HCV and lipoproteins: Is oxLDL an Achilles' heel of the Trojan horse?

Anotable difference between hepatitis C virus (HCV) and the other members of the Flaviviridae family is the absence of a conventional model of free HCV particle in vivo, whereas the structure of the flavivirus virion has been described in detail. HCV has indeed been detected in many heterogeneous forms of diverse buoyant density (d 1.06 to 1.25 g/mL). In the blood of infected patients, HCV presents itself either in “free” forms, complexed with immunogobulins, associated with high-, lowor very low-density lipoproteins, or “encrusted” in -lipoproteins as so called lipo-viro-particles (LVPs). 1-5 Indirect evidence suggests that low-density HCV (i.e., LVPs or other lipoprotein-associated HCV forms) are more infectious than the lipoprotein-free viral forms of higher densities.2,3 This could be due to neutralization of the viral forms of high densities by immunoglobulins, to protection of low-density HCV against neutralizing antibodies, and/or to lipoprotein-association that stimulates HCV infection. Remarkably, in contrast to the positive modulation of lipoproteins on HCV infection, oxidized forms of lipoproteins may specifically inhibit HCV infection. As reported in this issue, von Hahn and collaborators demonstrate a significant and specific inhibition of HCV (IC50 at ca. 1 g/mL) in infection assays in vitro by oxLDL or oxHDL, most likely induced via their oxidized lipid moieties. The inhibitory effect is conserved across diverse HCV genotypes (genotypes 1a, 1b, 2a) and for all target cells tested. The authors further examined the mechanisms of inhibition and they propose that the oxidized lipoproteins inhibit cell entry by interfering with the scavenger receptor BI (SR-BI), one of the putative receptors of the virus. The investigation of HCV, its many different forms, and its receptors is a particularly complex task since ex vivo characterization of HCV derived from plasma has proven to be extremely difficult. First, the efficacy of the virus to establish productive infection of primary hepatocytes or hepatoma cell lines is very low; second, the availability of primary hepatocytes and of well-characterized native HCV populations is significantly restricted; third, purification of plasma-derived HCV may alter the properties of the viral particles and/or their association with lipoproteins.4 A significant number of model systems of HCV particles have been developed in an attempt to overcome these severe limitations associated with the study of HCV structure and cell entry.6 They include (1) non-infectious HCV-like particles (HCV-LP),7 (2) “infectious” HCV pseudo-particles derived from vesicular stomatitis virus (VSV)8 or from retroviruses (HCVpp),9,10 (3) cell culture– grown authentic HCV (HCVcc) that produces infectious virus particles.11-13 HCVpp and HCVcc allow a robust investigation of most functions mediated by the HCV glycoproteins and, hence, may reproduce some cell entry features of native HCV.11-18 Of note, these different HCV model systems are generated in vitro from transformed cell lines, which could preclude some feature of HCV association with lipoprotein metabolism. However, recent results suggest that there may be more similarities than anticipated between current in vitro HCV models and virus purified from patients’ plasma. HCV E1E2targeted antibodies have been detected in patients’ blood, or induced in immunized animals, that prevented contamination of patients, or infection of chimpanzees, with plasma-derived HCV19,20 and that readily neutralized both HCVpp and/or HCVcc,20,21 (Dreux et al., unpublished observations, 2006), indicating some shared serological and antigenic properties. Moreover, HCVcc with the highest specific infectivity was shown to have a low buoyant density,11 similar to clinical HCV isolates with high infectivity in animals,2 indicating that they may associate with lipoproteins. Finally, several recent reports,15,17,18 including that of von Hahn et al.,22 have addressed the fascinating complexity of the interrelation between HCV, its receptors and serum components as reconstituted in vitro, using either HCV infection models. Cell attachment of flaviviruses generally leads to endocytosis of bound virions, an event required to induce fusion between viral and cell membranes in acidic intracellular vesicles and subsequent initiation of viral replication. As the liver is the major organ known to replicate HCV, the expression pattern of the cellular HCV receptor(s) has been suggested to be liver specific, or domAbbreviations: HCV, hepatitis C virus; sE2, soluble recombinant E2; LDL, low-density lipoprotein; HDL, high-density lipoprotein. Address reprint requests to: François-Loı̈c Cosset, INSERM, U758, Ecole Normale Supérieure de Lyon, Lyon, France. E-mail: flcosset@tieuf.fr. Copyright © 2006 by the American Association for the Study of Liver Diseases. Published online in Wiley InterScience (www.interscience.wiley.com). DOI 10.1002/hep.21202 Potential conflict of interest: Nothing to report.