title: Infectivity of hepatitis C virus is influenced by association with apolipoprotein E isoforms.
abstract: Hepatitis C virus (HCV) is a causative agent of chronic hepatitis, liver cirrhosis, and hepatocellular carcinoma. HCV in circulating blood associates with lipoproteins such as very low density lipoprotein (VLDL) and low-density lipoprotein (LDL). Although these associations suggest that lipoproteins are important for HCV infectivity, the roles of lipoproteins in HCV production and infectivity are not fully understood. To clarify the roles of lipoprotein in the HCV life cycle, we analyzed the effect of apolipoprotein E (ApoE), a component of lipoprotein, on virus production and infectivity. The production of infectious HCV was significantly reduced by the knockdown of ApoE. When an ApoE mutant that fails to be secreted into the culture medium was used, the amount of infectious HCV in the culture medium was dramatically reduced; the infectious HCV accumulated inside these cells, suggesting that infectious HCV must associate with ApoE prior to virus release. We performed rescue experiments in which ApoE isoforms were ectopically expressed in cells depleted of endogenous ApoE. The ectopic expression of the ApoE2 isoform, which has low affinity for the LDL receptor (LDLR), resulted in poor recovery of infectious HCV, whereas the expression of other isoforms, ApoE3 and ApoE4, rescued the production of infectious virus, raising it to an almost normal level. Furthermore, we found that the infectivity of HCV required both the LDLR and scavenger receptor class B, member I (SR-BI), ligands for ApoE. These findings indicate that ApoE is an essential apolipoprotein for HCV infectivity.
authors.affiliation: Research Institute, Chiba Institute of Technology, Narashino City, Chiba 275-0016, Japan. takayuki.hishiki@it-chiba.ac.jp
authors.forename: Takayuki
authors.initials: T
authors.lastname: Hishiki
authors.forename: Yuko
authors.initials: Y
authors.lastname: Shimizu
authors.forename: Reiri
authors.initials: R
authors.lastname: Tobita
authors.forename: Kazuo
authors.initials: K
authors.lastname: Sugiyama
authors.forename: Kazuya
authors.initials: K
authors.lastname: Ogawa
authors.forename: Kenji
authors.initials: K
authors.lastname: Funami
authors.forename: Yuki
authors.initials: Y
authors.lastname: Ohsaki
authors.forename: Toyoshi
authors.initials: T
authors.lastname: Fujimoto
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Takaku
authors.forename: Takaji
authors.initials: T
authors.lastname: Wakita
authors.forename: Thomas F
authors.initials: TF
authors.lastname: Baumert
authors.forename: Yusuke
authors.initials: Y
authors.lastname: Miyanari
authors.forename: Kunitada
authors.initials: K
authors.lastname: Shimotohno
mesh_terms: D053329:Apolipoprotein E2 / Q000235:genetics / Q000378:metabolism*; D053318:Apolipoprotein E3 / Q000235:genetics / Q000378:metabolism*; D053327:Apolipoprotein E4 / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000502:physiology*; D006526:Hepatitis C / Q000235:genetics / Q000378:metabolism* / Q000821:virology; D006801:Humans; D011485:Protein Binding
chemical_list: D053329:Apolipoprotein E2; D053318:Apolipoprotein E3; D053327:Apolipoprotein E4
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