Functional and Biochemical Characterization of Hepatitis C Virus (HCV) Particles Produced in a Humanized Liver Mouse Model

• Published in: The Journal of biological chemistry Vol. 290; no. 38; pp. 23173 - 23187
• Main Authors: Calattini, Sara, Fusil, Floriane, Mancip, Jimmy, Dao Thi, Viet Loan, Granier, Christelle, Gadot, Nicolas, Scoazec, Jean-Yves, Zeisel, Mirjam B., Baumert, Thomas F., Lavillette, Dimitri, Dreux, Marlène, Cosset, François-Loïc
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 18-09-2015; American Society for Biochemistry and Molecular Biology
• Subjects: animal model; Animals; apolipoprotein; Apolipoproteins E - genetics; Apolipoproteins E - metabolism; Cell Line; Disease Models, Animal; Hepacivirus - genetics; Hepacivirus - metabolism; Hepatitis C - genetics; Hepatitis C - metabolism; Hepatitis C - pathology; hepatitis C virus (HCV); Human health and pathology; Humans; in vivo study; Life Sciences; lipoprotein; Liver - metabolism; Liver - pathology; Liver - virology; Mice; Mice, Knockout; Microbiology; scavenger receptor; Scavenger Receptors, Class B - genetics; Scavenger Receptors, Class B - metabolism; Viral Envelope Proteins - genetics; Viral Envelope Proteins - metabolism; virus entry; Virus Internalization; hepatitis C virus (HCV); apolipoprotein; scavenger receptor; lipoprotein; virus entry; in vivo study; animal model
• ISSN: 0021-9258; 1083-351X
• DOI: 10.1074/jbc.M115.662999

Lipoprotein components are crucial factors for hepatitis C virus (HCV) assembly and entry. As hepatoma cells producing cell culture-derived HCV (HCVcc) particles are impaired in some aspects of lipoprotein metabolism, it is of upmost interest to biochemically and functionally characterize the in vivo produced viral particles, particularly regarding how lipoprotein components modulate HCV entry by lipid transfer receptors such as scavenger receptor BI (SR-BI). Sera from HCVcc-infected liver humanized FRG mice were separated by density gradients. Viral subpopulations, termed HCVfrg particles, were characterized for their physical properties, apolipoprotein association, and infectivity. We demonstrate that, in contrast to the widely spread distribution of apolipoproteins across the different HCVcc subpopulations, the most infectious HCVfrg particles are highly enriched in apoE, suggesting that such apolipoprotein enrichment plays a role for entry of in vivo derived infectious particles likely via usage of apolipoprotein receptors. Consistent with this salient feature, we further reveal previously undefined functionalities of SR-BI in promoting entry of in vivo produced HCV. First, unlike HCVcc, SR-BI is a particularly limiting factor for entry of HCVfrg subpopulations of very low density. Second, HCVfrg entry involves SR-BI lipid transfer activity but not its capacity to bind to the viral glycoprotein E2. In conclusion, we demonstrate that composition and biophysical properties of the different subpopulations of in vivo produced HCVfrg particles modulate their levels of infectivity and receptor usage, hereby featuring divergences with in vitro produced HCVcc particles and highlighting the powerfulness of this in vivo model for the functional study of the interplay between HCV and liver components.
Background: We compared viral subpopulations derived from humanized liver mouse model versus cell culture.
Results:In vivo and in vitro produced particles show different biophysical properties and receptor usage.
Conclusion:In vivo models allow functional investigations on how lipid metabolism and hepatic environment influence HCV entry.
Significance: HCV produced from humanized liver mice may better reflect the characteristics of virus from HCV-infected patients.