The exchangeable apolipoprotein ApoC-I promotes membrane fusion of hepatitis C virus.
Cell entry of hepatitis C virus (HCV) is strikingly linked to lipoproteins and their receptors. Particularly, high density lipoprotein (HDL) enhances infectivity of HCV by involving the lipid-transfer function of the scavenger receptor BI, a receptor for both HDL and HCV. Here, we demonstrate that apoC-I, an exchangeable apolipoprotein that predominantly resides in HDL, specifically enhances HCVcc and HCVpp infectivity and increases the fusion rates between viral and target membranes via a direct interaction with the HCV surface. We identify the hypervariable region 1, located at the N terminus of the HCV E2 glycoprotein, as an essential viral component that modulates apoC-I-mediated enhancement of HCV fusion properties. The affinity of apoC-I for the HCV membrane may predispose it for fusion with a target membrane via alterations of its outer phospholipid layer. Conversely, we found that excess apoC-I provided as lipoprotein-free protein induces the disruption of the HCV membrane and subsequent loss of infectivity. Furthermore, our data indicate that HDL neither interacts nor spontaneously exchanges apoC-I with HCV virions. Because apoC-I is not present in serum as a lipoprotein-free form, our results suggest that HDL-embedded apoC-I could be released from the lipoprotein particle through a fine-tuned mechanism regulated via a triple interplay between hypervariable region 1, HDL, and scavenger receptor BI, resulting in optimal apoC-I recruitment on the viral membrane. These results provide the first description of a host serum factor helping the fusion process of an enveloped virus.
Dreux
Marlène
M
Université de Lyon, (UCB-Lyon1), IFR128, INSERM, U758, and Ecole Normale Supérieure de Lyon, Lyon, F-69007, France.
Boson
Bertrand
B
Ricard-Blum
Sylvie
S
Molle
Jennifer
J
Lavillette
Dimitri
D
Bartosch
Birke
B
Pécheur
Eve-Isabelle
EI
Cosset
Francois-Loïc
FL
D053302:Apolipoprotein C-I / Q000378:metabolism*; D045744:Cell Line, Tumor; D016174:Hepacivirus / Q000502:physiology*; D006801:Humans; D008075:Lipoproteins, HDL / Q000378:metabolism; D051122:Scavenger Receptors, Class B / Q000378:metabolism; D014764:Viral Proteins / Q000378:metabolism; D053586:Virus Internalization
C505803:APOC1 protein, human; D053302:Apolipoprotein C-I; C400562:HVR1 protein, Hepatitis C virus; D008075:Lipoproteins, HDL; C495124:SCARB1 protein, human; D051122:Scavenger Receptors, Class B; D014764:Viral Proteins