Sagan Selena M, Rouleau Yanouchka, Leggiadro Cynthia, Supekova Lubica, Schultz Peter G, Su Andrew I, Pezacki John Paul
Steacie Institute for Molecular Sciences, National Research Council of Canada, Ottawa, ON.
Biochem Cell Biol. 2006 Feb;84(1):67-79. doi: 10.1139/o05-149.
The hepatitis C virus (HCV) replicates on a membrane protein complex composed of viral proteins, replicating RNA, and altered cellular membranes. Small-molecule inhibitors of cellular lipid-cholesterol metabolism such as 25-hydroxycholesterol, cerulenin, lovastatin, and GGTI-286 all show a negative effect on HCV replication. Perturbation of host cell lipid and cholesterol metabolism can disrupt replication complexes by altering membranous structures where replication occurs. Changes in cholesterol and (or) lipid composition can have a general effect on membrane structure. Alternatively, metabolic changes can exert a more subtle influence over replication complexes by altering localization of host proteins through alterations in lipid anchoring. Here, we use Huh-7 cells harboring subgenomic HCV replicons to demonstrate that 25-hydroxycholesterol, cerulenin, lovastatin, and GGTI-286 do not disrupt the membranous web where replication occurs, whereas cholesterol-depleting agents such as beta-cyclodextrin do. Cellular imaging suggests that the HCV RNA can remain associated with subcellular compartments connected with replication complexes in the presence of metabolic inhibitors. Therefore, at least 2 different molecular mechanisms are possible for the inhibition of HCV replication through the modulation of cellular lipid and cholesterol metabolism.
丙型肝炎病毒（HCV）在由病毒蛋白、复制RNA和改变的细胞膜组成的膜蛋白复合物上进行复制。细胞脂质-胆固醇代谢的小分子抑制剂，如25-羟基胆固醇、浅蓝菌素、洛伐他汀和GGTI-286，均对HCV复制显示出负面影响。宿主细胞脂质和胆固醇代谢的扰动可通过改变发生复制的膜结构来破坏复制复合物。胆固醇和（或）脂质组成的变化可对膜结构产生普遍影响。或者，代谢变化可通过脂质锚定的改变来改变宿主蛋白的定位，从而对复制复合物产生更微妙的影响。在此，我们使用携带亚基因组HCV复制子的Huh-7细胞来证明，25-羟基胆固醇、浅蓝菌素、洛伐他汀和GGTI-286不会破坏发生复制的膜网，而β-环糊精等胆固醇消耗剂则会。细胞成像表明，在存在代谢抑制剂的情况下，HCV RNA可与与复制复合物相连的亚细胞区室保持关联。因此，通过调节细胞脂质和胆固醇代谢来抑制HCV复制至少有2种不同的分子机制。
