病毒和肝炎病毒的免疫学

StephenW

Virology and Immunology of Hepatitis Viruses

    Authors: Raymond T. Chung, MD; Esperance Anne Kreek Schaefer, MD, MPH (More Info)
    Editors In Chief: Nezam H. Afdhal, MD, FRCPI; Stefan Zeuzem, MD
    Last Reviewed: 8/6/14 (What's New)

Therapeutic Targets
Summary

    Therapy for HBV infection currently includes interferon and nucleos(t)ide analogues that inhibit HBV polymerase
    Peginterferon alfa-2a is administered for 1 year and leads to a 27% chance of HBeAg seroconversion and a 3% chance of HBsAg loss[Dienstag 2008]
        A subset of patients will require retreatment
    5 nucleos(t)ide analogues are currently approved for HBV treatment: lamivudine, telbivudine, adefovir, entecavir, and tenofovir.
    Targeting other steps in the viral life cycle (eg, encapsidation and viral entry), stimulating the innate immune response, and therapeutic vaccination, as well as RNA interference–based strategies are currently under investigation

Two major classes of therapies are currently used for the treatment of chronic hepatitis B virus (HBV) infection: interferon and nucleos(t)ide analogues (NAs) that are HBV polymerase inhibitors.

Therapy with peginterferon alfa 2a is administered for 1 year and leads to a 27% chance of hepatitis B e antigen (HBeAg) seroconversion and a 3% chance of hepatitis B surface antigen (HBsAg) loss.[Dienstag 2008] A subset of these patients will have persistently high HBV DNA levels after HBeAg seroconversion, meaning they will progress to HBeAg-negative chronic HBV infection, and will require retreatment.[Buster 2008; Wong 2010]

There are 5 NAs approved for HBV to date: lamivudine, telbivudine, adefovir, entecavir, and tenofovir. The NAs are integrated into the HBV DNA during replication, leading to chain termination and inhibition of replication. Treatment with the NAs is generally indefinite in duration and leads to high rates of viral inhibition with the most potent agents but carries a risk of developing resistance that varies substantially, depending on the NA agent.

New potential therapeutic strategies that may lead to less risk of developing resistance include stimulation of the innate immune response via toll-like receptors, RNA interference–based strategies, therapeutic vaccination, and targeting viral entry. Treatment with the toll-like receptor 7 agonist, GS-9620, has been investigated in 2 animal models of chronic HBV infection, and resulted in sustained reduction of serum S antigen and seroconversion in the woodchuck model[Menne 2011] and sustained suppression of serum and liver HBV DNA and serum HBsAg and HBeAg in chimpanzees.[Lanford 2013] Two phase I clinical trials investigating the effects of GS-9620 treatment in patients with chronic HBV infection have recently been completed and a phase II trial is currently under way (Clinical Trial: NCT02166047). Therapeutic vaccination is also an active area of investigation using yeast or adenovirus-based approaches, and immunization with yeast expressing HBx, HBsAg, and HBcAg elicited antigen specific CD4 and CD8 T-cell responses in peripheral blood mononuclear cells from healthy individuals and in mice.[Kemmler 2012; Guo 2012]

Short-interfering RNA (siRNA) targeting HBV DNA or pregenomic RNA represents a therapeutic option that reduces viral load, allowing the immune system to more effectively clear the virus. Several proof-of-concept studies have shown that siRNA delivered to either HepG2 cells or mice models of HBV infection results in reduced viral antigen expression, viral transcripts, or viral DNA.[Li 2014a; Li 2014b; Giladi 2003; Huang 2014; Thongthae 2014] One promising system demonstrated successful targeting of siRNAs to hepatocytes in mice by coinjection of an N-acetylgalactosamine-conjugated melittin-like peptide with liver-tropic cholesterol-conjugated siRNAs targeted to conserved HBV gene sequences. In mouse models of chronic HBV infection, silencing of HBV transcripts reduced viral RNA, protein and DNA production.[Wooddell 2013] This RNAi system, termed ARC-520, is currently being evaluated in a phase II trial of patients with chronic HBV infection (Clinical Trial: NCT02065336).

The bile acid transporter Na+/taurocholate cotransporting polypeptide (NTCP) has recently been identified as an HBV entry receptor in hepatocytes and provides an attractive therapeutic target to block the initial stages of HBV infection.[Yan 2012] Several NTCP inhibitors are effective in inhibiting HBV infection including cyclosporine A,[Watashi 2014a; Nkongolo 2014] progesterone, propranolol, bosentan, ezetimibe,[Watashi 2014b; Lucifora 2013] and Myrcludex-B, a synthetic lipopeptide of the myristoylated region of preS1.[Petersen 2008] Following the success of Myrcludex-B’s demonstrated ability to inhibit NTCP transporter activity in the nanomolar range in cultured hepatocytes[Ni 2014] and prevent HBV infection in mice,[Petersen 2008] it is now being investigated in a phase II trial in Russia. Since it is likely that, even with NAs, new hepatocytes can still become infected, by combining virus entry inhibitors with NAs, a more effective way to eliminate the virus may be achieved in patients with chronic disease, especially in the case of blocking reoccurrence in patients receiving liver transplantation.[Urban 2014]

Keywords: Hepatitis B, Hepatitis B-Resistance, Hepatitis B-Treatment

StephenW

病毒和肝炎病毒的免疫学

    作者：雷蒙德吨仲医师;埃斯佩兰斯安妮Kreek舍费尔，医学博士，公共卫生硕士（更多信息）
    编辑总司令：NEZAM H. Afdhal，医学博士，FRCPI;斯特凡Zeuzem医师
    点评：14年8月6日（最新消息）

治疗靶点
摘要

    治疗乙肝病毒感染目前包括干扰素和核苷（酸）类似物抑制乙肝病毒聚合酶
    聚乙二醇干扰素α-2a被给予1年，并导致HBeAg血清学转换的27％的机会和HBsAg消失的3％的几率[Dienstag2008]
        患者需要再次治疗的一个子集
    5核苷（酸）类似物是目前被批准用于乙肝治疗拉米夫定，替比夫定，阿德福韦，恩替卡韦和替诺福韦。
    针对其他步骤在病毒生命周期（例如，衣壳和病毒进入），刺激的先天免疫应答，和治疗性疫苗接种，以及基于RNA干扰的策略是目前正在研究中

目前用于治疗慢性乙型肝炎病毒（HBV）感染的治疗疗法两大类：干扰素和核苷（酸）类似物（NAS）是乙肝病毒聚合酶抑制剂。

治疗与聚乙二醇干扰素α2A投1年，并导致乙肝e抗原（HBeAg）血清学转换27％的机会和乙肝表面抗原（HBsAg）损失3％的几率。[2008 Dienstag]这些病人的一个子集将有持续高HBV DNA水平HBeAg血清学转换后，这意味着他们将发展为HBeAg阴性的慢性HBV感染者，也需要复治[2008巴斯特。黄先生2010]

有批准用于乙肝的最新5佐：拉米夫定，替比夫定，阿德福韦，恩替卡韦和替诺福韦。在NAS在复制过程中融入了HBV-DNA，导致链终止和抑制复制。治疗与NAS通常是不定的持续时间，并导致了最有效的药物率高的病毒抑制的但带有显影性而变化基本上，根据不同的NA剂的风险。

新的潜在的治疗策略，可能导致显影性的风险少包括刺激经由Toll样受体，RNA干扰为基础的策略，治疗性疫苗接种的先天免疫应答，并靶向病毒进入。治疗与Toll样受体7激动剂，GS-9620，一直在研究慢性HBV感染2动物模型，并导致了土拨鼠模型[Menne2011]持续减少血清中的S抗原血清转换，并持续抑制血清和肝脏HBV DNA和血清HBsAg和HBeAg的黑猩猩。[兰福德2013]两个阶段调查GS-9620治疗慢性HBV感染的影响I期临床试验最近已经完成，第二阶段试验目前正在进行中（临床试用：NCT02166047）。治疗性疫苗接种也是采用酵母或腺病毒为基础的方法，和用酵母表达HBx蛋白，乙肝表面抗原免疫接种研究的一个活跃领域，和HBcAg的诱发抗原特异性CD4和CD8 T细胞应答在来自健康个体和小鼠外周血单核细胞。 [KEMMLER2012;郭2012]

短干扰RNA（siRNA）靶向HBV DNA或者前基因组RNA的表示一种治疗选择是降低病毒载量，使免疫系统能更有效地清除病毒。概念验证的数项研究已经表明，siRNA的递送到任何HepG2细胞或HBV感染的结果是降低了病毒抗原的表达，病毒转录物，或病毒DNA的小鼠模型[李2014A。李2014B; Giladi2003; 2014年黄; Thongthae2014]一种有前途的系统由一个N-乙酰半乳糖胺共轭蜂毒肽样肽与针对保守的HBV基因序列的肝向性的胆固醇缀合的siRNA的共注射证实siRNA的成功定位到小鼠肝细胞。在慢性HBV感染小鼠模型中，乙肝病毒的转录沉默降低病毒RNA，蛋白质和DNA的生产。[Wooddell2013]该RNA干扰系统，被称为ARC-520，目前正在对慢性HBV感染的II期试验评估（临床试验：NCT02065336）。

胆汁酸转运体的Na +/牛磺胆cotransporting多肽（NTCP）最近被鉴定为在肝细胞中的乙肝病毒的受体，并提供一个有吸引力的治疗靶标来阻止HBV感染的初始阶段。【严2012]几种NTCP抑制剂能有效地抑制HBV的感染包括环孢素A，[渡2014A; Nkongolo2014]孕酮，普萘洛尔，波生坦，依泽替米贝，[渡2014B; Lucifora2013]和Myrcludex-B，前S1的肉豆蔻地区的合成脂肽。[2008彼得森]继Myrcludex-B的抑制NTCP转运活动在纳摩尔范围内培养肝细胞[镍2014表现出来的能力成功]，防止乙肝病毒感染小鼠，[2008彼得森]它现在正在研究在一项II期临床试验在俄罗斯。因为它是可能的，甚至使用NAS，新肝细胞仍可以受到感染，通过结合病毒进入抑制剂使用NAS，以消除可能在慢性疾病来实现病毒的更有效的方法，特别是在阻塞复发中的情况下患者接受肝移植。[都市2014]

关键词：B型肝炎，B型肝炎，耐药，乙肝，治疗