研究人员发现了对乙型肝炎感染至关重要的蛋白质

StephenW

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Proteins vital for hepatitis B infection discovered by researchers

A new study has revealed five factors and proteins that hepatitis B infection needs for replication of its DNA, providing insight into the disease.
Hepatitis B

Researchers at Princeton University, US, have identified a set of proteins that the hepatitis B virus (HBV) uses to establish itself permanently inside liver cells. According to the researchers, their findings could suggest new directions for therapies to treat chronic HBV infection.

When HBV first enters its host’s liver cells, its DNA genome contains several gaps and other imperfections that need to be repaired before the virus can establish a permanent infection. To do this, HBV must enlist the help of its host cell’s DNA repair machinery, but exactly which components of this machinery the virus needs has remained unknown.

To identify the components required to repair HBV DNA, Alexander Ploss, an associate professor of molecular biology at Princeton and postdoctoral fellow Lei Wei, recreated the process in a test tube. The researchers tested dozens of DNA repair factors and found that a set of just five factors purified from human cells was sufficient for the repair process. Removing even one of these five factors prevented the repair process from being successfully completed, suggesting that targeting any of these five factors can potentially prevent HBV infection.

Human hepatoma cells harbouring modified hepatitis B virus cccDNA are labelled by green fluorescent proteins. Blue oval shapes are cell nuclei labelled by fluorescent Hoechst dye, which stains DNA. Nuclei without green fluorescent protein are cells that do not contain hepatitis B virus cccDNA (credit: Lei Wei and Alexander Ploss, Princeton University).

One of the essential repair factors, an enzyme known as DNA polymerase delta, is inhibited by a drug called aphidicolin. Wei and Ploss found that aphidicolin treatment can prevent the repair of HBV DNA, not only in the test tube but also in virally infected liver cells.

Ploss hopes that further studies will reveal exactly how the five repair factors work together to fix the HBV genome: “Our study is an excellent starting point to finally answer the decades-old question of how the stable form of the virus’s DNA is generated,” he said. “Until we understand this process, which is crucial for HBV persistence, targeted clinical therapies that can completely clear the infection will remain out of reach.”

The study was published in Nature Microbiology.

StephenW

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研究人员发现了对乙型肝炎感染至关重要的蛋白质

一项新研究揭示了乙型肝炎感染复制其DNA所需的五种因子和蛋白质，从而提供了对该疾病的洞察力。
乙型肝炎

美国普林斯顿大学的研究人员已经鉴定出一组蛋白质，这些蛋白质可被乙型肝炎病毒（HBV）永久性地建立在肝细胞内部。研究人员称，他们的发现可能为治疗慢性HBV感染提供新的方向。

当HBV首次进入其宿主的肝细胞时，其DNA基因组包含多个缺口和其他缺陷，在病毒能够建立永久感染之前，需要对其进行修复。为此，HBV必须寻求其宿主细胞的DNA修复机制的帮助，但是该病毒究竟需要哪种机制仍然未知。

为了确定修复HBV DNA所需的成分，普林斯顿大学分子生物学副教授，博士后研究员雷威（Rei Wei）亚历山大·普洛斯（Alexander Ploss）在试管中重新创建了该过程。研究人员测试了数十种DNA修复因子，发现从人细胞中纯化出的仅五种因子就足以完成修复过程。即使除去这五个因素之一，也无法成功完成修复过程，这表明针对这五个因素中的任何一个都可以潜在地预防HBV感染。

携带修饰的乙型肝炎病毒cccDNA的人肝癌细胞被绿色荧光蛋白标记。蓝色椭圆形是被荧光Hoechst染料标记的细胞核，可以染色DNA。没有绿色荧光蛋白的细胞核是不包含乙型肝炎病毒cccDNA的细胞（来源：普林斯顿大学的Lei Wei和Alexander Ploss）。

一种基本的修复因子，一种称为DNA聚合酶δ的酶，被一种被称为蚜虫的药物抑制。 Wei和Ploss发现，蚜虫毒素治疗不仅可以在试管中而且可以在病毒感染的肝细胞中阻止HBV DNA的修复。

Ploss希望进一步的研究能够准确揭示五个修复因子如何共同修复HBV基因组：“我们的研究是一个很好的起点，可以最终回答几十年来关于如何稳定生成病毒DNA的问题，”他说。 “直到我们了解这一对HBV持久性至关重要的过程，才能完全清除感染的靶向临床疗法仍遥不可及。”

该研究发表在《自然微生物学》上。