Breaking the species barrier for hepatitis delta virus.
Breaking the species barrier for hepatitis delta virus.
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DOI：
10.1002/hep.28129
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发表时间：
2016-01
期刊：
影响因子：
--
通讯作者：
Ploss A
中科院分区：
文献类型：
--
作者：
Winer BY;Ploss A
丁型肝炎病毒（HDV）是一种卫星病毒，其需要来自B型肝炎病毒（HBV）的包膜蛋白来形成感染性病毒体。与HBV单一感染相比，HBV和HDV的合并感染导致更严重的肝脏疾病，并且发病机制通常更加速。考虑到HDV对HBV的依赖性，这两种病毒具有相同的有限宿主嗜性，仅感染黑猩猩和人类，这并不奇怪。虽然HBV疫苗也可以保护个体免受HDV感染，但目前还没有直接作用于HDV的抗病毒疗法。由于缺乏合适的动物模型，这种抗病毒疗法的发展和深入了解HDV与哺乳动物宿主的相互作用受到阻碍。为了解决这一需求，Wenhui He等人最近描述了表达HDV和HBV进入受体（人牛磺胆酸钠共转运多肽（hNTCP））的转基因小鼠模型的开发，所述转基因小鼠模型对HDV感染敏感。HDV是五种已知的人类肝炎病毒之一。HDV是一种约1，600个碱基对的单链负义RNA病毒，表达单基因产物HDV抗原（HDAg）。由于HDV只能在HBV存在的情况下繁殖，因此它被认为是亚病毒卫星病毒。HBV/HDV合并感染是一个全球性的健康问题。在全世界约3.5亿慢性感染HBV的患者中，有1500万至2000万人合并感染HDV。虽然HBV疫苗在预防感染方面非常有效，并导致针对HBV和HDV的保护，但没有治愈方法，并且目前使用聚乙二醇化干扰素（IFN）的治疗选择是昂贵的并且相当无效。由于缺乏细胞培养系统和HDV易感性小动物模型，新疗法的开发受到阻碍。hNTCP作为真正的HBV受体的发现是一个分水岭。hNTCP在人肝癌细胞系中的过表达使细胞对HBV和HDV感染敏感。1这导致了一种用于体外研究这两种病毒的人类细胞培养系统。然而，当hNTCP在小鼠肝癌细胞中过表达时，这些细胞允许HDV感染，但不允许HBV感染，这表明显性阴性鼠因子可能限制HBV进入或HBV摄取需要其他人类宿主因子。2表达hNTCP的培养鼠肝细胞对HDV感染的易感性增加了hNTCP在转基因小鼠肝脏中的体内表达可能导致鼠肝细胞的HDV感染的可能性。在20世纪90年代早期，来自慢性感染土拨鼠肝炎B病毒（WHBV）的土拨鼠的HDV 1血清被用于接种CB17小鼠和具有严重联合免疫缺陷（CB17-SCID）的CB17小鼠。3有趣的是，这些包装有WHBV包膜蛋白的HDV病毒粒子能够感染小鼠肝细胞，尽管感染后5天的水平非常低，不超过0.5%的细胞。在CB17-SCID小鼠中感染后5 - 10天仍检测到HDV RNA，但到20天消失。因此，HDV的存在可能不代表真正的感染，而是可能是由于HDV颗粒在小鼠肝脏中的捕获。这些数据表明，考虑到CB17-SCID小鼠缺乏功能性T和B淋巴细胞，病毒清除可能不依赖于T细胞和B细胞。3最近，通过将人肝细胞移植到合适的异种受体中来建立HDV单感染以及HBV/HDV共感染的宿主适应性已经被探索。在由此产生的慢性感染HBV的人肝嵌合小鼠中...
Hepatitis delta virus (HDV) is a satellite virus that requires the envelope proteins from hepatitis B virus (HBV) to form infectious virions. Coinfections with HBV and HDV cause more exacerbated liver disease, as compared to HBV monoinfections, and the pathogenesis is frequently more accelerated. Given the dependence of HDV on HBV, it is not surprising that both viruses share the same limited host tropism, robustly infecting only chimpanzees and humans. Though the vaccine for HBV also protects individuals from HDV infection, there currently are no direct-acting antiviral therapies for HDV. The development of such antiviral therapies and an indepth understanding of HDV’s interaction with the mammalian host have been hampered by the scarcity of suitable animal models. Addressing this need, Wenhui He et al. recently described the development of a transgenic mouse model expressing the HDV and HBV entry receptor, human sodium taurocholate cotransporting polypeptide (hNTCP), which is susceptible to HDV infection. HDV is one of five known human hepatitis viruses. HDV is a single-stranded, negative-sense RNA virus of approximately 1,600 base pairs expressing a single-gene product, the HDV antigen (HDAg). Because HDV can only propagate in the presence of HBV, it is considered a subviral satellite virus. HBV/HDV coinfections are a global health problem. Of the approximately 350 million chronically infected HBV patients worldwide, 15-20 million are coinfected with HDV. Although the HBV vaccine is highly efficacious in preventing infection and leads to protection against both HBV and HDV, there is no cure and current treatment options utilizing pegylated interferon (IFN) are costly and rather ineffective. The development of novel therapies has been hampered by the lack of a cell-culture system and small animal models with HDV susceptibility. The discovery of hNTCP as a bona-fide HBV receptor was a watershed moment. Overexpression of hNTCP in a human hepatoma cell line rendered cells susceptible to both HBV and HDV infection. 1 This led to a human cell-culture system for studying both viruses in vitro. However, when hNTCP is overexpressed in murine hepatoma cells, these cells are permissive to HDV, but not HBV, infection, indicating that dominantnegative murine factors might restrict HBV entry or that other human host factors are needed for HBV uptake. 2 The susceptibility of cultured murine hepatocytes expressing hNTCP to HDV infection raises the possibility that in vivo expression of hNTCP in a transgenic mouse’s liver could lead to HDV infection of murine hepatocytes. In the early 1990s, HDV1 serum from a woodchuck chronically infected with woodchuck hepatitis B virus (WHBV) was used to inoculate both CB17 mice and CB17 mice with severe combined immunodeficiency (CB17-SCID). 3 Interestingly, these HDV virions packaged with WHBV envelope proteins were capable of infecting murine hepatocytes, albeit at very low levels not exceeding 0.5% of cells 5 days postinfection. HDV RNA was still detected 5-10 days postinfection in CB17-SCID mice, but disappeared by day 20. Thus, the presence of HDV may not represent a true infection, but rather could be owing to trapping of HDV particles in mouse liver. These data suggest that viral clearance is likely T-and B-cell independent given that CB17-SCID mice lack functional T and B lymphocytes. 3 More recently, host adaptation through transplantation of human hepatocytes into suitable xenorecipients has been explored to establish both HDV monoinfection as well as HBV/HDV coinfection. In the resulting human liver chimeric mice chronically infected with HBV …