Chronic hepatitis B (CHB) puts 250 million people or more at a greatly increased risk to develop terminal liver disease.1 The causative agent, hepatitis B virus (HBV), is a small hepatotropic DNA virus that replicates via reverse transcription.2 Persistence of infection is the combined result of an inadequate host immune response3 and the stability of a special episomal form of the virus genome termed covalently closed circular (ccc) DNA.4 5 Associating with host and viral proteins into a minichromosome, cccDNA serves as template for all viral RNAs and thus progeny virions (figure 1). A true cure of CHB would thus require elimination of cccDNA from a patient’s liver; this is rarely achieved by current CHB therapies with type I interferon or nucleos(t)ide analogues (NAs) which inhibit HBV reverse transcription. Also, none of the new anti-HBV drugs in clinical development,6 including entry inhibitors such as Myrcludex-B (Myr-B)7 which block the interaction between HBV and its receptor Na+-taurocholate cotransporting polypeptide (NTCP; figure 1), directly target cccDNA. Not even recovery from acute self-limited hepatitis B appears to eradicate all cccDNA molecules although their number (corresponding to at least the ~1010 infected hepatocytes at the peak of infection) is massively reduced by the immune system within a few weeks,3 mostly with fully maintained liver function. Figure 1 Hepatitis B virus (HBV) covalently closed circular (ccc) DNA synthesis and immune-mediated loss. (A) HBV cccDNA synthesis and amplification from relaxed circular (rc) DNA. Hepatitis B virions exploit the bile acid transporter Na+-taurocholate cotransporting polypeptide (NTCP) as entry receptor into human hepatocytes. After the envelope is stripped off, the nucleocapsids (NC) transport the rcDNA genome to the nucleus where conversion into cccDNA takes place. cccDNA associates with host and viral factors into a minichromosome (not shown) that serves as transcription template for the viral RNA; …

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慢性乙型肝炎：分而治之？

慢性乙型肝炎 (CHB) 使 2.5 亿或更多人患晚期肝病的风险大大增加。1 病原体乙型肝炎病毒 (HBV) 是一种通过逆转录复制的小型嗜肝 DNA 病毒。2感染是宿主免疫反应不足 3 和称为共价闭合环状 (ccc) DNA 的特殊附加型病毒基因组稳定性的综合结果。4 5 cccDNA 与宿主和病毒蛋白结合形成微染色体，作为所有病毒的模板病毒 RNA 和后代病毒粒子（图 1）。因此，真正治愈 CHB 需要消除患者肝脏中的 cccDNA；目前使用 I 型干扰素或核苷（酸）类似物 (NA) 抑制 HBV 逆转录的 CHB 疗法很少能实现这一点。还，临床开发中的新抗 HBV 药物 6 包括阻断 HBV 与其受体 Na+-牛磺胆酸协同转运多肽（NTCP；图 1）之间相互作用的 Myrcludex-B (Myr-B)7 等进入抑制剂，均不直接靶向cccDNA。即使从急性自限性乙型肝炎中恢复似乎也不能根除所有 cccDNA 分子，尽管它们的数量（至少对应于感染高峰时约 1010 个受感染的肝细胞）在几周内被免疫系统大量减少，3 主要是完全维持肝功能。图 1 乙型肝炎病毒 (HBV) 共价闭合环状 (ccc) DNA 合成和免疫介导的丢失。(A) 从松弛环状 (rc) DNA 合成和扩增 HBV cccDNA。乙型肝炎病毒粒子利用胆汁酸转运蛋白 Na+-牛磺胆酸协同转运多肽 (NTCP) 作为进入人类肝细胞的受体。包膜被剥离后，核衣壳 (NC) 将 rcDNA 基因组运输到细胞核，在那里转化为 cccDNA。cccDNA 与宿主和病毒因子结合形成微染色体（未显示），作为病毒 RNA 的转录模板；…