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Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry

Nature volume 446, pages 801–805 (2007)Cite this article

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Abstract

Hepatitis C virus (HCV) is a leading cause of cirrhosis and liver cancer worldwide. A better understanding of the viral life cycle, including the mechanisms of entry into host cells, is needed to identify novel therapeutic targets. Although HCV entry requires the CD81 co-receptor, and other host molecules have been implicated, at least one factor critical to this process remains unknown (reviewed in refs 1–3). Using an iterative expression cloning approach we identified claudin-1 (CLDN1), a tight junction component that is highly expressed in the liver4, as essential for HCV entry. CLDN1 is required for HCV infection of human hepatoma cell lines and is the first factor to confer susceptibility to HCV when ectopically expressed in non-hepatic cells. Discrete residues within the first extracellular loop (EL1) of CLDN1, but not protein interaction motifs in intracellular domains, are critical for HCV entry. Moreover, antibodies directed against an epitope inserted in the CLDN1 EL1 block HCV infection. The kinetics of this inhibition indicate that CLDN1 acts late in the entry process, after virus binding and interaction with the HCV co-receptor CD81. With CLDN1 we have identified a novel key factor for HCV entry and a new target for antiviral drug development.

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Figure 1: CLDN1 expression confers susceptibility to HCV infection.
Figure 2: CLDN1 expression is associated with susceptibility to HCVpp in human cell lines.
Figure 3: CLDN1 silencing inhibits HCV entry.
Figure 4: HCVpp susceptibility depends on residues in the first extracellular loop of CLDN1.
Figure 5: Analysis of CLDN1 function in the HCV entry process.

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Change history

  • 12 April 2007

    In the AOP version of this Letter, the label 'K48V' in Fig. 4h should have read 'K48E'. This figure has now been corrected for both print and online publication on 12 April 2007. The mistake did not affect any results.

References

  1. Bartosch, B. & Cosset, F. L. Cell entry of hepatitis C virus. Virology 348, 1–12 (2006)

    Article  CAS  Google Scholar 

  2. Cocquerel, L., Voisset, C. & Dubuisson, J. Hepatitis C virus entry: potential receptors and their biological functions. J. Gen. Virol. 87, 1075–1084 (2006)

    Article  CAS  Google Scholar 

  3. Barth, H., Liang, T. J. & Baumert, T. F. Hepatitis C virus entry: molecular biology and clinical implications. Hepatology 44, 527–535 (2006)

    Article  CAS  Google Scholar 

  4. Furuse, M., Fujita, K., Hiiragi, T., Fujimoto, K. & Tsukita, S. Claudin-1 and -2: novel integral membrane proteins localizing at tight junctions with no sequence similarity to occludin. J. Cell Biol. 141, 1539–1550 (1998)

    Article  CAS  Google Scholar 

  5. Hsu, M. et al. Hepatitis C virus glycoproteins mediate pH-dependent cell entry of pseudotyped retroviral particles. Proc. Natl Acad. Sci. USA 100, 7271–7276 (2003)

    Article  ADS  CAS  Google Scholar 

  6. Bartosch, B. et al. Cell entry of hepatitis C virus requires a set of co-receptors that include the CD81 tetraspanin and the SR-B1 scavenger receptor. J. Biol. Chem. 278, 41624–41630 (2003)

    Article  CAS  Google Scholar 

  7. Meertens, L., Bertaux, C. & Dragic, T. Hepatitis C Virus entry requires a critical postinternalization step and delivery to early endosomes via clathrin-coated vesicles. J. Virol. 80, 11571–11578 (2006)

    Article  CAS  Google Scholar 

  8. Blanchard, E. et al. Hepatitis C virus entry depends on clathrin-mediated endocytosis. J. Virol. 80, 6964–6972 (2006)

    Article  CAS  Google Scholar 

  9. Tscherne, D. M. et al. Time- and temperature-dependent activation of hepatitis C virus for low-pH-triggered entry. J. Virol. 80, 1734–1741 (2006)

    Article  CAS  Google Scholar 

  10. Koutsoudakis, G. et al. Characterization of the early steps of hepatitis C virus infection by using luciferase reporter viruses. J. Virol. 80, 5308–5320 (2006)

    Article  CAS  Google Scholar 

  11. Blight, K. J., McKeating, J. A. & Rice, C. M. Highly permissive cell lines for subgenomic and genomic hepatitis C virus RNA replication. J. Virol. 76, 13001–13014 (2002)

    Article  CAS  Google Scholar 

  12. Van Itallie, C. M. & Anderson, J. M. Claudins and epithelial paracellular transport. Annu. Rev. Physiol. 68, 403–429 (2006)

    Article  CAS  Google Scholar 

  13. Lindenbach, B. D. et al. Complete replication of hepatitis C virus in cell culture. Science 309, 623–626 (2005)

    Article  ADS  CAS  Google Scholar 

  14. Kato, T. et al. Nonhepatic cell lines HeLa and 293 support efficient replication of the hepatitis C virus genotype 2a subgenomic replicon. J. Virol. 79, 592–596 (2005)

    Article  CAS  Google Scholar 

  15. Zhang, J. et al. CD81 is required for hepatitis C virus glycoprotein-mediated viral infection. J. Virol. 78, 1448–1455 (2004)

    Article  CAS  Google Scholar 

  16. McKeating, J. A. et al. Diverse hepatitis C virus glycoproteins mediate viral infection in a CD81-dependent manner. J. Virol. 78, 8496–8505 (2004)

    Article  CAS  Google Scholar 

  17. Cormier, E. G. et al. CD81 is an entry coreceptor for hepatitis C virus. Proc. Natl Acad. Sci. USA 101, 7270–7274 (2004)

    Article  ADS  CAS  Google Scholar 

  18. Heiskala, M., Peterson, P. A. & Yang, Y. The roles of claudin superfamily proteins in paracellular transport. Traffic 2, 93–98 (2001)

    Article  CAS  Google Scholar 

  19. Wu, L. et al. CD4-induced interaction of primary HIV-1 gp120 glycoproteins with the chemokine receptor CCR-5. Nature 384, 179–183 (1996)

    Article  ADS  CAS  Google Scholar 

  20. Tiwari-Woodruff, S. K. et al. OSP/claudin-11 forms a complex with a novel member of the tetraspanin super family and β1 integrin and regulates proliferation and migration of oligodendrocytes. J. Cell Biol. 153, 295–305 (2001)

    Article  CAS  Google Scholar 

  21. Furuse, M. et al. Claudin-based tight junctions are crucial for the mammalian epidermal barrier: a lesson from claudin-1-deficient mice. J. Cell Biol. 156, 1099–1111 (2002)

    Article  CAS  Google Scholar 

  22. Barton, E. S. et al. Junction adhesion molecule is a receptor for reovirus. Cell 104, 441–451 (2001)

    Article  CAS  Google Scholar 

  23. Bergelson, J. M. et al. Isolation of a common receptor for Coxsackie B viruses and adenoviruses 2 and 5. Science 275, 1320–1323 (1997)

    Article  CAS  Google Scholar 

  24. Coyne, C. B. & Bergelson, J. M. Virus-induced Abl and Fyn kinase signals permit coxsackievirus entry through epithelial tight junctions. Cell 124, 119–131 (2006)

    Article  CAS  Google Scholar 

  25. Borlak, J., Meier, T., Halter, R., Spanel, R. & Spanel-Borowski, K. Epidermal growth factor-induced hepatocellular carcinoma: gene expression profiles in precursor lesions, early stage and solitary tumours. Oncogene 24, 1809–1819 (2005)

    Article  CAS  Google Scholar 

  26. Swisshelm, K., Macek, R. & Kubbies, M. Role of claudins in tumorigenesis. Adv. Drug Deliv. Rev. 57, 919–928 (2005)

    Article  CAS  Google Scholar 

  27. Dhawan, P. et al. Claudin-1 regulates cellular transformation and metastatic behavior in colon cancer. J. Clin. Invest. 115, 1765–1776 (2005)

    Article  CAS  Google Scholar 

  28. Doughty, A. L., Spencer, J. D., Cossart, Y. E. & McCaughan, G. W. Cholestatic hepatitis after liver transplantation is associated with persistently high serum hepatitis C virus RNA levels. Liver Transpl. Surg. 4, 15–21 (1998)

    Article  CAS  Google Scholar 

  29. Schluger, L. K. et al. Severe recurrent cholestatic hepatitis C following orthotopic liver transplantation. Hepatology 23, 971–976 (1996)

    Article  CAS  Google Scholar 

Download references

Acknowledgements

The authors thank J. Tassello, M. Hunter and N. Torres for excellent technical assistance; S. You for providing HCVcc/Rluc virus stocks; D. Schmid and M. Landthaler for expert advice on RNAi; and M. MacDonald and L. Dustin for reviewing the manuscript. This work was supported by the Greenberg Medical Research Institute, the Ellison Medical Foundation, the Starr Foundation, the Ronald A. Shellow Memorial Fund, the Richard Salomon Family Foundation, and the National Institutes of Health (grants to M.J.E., T.v.H., D.M.T., A.J.S., P.D.B. and C.M.R.). P.D.B. is an Elizabeth Glaser Pediatric AIDS Foundation Scientist. C.M.R. is an Ellison Medical Foundation Senior Scholar in Global Infectious Diseases. T.v.H. and B.W. were supported by postdoctoral fellowships from the Deutsche Forschungsgemeinschaft. This work was presented in part at the 13th International Meeting on Hepatitis C Virus & Related Viruses, Cairns, Australia, 27–31 August, 2006.

Author Contributions M.E., T.v.H. and C.M.R. designed the project, analysed results and wrote the manuscript. M.E., T.v.H., D.M.T., A.J.S., M.P. and B.W. performed the experimental work. T.H. and P.D.B developed the screening technology and assisted in its implementation. T.v.H. and J.A.M were involved in preliminary experiments identifying and characterizing HCV nonpermissive cell lines.

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Author notes

  1. Jane A. McKeating

    Present address: Present address: Division of Immunity and Infection, Institute of Biomedical Research, Medical School, University of Birmingham, Birmingham B15 2TT, UK.,

  2. Matthew J. Evans and Thomas von Hahn: These authors contributed equally to this work.

Authors and Affiliations

  1. Center for the Study of Hepatitis C, The Rockefeller University, 1230 York Ave, New York 10021, USA,

    Matthew J. Evans, Thomas von Hahn, Donna M. Tscherne, Andrew J. Syder, Maryline Panis, Benno Wölk, Jane A. McKeating & Charles M. Rice

  2. Aaron Diamond AIDS Research Center, The Rockefeller University, 455 First Avenue, New York 10016, USA,

    Theodora Hatziioannou & Paul D. Bieniasz

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Correspondence to Charles M. Rice.

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Competing interests

The authors declare the following conflicts of interest, which are managed under University policy: C.M.R. has equity in Apath, LLC, which holds commercial licenses for the Huh-7.5 cell line and the HCVcc cell culture system; Rockefeller University has filed a patent on commercial applications of the claudin-I HCV entry factor (inventors M.J.E., T.v.H. and C.M.R.)

Supplementary information

Supplementary Methods and Notes

This file contains Supplementary Methods and Notes with a more in-depth description of the methods and materials employed in this study, additional references and Supplementary Figures 1-8 with Legends. The Supplementary Figures provide additional information on the screening approach that led to the identification of CLDN1 as an HCV co-receptor. They also show more data to support its essential role at the post-binding stage of the HCV entry process. (PDF 4523 kb)

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Evans, M., von Hahn, T., Tscherne, D. et al. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature 446, 801–805 (2007). https://doi.org/10.1038/nature05654

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