潜在治疗丙型肝炎的新方法 HCV

英国哥伦比亚大学的研究人员发现了阻断丙型肝炎病毒（HCV）感染的新方法，可能促成治疗丙型肝炎或其他传染性疾病的新疗法。

全球有超过1.7亿人患有丙型肝炎，它是由丙型肝炎病毒HCV感染所致。这种疾病影响肝脏功能，是导致世界各地肝癌和肝移植的主要原因之一。HCV经由血液接触传播，目前尚无防治它的疫苗。目前治疗丙型肝炎的疗法只有部分疗效，而且有严重的副作用。

"当HCV感染人时，它需要肝脏中的脂肪滴来形成新的病毒颗粒，"Francois Jean说，哥伦比亚大学微生物及免疫学副教授、传染病和流行病研究基金会（FINDER）科学系主任。"在这个过程中，它引起脂肪在肝脏的积累并最终导致慢性的器官功能障碍。"

"HCV不断的突变，使得很难开发出能靶向病毒自身的抗病毒疗法，"Jean说，"所以我们采取了一种新的方法。"

Jean和他的团队开发了一种抑制剂，能够减小肝细胞中脂肪滴的大小，来阻止HCV的"定居"、增殖及感染其它细胞。

"我们的方法能够从本质上阻断病毒的生命周期，使它不能够传播及造成肝脏的进一步损害，"Jean说。该小组的方法详述于PLoS Pathogens期刊上。

据Jean所说，HCV是人体内需要脂肪进行复制的多种病毒之一。这种抑制HCV复制的新方法可以转化为类似的疗法用于治疗其它相关的复发性病毒所引发严重危及生命的感染，如革登热病毒。革登热在100多个国家流行，全球约2.5亿人有感染革登热病毒的风险。在一些国家，革登热已成为导致儿童死亡的首要原因。

doi:10.1371/journal.ppat.1002468

Human Subtilase SKI-1/S1P Is a Master Regulator of the HCV Lifecycle and a Potential Host Cell Target for Developing Indirect-Acting Antiviral Agents

Andrea D. Olmstead, Wolfgang Knecht, Ina Lazarov, Surjit B. Dixit, François Jean

Abstract： HCV infection is a major risk factor for liver cancer and liver transplantation worldwide. Overstimulation of host lipid metabolism in the liver by HCV-encoded proteins during viral infection creates a favorable
environment for virus propagation and pathogenesis. In this study, we hypothesize that targeting cellular enzymes acting as master regulators of lipid homeostasis could represent a powerful approach to developing a novel class of broad-spectrum antivirals against infection associated with human Flaviviridae viruses such as hepatitis C virus (HCV), whose assembly and pathogenesis depend on interaction with lipid droplets (LDs). One such master regulator of cholesterol metabolic pathways is the host subtilisin/kexin-isozyme-1 (SKI-1) – or site-1 protease (S1P). SKI-1/S1P plays a critical role in the proteolytic activation of sterol regulatory element binding proteins (SREBPs), which control expression of the key enzymes of cholesterol and fatty-acid biosynthesis. Here we report the development of a SKI-1/S1P-specific protein-based inhibitor and its application to blocking the SREBP signaling cascade. We demonstrate that SKI-1/S1P inhibition effectively blocks HCV from establishing infection in hepatoma cells. The inhibitory mechanism is associated with a dramatic reduction in the abundance of neutral lipids, LDs, and the LD marker: adipose differentiation-related protein (ADRP)/perilipin 2. Reduction of LD formation inhibits virus assembly from infected cells. Importantly, we confirm that SKI-1/S1P is a key host factor for HCV infection by using a specific active, site-directed, small-molecule inhibitor of SKI-1/S1P: PF-429242. Our studies identify SKI-1/S1P as both a novel regulator of the HCV lifecycle and as a potential host-directed therapeutic target against HCV infection and liver steatosis. With identification of an increasing number of human viruses that use host LDs for infection, our results suggest that SKI-1/S1P inhibitors may allow development of novel broad-spectrum biopharmaceuticals that could lead to novel indirect-acting antiviral options with the current standard of care.