德科学家揭示乙肝病毒成熟机制

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德科学家揭示乙肝病毒成熟机制 重大发现助力新型抗乙肝药物开发

一项关于乙肝病毒成熟进入机体过程的发现有助于解释为什么该病毒要较其他病毒更强有力的导致感染以及为何如此高效的靶向肝脏。

相关研究结果发表在 Cell Host & Microbe 杂志上，该项研究结果的发现同时也给靶向阻断该过程的药物开发提供了新的方法——给慢乙肝患者的治疗提供新的希望。

科学家早已清楚乙肝病毒仅仅感染肝脏细胞，尽管病毒特异性结合附着于细胞的主要糖蛋白受体硫酸乙酰肝素蛋白多糖（HSPG）分子存在于几乎所有细胞类型中。

“对于需要长距离从感染地达到一个靶器官来说的病毒，可以想象 HSPG 看起来是最没有优势的附着受体，”该研究的主要研究作者 Stefan Seitz 博士在一份新闻稿中说道。该乙肝病毒的毒性能力——相较于其他导致动物感染的病毒来说更能导致感染，且对于它的选择性附着受体还在长期困扰着科学家。

一条解决这个谜底的线索来源于早期的研究，早期的研究显示该病毒在机体内有两种表达形式，具有非常不一样的外表。此外，在病毒包膜表达的蛋白——该结构包封着病毒——可以采取有两种不同的3D结构来实现。其中一种结构，部分蛋白需要跟 HSPG 结合——指向内部，另一部分，则暴露于外部。

联想到这两个发现， Stefan Seitz 博士和他来自德国癌症研究中心和海德堡大学医院的合作者就假设该病毒可以以两种状态表达，这就决定了它导致疾病的能力。

研究人员发明了一种办法，在“A Slow Maturation Process Renders Hepatitis B Virus Infectious”研究中有进行详细的描述，该方法能够区别病毒颗粒附着HSPG的部分，他们将这颗粒称为B型，以及那些太成熟而不能附着的部分颗粒，他们称之为N型。

通过对它们生命周期的跟踪，研究团队发现病毒是以细胞的N型颗粒形式释放的。一直以来，这些病毒颗粒通过将其结合蛋白伸向外部的形式成长为B型，因此，它暴露在了各个颗粒的表面上。

研究团队同时还报道了给小鼠注射数量较少的病毒颗粒，多数B型颗粒很罕见发展为感染，因为成熟的颗粒实际上更具粘性，在结合细胞类型上除了肝细胞之外。但是N型病毒能有效的导致肝脏感染。科学家相信减缓病毒成熟是一项关键的步骤，在使得病毒具有如此感染力前。

“这是一项新的高度优雅的范例对于病毒成熟机制来说，其根本不同于所有现在已知的病毒成熟机制，”他补充说道。“我们的研究还提示乙肝病毒颗粒并不是处于静止和僵硬的状态，而是具有高精度运行随机发条的纳米机器。从字面上看，他们可是小型定时油炸弹，随时都有可能喷射出分子抓钩。”

更重要的是，该研究发现将开启治疗乙肝病毒感染的新途径的大门。“它为‘锁住’或‘冻住’乙肝病毒颗粒使其处于未成熟状态的抑制剂的开发提供了可能，因为只要乙肝病毒处于未成熟状态则其就处于未能感染的状态。目前仍未能治愈慢乙肝，而其也是导致肝癌的主要原因，这种抑制剂可用于支持慢乙肝的治疗。”Seitz说道。

探索一个额外的机制控制这个病毒开关，以及寻找将可以治疗乙肝的药物，正是研究团队正在聚焦的。“显然，破坏慢性的乙肝病毒感染并且清除病毒将会降低感染者发展为肝细胞肝癌的风险”Bartenschlager 总结道。


英文原文


Potency of Hepatitis B Virus Traced to ‘Grappling Hooks’ Virus Acquires as It Matures


A discovery of the process by which the hepatitis B virus matures inside the body helps to explain why the virus is much more potent that others in causing infection, and how it so effectively targets the liver.

The findings, published in the journal Cell Host & Microbe, also provide new avenues for drug development approaches that target the process — offering hope to chronic hepatitis patients.

Scientists have long known that the hepatitis B virus infects only liver cells, despite the fact that the molecule — heparan sulfate proteoglycans, or HSPG — needed for the virus to dock to cells is present on virtually all cell types.

“For a virus which has to reach a target organ in far distance from the transmission site, HSPG seemed to be the most disadvantageous attachment receptors one could imagine,” the study’s lead author, Dr. Stefan Seitz, said in a press release. The virus’ virulence — it is much more effective in causing infections than most other animal viruses —and its selective docking receptors have long confused scientists.

A clue to solving this mystery came in earlier studies showing that the virus is present in two forms in the body, with rather different looks. Also, a protein present in the viral envelope —  the structure encapsulating a virus — can adopt two different 3-D structures. In one structure, the part of the protein needed for binding to the HSPG receptor is pointing inward; in the other, it is exposed on the outside.

Linking the two findings, Dr. Seitz and his colleagues at the German Cancer Research Center and Heidelberg University Hospital hypothesized that the virus can be present in two different states, which determine its ability to cause disease.

Researchers developed a method, described in the study “A Slow Maturation Process Renders Hepatitis B Virus Infectious,” capable of distinguishing between the viral particles able to bind to HSPG, which they referred to as the B-type, and those too immature to bind, which they called the N-type.

Tracking its life cycle, the team discovered that the virus is released from cells as N-type particles. Over time, these viral particles mature into the B-type by turning their binding protein outward, so it is exposed on each particle’s surface.

The team also reported that mice injected with low numbers of virus particles, mostly B-types, rarely developed infection because the mature particles were essentially more sticky, binding to cell types other than those of the liver. But the N-type viruses effectively caused liver infection. Scientists believe that slow virus maturation is a key step in making the virus so infectious.

“In the immature N-type state, the viral particles are inert and hence can cycle in the bloodstream continuously until they once reach the liver where they finally will be trapped. Conversion into mature particles afterward will lead to a productive infection,” Professor Ralf Bartenschlager, the study’s senior author, said.

“It is a novel and highly elegant paradigm for a viral maturation mechanism that differs fundamentally from all previously described viral maturation mechanisms,” he added. “Our study also shows that hepatitis B virus particles are not stiff and static objects, but highly dynamic nanomachines with a precisely running stochastic clockwork. Literally, they are little ticking time bombs which suddenly shoot out molecular grappling hooks.”

More importantly, the findings might open up for new ways of treating hepatitis B infection. “It offers the possibility to develop inhibitors of the maturation mechanism that lead to a “lock-in” or “freezing” of hepatitis B particles in the immature, non-infectious state. Such inhibitors could be used to support therapy of chronic hepatitis B which is still incurable and represents a leading cause of cancer in mankind,” said Dr. Seitz.

Exploring the exact mechanism controlling this viral switch, as well as searching for drugs that might block it, is what the research group is now focusing on. “Obviously, breaking chronicity of hepatitis B infection and eradicating the virus would reduce the risk of infected individuals to develop hepatocellular carcinoma,” Dr. Bartenschlager concluded.