Z Gastroenterol 2006; 44 - A4_32
DOI: 10.1055/s-2006-931763

Investigations into the receptor requirements of Hepatitis C Virus (HCV) pseudoparticles and cell culture grown virions

T von Hahn 1, M Flint 1, BD Lindenbach 1, A Boullier 2, O Quehenberger 2, CM Rice 1, JA McKeating 3
  • 1Center for the Study of Hepatitis C, Rockefeller University, New York, NY, USA
  • 2Dept. of Medicine, UCSD, San Diego, USA
  • 3Division of Immunity and Infection, Inst. of Biomedical Research, Medical School, University of Birmingham, Birmingham, UK

Introduction & Methods: The study of the cell entry of Hepatitis C Virus (HCV) into target cells had until recently been hampered by the lack of robust in vitro systems that model these first events in the viral lifecycle. A substantial advance was the arrival of HIV-based pseudoparticles bearing HCV glycoproteins (HCV pseudoparticles, HCVpp). Using HCVpp several groups have provided ample evidence that CD81, scavenger receptor BI (SR-BI) and very likely other as yet unidentified molecules are required to allow cell entry of incoming HCV. Now that besides HCVpp complete HCV virions grown in cell culture (HCVcc) are available insights derived from HCVpp need to be validated using the HCVcc system.

Results: The tetraspanin CD81 has been shown to be required for entry by both HCVpp and HCVcc. We have found that apart from human CD81 both systems can also utilize a wide and almost identical range of CD81 sequences derived from diverse species including several (e.g. mouse, rat) that are clearly non-permissive to HCV infection in vivo. Besides underscoring the similarity of HCVpp and HCVcc with regard to the virus-CD81 interaction, this finding may have important implications for the development of a small animal model of HCV infection. The role of SR-BI for HCV entry is less well defined than that of CD81. We provide evidence for the importance of this molecule in the cell entry process by showing that oxidized LDL (oxLDL), a known ligand of SR-BI, is a potent and specific inhibitor of cell entry by both HCVpp and HCVcc. Furthermore, the inhibitory activity seems to reside in an oxidized lipid species contained in the oxLDL particle and involve an interaction between the inhibitory agent and the oxLDL binding site on the target cell.

Conclusion: Our data suggest that HCVpp and HCVcc are very comparable with regard to their interaction with the host cell receptors CD81 and SR-BI.

Key words

CD81 - HCV - SR-BI - entry - oxLDL