Abstract
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.
Highlights
We compared viral subpopulations derived from humanized liver mouse model versus cell culture
As hepatoma cells producing cell culture-derived hepatitis C virus (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, regarding how lipoprotein components modulate HCV entry by lipid transfer receptors such as scavenger receptor BI (SR-BI)
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
Summary
In vivo models allow functional investigations on how lipid metabolism and hepatic environment influence HCV entry. A direct interaction between apoE and viral envelope glycoproteins has recently been demonstrated [11,12,13], further indicating a close relationship between viral particles and lipoprotein components Lipoproteins and their receptors as well as their associated lipid transfer activities are key factors for HCV entry into hepatocytes. We characterize HCV particles and viral subpopulations produced in humanized liver mice derived from the FRG mouse model (further designated HCVfrg), a triple mutant mouse knocked out for fumarylacetoacetate hydrolase (FAH), RAG2, and ␥c [35] that was previously shown to support HCV infection [36]. Altogether, our results suggest that the lipoprotein components incorporated on viral particles play a crucial role in entry of infectious particles, and our results highlight the powerfulness of this in vivo model for the functional study of the interplay between HCV and liver components
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