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Journal of Virology, September 2002, p. 9335-9344, Vol. 76, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.18.9335-9344.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.

Interaction of Hepatitis C Virus-Like Particles and Cells: a Model System for Studying Viral Binding and Entry

Miriam Triyatni,1 Bertrand Saunier,2,3 Padma Maruvada,4 Anthony R. Davis,1 Luca Ulianich,2 Theo Heller,1 Arvind Patel,5 Leonard D. Kohn,2,3 and T. Jake Liang1*

Liver Diseases Section,1 Cell Regulation Section,2 Clinical Endocrinology Branch, National Institute of Diabetes and DigestiveKidney Diseases, National Institutes of Health, Bethesda, Maryland 20892,4 Edison Biotechnology Institute, Ohio University, Athens, Ohio 45701,3 Institute of Virology, Medical Research Council, Glasgow, United Kingdom5

Received 24 April 2002/ Accepted 12 June 2002

Hepatitis C virus-like particles (HCV-LPs) containing the structural proteins of HCV H77 strain (1a genotype) was used as a model for HCV virion to study virus-cell interaction. HCV-LPs showed a buoyant density of 1.17 to 1.22 g/cm3 in a sucrose gradient and formed double-shelled particles 35 to 49 nm in diameter. Flow cytometry analysis by an indirect method (detection with anti-E2 antibody) and a direct method (use of dye-labeled HCV-LPs) showed that HCV-LPs binds to several human hepatic (primary hepatocytes, HepG2, HuH7, and NKNT-3) and T-cell (Molt-4) lines. HCV-LPs binding to cells occurred in a dose- and calcium-dependent manner and was not mediated by CD81. Scatchard plot analysis suggests the presence of two binding sites for HCV-LPs with high (Kd ~1 µg/ml) and low (Kd ~50 to 60 µg/ml) affinities of binding. Anti-E1 and -E2 antibodies inhibited HCV-LPs binding to cells. While preincubation of HCV-LPs with very-low-density lipoprotein (VLDL), low-density lipoprotein (LDL), or high-density lipoprotein (HDL) blocked its binding to cells, preincubation of cells with VLDL, LDL, HDL, or anti-LDL-R antibody did not. Confocal microscopy analysis showed that, after binding to cells, dye-labeled HCV-LPs were internalized into the cytoplasm. This process could be inhibited with anti-E1 or anti-E2 antibodies, suggesting that E1 and E2 proteins mediate HCV-LPs binding and, subsequently, their entry into cells. Altogether, our results indicate that HCV-LPs can be used to further characterize the mechanisms involved in the early steps of HCV infection.

* Corresponding author. Mailing address: Liver Diseases Section, National Institute of Diabetes and Digestive and Kidney Diseases, NIH, Bldg. 10, Rm. 9B06, 10 Center Dr., Bethesda, MD 20892. Phone: (301) 496-1721. Fax: (301) 402-0491. E-mail: JLiang{at}nih.gov.

Journal of Virology, September 2002, p. 9335-9344, Vol. 76, No. 18
0022-538X/02/$04.00+0     DOI: 10.1128/JVI.76.18.9335-9344.2002
Copyright © 2002, American Society for Microbiology. All Rights Reserved.



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