrated that T cells responding to HBV antigens from these subjects have an exhausted phenotype and are less responsive to HBV antigens.[59] Furthermore, HBV antigens have been shown to interfere with innate immune recognition, by specifically hindering signaling of Toll-like receptor (TLR) 2, 7 and 9 molecules. These molecules are vital in generating an effective innate adaptive crosstalk that is the cornerstone of an effective anti-HBV immunity.
主机病毒的相互作用。当那些谁已经解决急性感染相比，适应性免疫应答对HBV有减弱慢性乙型肝炎科目。研究已经表明，T细胞从这些受试者响应HBV抗原有一个耗尽型，而且不太响应于乙型肝炎病毒的抗原。[59]此外，HBV抗原已被证明是干扰先天免疫识别，通过特异性阻碍的信令Toll样受体（TLR）2，7和9的分子。这些分子产生有效的先天性自适应串扰是一种有效的抗HBV免疫的基础是至关重要的。

newchinabok

熬！什么时间熬出头。

lgs1

结论是否就是一句话
表面抗原干扰了人体自身免疫?

那么520类药物马上就能验证这点了