The Postbinding Activity of Scavenger Receptor Class B Type I Mediates Initiation of Hepatitis C Virus Infection and Viral Dissemination

Abstract

Scavenger receptor class B type I (SR-BI) is a high-density lipoprotein (HDL) receptor highly expressed in the liver and modulating HDL metabolism. Hepatitis C virus (HCV) is able to directly interact with SR-BI and requires this receptor to efficiently enter into hepatocytes to establish productive infection. A complex interplay between lipoproteins, SR-BI and HCV envelope glycoproteins has been reported to take place during this process. SR-BI has been demonstrated to act during binding and postbinding steps of HCV entry. Although the SR-BI determinants involved in HCV binding have been partially characterized, the postbinding function of SR-BI remains largely unknown. To uncover the mechanistic role of SR-BI in viral initiation and dissemination, we generated a novel class of anti-SR-BI monoclonal antibodies that interfere with postbinding steps during the HCV entry process without interfering with HCV particle binding to the target cell surface. Using the novel class of antibodies and cell lines expressing murine and human SR-BI, we demonstrate that the postbinding function of SR-BI is of key impact for both initiation of HCV infection and viral dissemination. Interestingly, this postbinding function of SR-BI appears to be unrelated to HDL interaction but to be directly linked to its lipid transfer function. Conclusion: Taken together, our results uncover a crucial role of the SR-BI postbinding function for initiation and maintenance of viral HCV infection that does not require receptor-E2/HDL interactions. The dissection of the molecular mechanisms of SR-BI-mediated HCV entry opens a novel perspective for the design of entry inhibitors interfering specifically with the proviral function of SR-BI. (HEPATOLOGY 2013;57:492-504) H epatitis C virus (HCV) is a major cause of liver cirrhosis and hepatocellular carcinoma. Preventive modalities are nonexistent, and the current antiviral treatment is limited by resistance, toxicity, and high cost. 1 Viral entry is required for initiation, spread, and maintenance of infection, and thus is a promising target for antiviral therapy. HCV binding and entry into hepatocytes is a complex process involving the viral envelope glycoproteins E1 and E2, as well as several host factors,

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

“…To confirm SR-BI dependence for entry of HCVfrg viral subpopulations, cells were incubated prior to infection with the SR-BI antibody NK-8H5-E3 that has been shown previously to block HCVcc entry (39). In non-fractionated samples, blocking of SR-BI caused a marked decrease of infectivity of both HCVfrg and HCVcc samples in a dose-dependent manner (Fig.…”

Characterization of the inhibition of hepatitis C virus entry by In vitro –generated and patient-derived oxidized low-density lipoprotein

“…Of note, their major difference-G451R, but not DHVR1, directly bind SR-BI-has been shown only with sE2, but not complete virions. 35,36 Given that SR-BI is thought to act at more than one step of the HCV-entry process, 21,22 further work will clearly be needed to define the exact effects of the different viral variants and inhibitors of the virus-SR-BI interactions. In addition, it is interesting to speculate how oxidative modification of apolipoproteins, such as ApoE and ApoC1, currently known to be associated with HCV, would affect HCV infectivity.…”

“…20 Recent work has suggested that SR-BI fulfils at least two distinct functions during viral entry: one related to initial attachment and another during post-binding. 5,21,22 Among SR-BI ligands, HDL has a modest enhancing effect on HCV entry, 23 whereas oxLDL has been found to be a strong inhibitor. 24 oxLDL is a modified form of LDL that is generated early on in the pathogenesis of atherosclerosis, when native LDL deposited in early atherosclerotic lesions (''fatty streaks'') undergoes oxidative modifications.…”

HDL in Infectious Diseases and Sepsis

“…A human anti-SR-BI mAb has been reported to inhibit HDL binding, to interfere with cholesterol efflux, and to decrease cell culture-derived HCV (HCVcc) entry during attachment steps without having a relevant impact on SR-BI-mediated post-binding steps (Catanese et al 2007(Catanese et al , 2010. However, SR-BI mediates the uptake of HDL-C in a two-step process including HDL binding and subsequent transfer of CE into the cell without internalization of HDL; a novel emerging hypothesis suggests that the interference with SR-BI lipid transfer function may be relevant for both initiation of HCV infection and viral dissemination independently of HDL function (Zahid et al 2013).…”

“…In this context, the post-binding activity of SR-BI is of key relevance for cell-free HCV infection as well as cell-tocell transmission and by using antibodies which do not inhibit HDL binding to SR-BI; it was observed that post-binding function of SR-BI appears to be unrelated to HDL interaction but to be directly linked to its lipid transfer function (Zahid et al 2013). So far small molecules and mAbs targeting SR-BI and interfering with HCV infection have been described (Bartosch et al 2003;Catanese et al 2007;Syder et al 2011).…”