Scheel Troels K H, Kapoor Amit, Nishiuchi Eiko, Brock Kenny V, Yu Yingpu, Andrus Linda, Gu Meigang, Renshaw Randall W, Dubovi Edward J, McDonough Sean P, Van de Walle Gerlinde R, Lipkin W Ian, Divers Thomas J, Tennant Bud C, Rice Charles M
Laboratory of Virology and Infectious Disease, Center for the Study of Hepatitis C, The Rockefeller University, New York, NY 10065; Copenhagen Hepatitis C Program, Department of Infectious Disease and Clinical Research Centre, Copenhagen University Hospital, DK-2650 Hvidovre, Denmark; Department of International Health, Immunology, and Microbiology, Faculty of Health and Medical Sciences, University of Copenhagen, DK-2200 Copenhagen, Denmark;
Center for Infection and Immunity, Columbia University, New York, NY 10032;
Proc Natl Acad Sci U S A. 2015 Feb 17;112(7):2192-7. doi: 10.1073/pnas.1500265112. Epub 2015 Feb 2.
Nonprimate hepacivirus (NPHV) is the closest known relative of hepatitis C virus (HCV) and its study could enrich our understanding of HCV evolution, immunity, and pathogenesis. High seropositivity is found in horses worldwide with ∼ 3% viremic. NPHV natural history and molecular virology remain largely unexplored, however. Here, we show that NPHV, like HCV, can cause persistent infection for over a decade, with high titers and negative strand RNA in the liver. NPHV is a near-universal contaminant of commercial horse sera for cell culture. The complete NPHV 3'-UTR was determined and consists of interspersed homopolymer tracts and an HCV-like 3'-terminal poly(U)-X-tail. NPHV translation is stimulated by miR-122 and the 3'-UTR and, similar to HCV, the NPHV NS3-4A protease can cleave mitochondrial antiviral-signaling protein to inactivate the retinoic acid-inducible gene I pathway. Using an NPHV consensus cDNA clone, replication was not observed in primary equine fetal liver cultures or after electroporation of selectable replicons. However, intrahepatic RNA inoculation of a horse initiated infection, yielding high RNA titers in the serum and liver. Delayed seroconversion, slightly elevated circulating liver enzymes and mild hepatitis was observed, followed by viral clearance. This establishes the molecular components of a functional NPHV genome. Thus, NPHV appears to resemble HCV not only in genome structure but also in its ability to establish chronic infection with delayed seroconversion and hepatitis. This NPHV infectious clone and resulting acute phase sera will facilitate more detailed studies on the natural history, pathogenesis, and immunity of this novel hepacivirus in its natural host.
非灵长类肝炎病毒（NPHV）是已知与丙型肝炎病毒（HCV）亲缘关系最近的病毒，对其进行研究有助于我们更深入地了解HCV的进化、免疫和发病机制。在全球范围内的马匹中发现了较高的血清阳性率，约3%的马匹存在病毒血症。然而，NPHV的自然史和分子病毒学在很大程度上仍未得到充分探索。在此，我们发现，与HCV一样，NPHV可导致持续十多年的感染，肝脏中病毒滴度高且存在负链RNA。NPHV几乎是细胞培养用商业马血清中的普遍污染物。已确定NPHV完整的3'-UTR，其由散布的同聚物序列和类似HCV的3'-末端聚（U）-X尾组成。miR-122和3'-UTR可刺激NPHV的翻译，并且与HCV相似，NPHV NS3-4A蛋白酶可切割线粒体抗病毒信号蛋白，从而使视黄酸诱导基因I途径失活。使用NPHV共有cDNA克隆，在原代马胎儿肝培养物中或在对可选择复制子进行电穿孔后均未观察到复制。然而，对一匹马进行肝内RNA接种引发了感染，血清和肝脏中产生了高RNA滴度。观察到血清转化延迟、循环肝酶略有升高以及轻度肝炎，随后病毒清除。这确定了功能性NPHV基因组的分子组成部分。因此，NPHV似乎不仅在基因组结构上与HCV相似，而且在建立伴有血清转化延迟和肝炎的慢性感染的能力方面也与HCV相似。这种NPHV感染性克隆及由此产生的急性期血清将有助于对这种新型肝炎病毒在其自然宿主中的自然史、发病机制和免疫进行更详细的研究。
