Cellular and Molecular Life Sciences

, Volume 75, Issue 21, pp 3895–3905 | Cite as

The functional role of sodium taurocholate cotransporting polypeptide NTCP in the life cycle of hepatitis B, C and D viruses

  • Carla Eller
  • Laura Heydmann
  • Che C. Colpitts
  • Eloi R. Verrier
  • Catherine Schuster
  • Thomas F. Baumert


Chronic hepatitis B, C and D virus (HBV, HCV and HDV) infections are a major cause of liver disease and cancer worldwide. Despite employing distinct replication strategies, the three viruses are exclusively hepatotropic, and therefore depend on hepatocyte-specific host factors. The sodium taurocholate co-transporting polypeptide (NTCP), a transmembrane protein highly expressed in human hepatocytes that mediates the transport of bile acids, plays a key role in HBV and HDV entry into hepatocytes. Recently, NTCP has been shown to modulate HCV infection of hepatocytes by regulating innate antiviral immune responses in the liver. Here, we review the current knowledge of the functional role and the molecular and cellular biology of NTCP in the life cycle of the three major hepatotropic viruses, highlight the impact of NTCP as an antiviral target and discuss future avenues of research.


Liver cell biology Bile acid transport Host factor Anti-viral therapy Hepatocytes 



This work was supported by Inserm, the University of Strasbourg, the European Union (ERC-2014-AdG-671231-HEPCIR, Infect-ERA hepBccc, EU H2020 Hep-CAR 667273), ANRS (2015/1099), the French Cancer Agency (ARC IHU201301187) and the National Institute of Allergy and Infectious Diseases of the National Institutes of Health under award number R03AI131066. CCC acknowledges fellowships from the Canadian Institutes of Health Research (201411MFE-338606-245517) and the Canadian Network on Hepatitis C. ERV is the recipient of an ANRS fellowship (ECTZ50121).

Author contributions

CFE, LH, CCC, ERV, CS, TFB wrote the manuscript.

Compliance with ethical standards

Conflict of interest

The authors have no conflicting interests to disclose.


  1. 1.
    World Health Organization (2016) Global health sector strategy on viral hepatitis 2016–2021. Towards ending viral hepatitis. World Health Organization.
  2. 2.
    Schweitzer A, Horn J, Mikolajczyk RT, Krause G, Ott JJ (2015) Estimations of worldwide prevalence of chronic hepatitis B virus infection: A systematic review of data published between 1965 and 2013. Lancet 386:1546–1555. CrossRefGoogle Scholar
  3. 3.
    World Health Organization (2017) Global hepatitis report 2017. World Health Organization. License: CC BY-NC-SA 3.0 IGO.
  4. 4.
    Sultanik P, Pol S (2016) Hepatitis delta virus: epidemiology, natural course and treatment. J Infect Dis Ther 4:2–7. CrossRefGoogle Scholar
  5. 5.
    Chung RT, Baumert TF (2014) Curing chronic hepatitis C—the arc of a medical triumph. New Engl J Med 370:1576–1578. CrossRefGoogle Scholar
  6. 6.
    Werle-Lapostolle B, Bowden S, Locarnini S, Wursthorn K, Petersen J, Lau G, Trepo C, Marcellin P, Goodman Z, Delaney WE, Xiong S, Brosgart CL, Chen S, Gibbs CS, Zoulim F (2004) Persistence of cccDNA during the natural history of chronic hepatitis B and decline during adefovir dipivoxil therapy. Gastroenterology 126:1750–1758. CrossRefGoogle Scholar
  7. 7.
    Papatheodoridis GV, Idilman R, Dalekos GN, Buti M, Chi H, Van Boemmel F, Calleja JL, Sypsa V, Goulis J, Manolakopoulos S, Loglio A, Siakavellas S, Keskın O, Gatselis N, Hansen BE, Lehretz M, De Revilla J, Savvidou S, Kourikou A, Vlachogiannakos I, Galanis K, Yurdaydin C, Berg T, Colombo M, Esteban R, Janssen HLA, Lampertico P (2017) The risk of hepatocellular carcinoma decreases after the first 5 years of entecavir or tenofovir in Caucasians with chronic hepatitis B. Hepatology 66:1444–1453. CrossRefGoogle Scholar
  8. 8.
    Baumert TF, Jühling F, Ono A, Hoshida Y (2017) Hepatitis C-related hepatocellular carcinoma in the era of new generation antivirals. BMC Med 15:1–10. CrossRefGoogle Scholar
  9. 9.
    Baumert TF, Verrier ER, Nassal M, Chung RT, Zeisel MB (2015) Host-targeting agents for treatment of hepatitis B virus infection. Curr Opin Virol 14:41–46. CrossRefGoogle Scholar
  10. 10.
    Mailly L, Xiao F, Lupberger J, Wilson GK, Aubert P, Duong FHT, Calabrese D, Leboeuf C, Fofana I, Thumann C, Bandiera S, Lütgehetmann M, Volz T, Davis C, Harris HJ, Mee CJ, Girardi E, Chane-Woon-Ming B, Ericsson M, Fletcher N, Bartenschlager R, Pessaux P, Vercauteren K, Meuleman P, Villa P, Kaderali L, Pfeffer S, Heim MH, Neunlist M, Zeisel MB, Dandri M, McKeating JA, Robinet E, Baumert TF (2015) Clearance of persistent hepatitis C virus infection in humanized mice using a claudin-1-targeting monoclonal antibody. Nat Biotechnol 33:549–554. CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Zeisel MB, Baumert TF (2017) Clinical development of hepatitis C virus host-targeting agents. Lancet 389:674–675. CrossRefPubMedPubMedCentralGoogle Scholar
  12. 12.
    Yan H, Zhong G, Xu G, He W, Jing Z, Gao Z, Huang Y, Qi Y, Peng B, Wang H, Fu L, Song M, Chen P, Gao W, Ren B, Sun Y, Cai T, Feng X, Sui J, Li W (2012) Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. Elife 1:e000049. CrossRefGoogle Scholar
  13. 13.
    Ni Y, Lempp FA, Mehrle S, Nkongolo S, Kaufman C, Fälth M, Stindt J, Königer C, Nassal M, Kubitz R, Sültmann H, Urban S (2014) Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for species-specific entry into hepatocytes. Gastroenterology 146:1070–1083. CrossRefGoogle Scholar
  14. 14.
    Volz T, Allweiss L, Ben ḾBarek M, Warlich M, Lohse AW, Pollok JM, Alexandrov A, Urban S, Petersen J, Lütgehetmann M, Dandri M (2013) The entry inhibitor Myrcludex-B efficiently blocks intrahepatic virus spreading in humanized mice previously infected with hepatitis B virus. J Hepatol 58:861–867. CrossRefGoogle Scholar
  15. 15.
    Watashi K, Sluder A, Daito T, Matsunaga S, Ryo A, Nagamori S, Iwamoto M, Nakajima S, Tsukuda S, Borroto-Esoda K, Sugiyama M, Tanaka Y, Kanai Y, Kusuhara H, Mizokami M, Wakita T (2014) Cyclosporin A and its analogs inhibit hepatitis B virus entry into cultured hepatocytes through targeting a membrane transporter, sodium taurocholate cotransporting polypeptide (NTCP). Hepatology 59:1726–1737. CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Nkongolo S, Ni Y, Lempp FA, Kaufman C, Lindner T, Esser-Nobis K, Lohmann V, Mier W, Mehrle S, Urban S (2014) Cyclosporin A inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor. J Hepatol 60:723–731. CrossRefGoogle Scholar
  17. 17.
    Shimura S, Watashi K, Fukano K, Peel M, Sluder A, Kawai F, Iwamoto M, Tsukuda S, Takeuchi JS, Miyake T, Sugiyama M, Ogasawara Y, Park S, Tanaka Y, Kusuhara H, Mizokami M, Sureau C, Wakita T (2017) Cyclosporin derivatives inhibit hepatitis B virus entry without interfering with NTCP transporter activity. J Hepatol 66:685–692. CrossRefGoogle Scholar
  18. 18.
    Donkers JM, Zehnder B, Van Westen GJP, Kwakkenbos MJ, Ijzerman AP, Elferink RPJO, Beuers U, Urban S, van de Graaf SFJ (2017) Reduced hepatitis B and D viral entry using clinically applied drugs as novel inhibitors of the bile acid transporter NTCP. Sci Rep 7:1–13. CrossRefGoogle Scholar
  19. 19.
    Kaneko M, Futamura Y, Tsukuda S, Kondoh Y, Sekine T, Hirano H, Fukano K, Ohashi H, Saso W, Morishita R, Matsunaga S, Kawai F, Ryo A, Park S-Y, Suzuki R, Aizaki H, Ohtani N, Sureau C, Wakita T, Osada H, Watashi K (2018) Chemical array system, a platform to identify novel hepatitis B virus entry inhibitors targeting sodium taurocholate cotransporting polypeptide. Sci Rep 8:1–13. CrossRefGoogle Scholar
  20. 20.
    Verrier ER, Colpitts CC, Schuster C, Zeisel MB, Baumert TF (2016) Cell culture models for the investigation of Hepatitis B and D Virus infection. Viruses 8:1–10. CrossRefGoogle Scholar
  21. 21.
    Döring B, Lütteke T, Geyer J, Petzinger E (2012) The SLC10 carrier family: transport functions and molecular structure. Curr Top Membr 70:105–168. CrossRefPubMedGoogle Scholar
  22. 22.
    Esteller A (2008) Physiology of bile secretion. World J Gastroenterol 14:5641–5649. CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Podevin P, Rosmorduc O, Conti F, Calmus Y, Meier PJ, Poupon R (1999) Bile acids modulate the interferon signalling pathway. Hepatology 29:1840–1847CrossRefPubMedGoogle Scholar
  24. 24.
    Graf D, Haselow K, Münks I, Bode JG, Häussinger D (2010) Inhibition of interferon-a-induced signaling by hyperosmolarity and hydrophobic bile acids. Biol Chem 391:1175–1187. CrossRefPubMedGoogle Scholar
  25. 25.
    Slijepcevic D, van de Graaf FJ (2017) Bile acid uptake transporters as targets for therapy. Dig Dis 35:251–258. CrossRefPubMedPubMedCentralGoogle Scholar
  26. 26.
    Geyer J, Wilke T, Petzinger E (2006) The solute carrier family SLC10: more than a family of bile acid transporters regarding function and phylogenetic relationships. Naunyn-Schmiedeberg’s Arch Pharmacol 372:413–431. CrossRefGoogle Scholar
  27. 27.
    Hagenbuch B, Meier PJ (1994) Molecular cloning, chromosomal localization, and functional characterization of a human liver Na +/bile acid cotransporter. J Clin Invest 93:1326–1331CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Mukhopadhyay S, Ananthanarayanan M, Stieger B, Meier PJ, Suchy FJ, Anwer MS (1998) Sodium taurocholate cotransporting polypeptide is a serine, threonine phosphoprotein and is dephosphorylated by cyclic adenosine monophosphate. Hepatology 92:1629–1636CrossRefGoogle Scholar
  29. 29.
    da Silva TC, Polli JE, Swaan PW (2013) The solute carrier family 10 (SLC10): beyond bile acid transport. Mol Aspects Med 34:252–269. CrossRefPubMedCentralGoogle Scholar
  30. 30.
    Hu N-J, Iwata S, Cameron AD, Drew D (2011) Crystal structure of a bacterial homologue of the bile acid sodium symporter ASBT. Nature 478:408–411. CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Dawson PA (2011) Role of the intestinal bile acid transporters in bile acid and drug disposition. Handb Exp Pharmacol 201:169–203. CrossRefGoogle Scholar
  32. 32.
    Dong Z, Ekins S, Polli JE (2013) Structure activity relationship for FDA approved drugs as inhibitors of the human sodium taurocholate co-transporting polypeptide (NTCP). Mol Pharm 10:1008–1019. CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Chiang JYL (2003) Bile acid regulation of hepatic physiology III. Bile acids and nuclear receptors. Am J Physiol Gastrointest Liver Physiol 284:G349–G356CrossRefGoogle Scholar
  34. 34.
    Goodwin B, Jones SA, Price RR, Watson MA, Mckee DD, Moore LB, Galardi C, Wilson JG, Lewis MC, Roth ME, Maloney PR, Willson TM, Kliewer SA (2000) A regulatory cascade of the nuclear receptors FXR, SHP-1, and LRH-1 represses bile acid biosynthesis. Mol Cell 6:517–526CrossRefGoogle Scholar
  35. 35.
    Lu TT, Makishima M, Repa JJ, Schoonjans K, Kerr TA, Auwerx J, Mangelsdorf DJ (2000) Molecular basis for feedback regulation of bile acid synthesis by nuclear receptors. Mol Cell 6:507–515CrossRefGoogle Scholar
  36. 36.
    Jonker JW, Stedman CAM, Liddle C, Downes M (2009) Hepatobiliary ABC transporters: physiology, regulation and implications for disease. Front Biosci 14:4904–4920. CrossRefGoogle Scholar
  37. 37.
    Chiang JYL (2009) Bile acids: regulation of synthesis. J Lipid Res 50:1955–1966. CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Gerloff T, Stieger B, Hagenbuch B, Madon J, Landmann L, Roth J, Hofmann AF, Meier PJ (1998) The sister of P-glycoprotein represents the canalicular bile salt export pump of mammalian liver. J Biol Chem 273:10046–10050CrossRefGoogle Scholar
  39. 39.
    Ananthanarayanan M, Balasubramanian N, Makishima M, Mangelsdorf DJ, Suchy FJ (2001) Human bile salt export pump promoter is transactivated by the farnesoid X receptor/bile acid receptor. J Biol Chem 276:28857–28865. CrossRefGoogle Scholar
  40. 40.
    Denson LA, Sturm E, Echevarria W, Zimmerman TL, Makishima M, Mangelsdorf DJ, Karpen SJ (2001) The orphan nuclear receptor, shp, mediates bile acid-induced inhibition of the rat bile acid transporter, ntcp. Gastroenterology 121:140–147. CrossRefGoogle Scholar
  41. 41.
    Jung D, Hagenbuch B, Fried M, Meier PJ, Kullak-Ublick GA (2004) Role of liver-enriched transcription factors and nuclear receptors in regulating the human, mouse, and rat NTCP gene. Am J Physiol Gastrointest Liver Physiol 286:752–761CrossRefGoogle Scholar
  42. 42.
    Geier A, Martin IV, Dietrich CG, Balasubramaniyan N, Strauch S, Suchy FJ, Gartung C, Trautwein C, Ananthanarayanan M (2008) Hepatocyte nuclear factor-4a is a central transactivator of the mouse Ntcp gene. Am J Physiol Gastrointest Liver Physiol 295:226–233. CrossRefGoogle Scholar
  43. 43.
    Li D, Zimmerman TL, Thevananther S, Lee H-Y, Kurie JM, Karpen SJ (2002) Interleukin-1b-mediated suppression of RXR:RAR transactivation of the Ntcp promoter Is JNK-dependent. J Biol Chem 277:31416–31422. CrossRefGoogle Scholar
  44. 44.
    Siewert E, Dietrich CG, Lammert F, Heinrich PC, Matern S, Gartung C, Geier A (2004) Interleukin-6 regulates hepatic transporters during acute-phase response. Biochem Biophys Res Commun 322:232–238. CrossRefGoogle Scholar
  45. 45.
    Le Vee M, Lecureur V, Stieger B, Fardel O (2009) Regulation of drug transporter expression in human hepatocytes exposed to the proinflammatory cytokines tumor necrosis factor-a or interleukin-6. Drug Metab Dispos 37:685–693. CrossRefGoogle Scholar
  46. 46.
    Zollner G, Fickert P, Silbert D, Fuchsbichler A, Marschall H-U, Zatloukal K, Denk H, Trauner M (2003) Adaptive changes in hepatobiliary transporter expression in primary biliary cirrhosis. J Hepatol 38:717–727. CrossRefGoogle Scholar
  47. 47.
    Kojima H, Nies AT, König J, Hagmann W, Spring H, Uemura M, Fukui H, Keppler D (2003) Changes in the expression and localization of hepatocellular transporters and radixin in primary biliary cirrhosis. J Hepatol 39:693–702. CrossRefGoogle Scholar
  48. 48.
    Kang J, Wang J, Cheng J, Cao Z, Chen R, Li H, Liu S, Chen X, Sui J, Lu F (2017) Down-regulation of NTCP expression by cyclin D1 in hepatitis B virus-related hepatocellular carcinoma has clinical significance. Oncotarget 8:56041–56050Google Scholar
  49. 49.
    Anwer MS (2014) Role of protein kinase C isoforms in bile formation and cholestasis. Hepatology 60:1090–1097. CrossRefPubMedPubMedCentralGoogle Scholar
  50. 50.
    Grüne S, Engelking LR, Anwer MS (1993) Role of intracellular calcium and protein kinases in the activation of hepatic Na +/taurocholate cotransport by cyclic AMP. J Biol Chem 268:17734–17741Google Scholar
  51. 51.
    Webster CRL, Blanch C, Anwer MS (2002) Role of PP2B in cAMP-induced dephosphorylation and translocation of NTCP. Am J Physiol Gastrointest Liver Physiol 283:G44–G50CrossRefGoogle Scholar
  52. 52.
    Anwer MS, Gillin H, Mukhopadhyay S, Balasubramaniyan N, Suchy FJ, Ananthanarayanan M (2005) Dephosphorylation of Ser-226 facilitates plasma membrane retention of Ntcp. J Biol Chem 280:33687–33692. CrossRefGoogle Scholar
  53. 53.
    Ho RH, Leake BF, Roberts RL, Lee W, Kim RB (2004) Ethnicity-dependent polymorphism in Na+ -taurocholate cotransporting polypeptide (SLC10A1) reveals a domain critical for bile acid substrate recognition. J Biol Chem 279:7213–7222. CrossRefGoogle Scholar
  54. 54.
    Pan W, Song I-S, Shin H-J, Kim M-H, Choi Y-L, Lim J, Kim W-Y, Lee S-S, Shin J-G (2011) Genetic polymorphisms in Na+ -taurocholate co-transporting polypeptide (NTCP) and ileal apical sodium-dependent bile acid transporter (ASBT) and ethnic comparisons of functional variants of NTCP among Asian populations. Xenobiotica 41:501–510. CrossRefGoogle Scholar
  55. 55.
    Sureau C, Guerra B, Lanford RE (1993) Role of the large hepatitis B virus envelope protein in infectivity of the hepatitis delta virion. J Virol 67:366–372PubMedPubMedCentralGoogle Scholar
  56. 56.
    Nassal M (2015) HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut 64:1972–1984. CrossRefGoogle Scholar
  57. 57.
    Lucifora J, Protzer U (2016) Attacking hepatitis B virus cccDNA—the holy grail to hepatitis B cure. J Hepatol 64:S41–S48. CrossRefGoogle Scholar
  58. 58.
    Rizzetto M, Hoyer B, Canese MG, Shih JW, Purcellt RH, Gerin JL (1980) Delta agent: association of delta antigen with hepatitis B surface antigen and RNA in serum of delta-infected chimpanzees. PNAS 77:6124–6128CrossRefGoogle Scholar
  59. 59.
    Sureau C, Negro F (2016) The hepatitis delta virus: replication and pathogenesis. J Hepatol 64:S102–S116. CrossRefGoogle Scholar
  60. 60.
    Marsh M, Helenius A (2006) Virus entry: open sesame. Cell 124:729–740. CrossRefGoogle Scholar
  61. 61.
    Abou Jaoude G, Sureau C (2005) Role of the antigenic loop of the hepatitis B virus envelope proteins in infectivity of hepatitis delta virus. J Virol 79:10460–10466. CrossRefGoogle Scholar
  62. 62.
    Abou Jaoude G, Sureau C (2007) Entry of hepatitis delta virus requires the conserved cysteine residues of the hepatitis B virus envelope protein antigenic loop and is blocked by inhibitors of thiol-disulfide exchange. J Virol 81:13057–13066. CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Persing DH, Varmus HE, Ganem DON (1987) The preS1 protein of hepatitis B virus is acylated at its amino terminus with myristic acid. J Virol 61:1672–1677PubMedPubMedCentralGoogle Scholar
  64. 64.
    Gripon P, Seyec JLE, Rumin S, Guguen-Guillouzo C (1995) Myristylation of the hepatitis B virus large surface protein is essential for viral infectivity. Virology 213:292–299CrossRefGoogle Scholar
  65. 65.
    Bruss V, Hagelstein J, Gerhardt E, Galle PR (1996) Myristylation of the large surface protein is required for hepatitis B virus in vitro infectivity. Virology 218:396–399CrossRefGoogle Scholar
  66. 66.
    Gripon P, Rumin S, Urban S, Le Seyec J, Glaise D, Cannie I, Guyomard C, Lucas J, Trepo C, Guguen-Guillouzo C (2002) Infection of a human hepatoma cell line by hepatitis B virus. Proc Natl Acad Sci USA. 99:15655–15660. CrossRefGoogle Scholar
  67. 67.
    Spillmann D (2001) Heparan sulfate: Anchor for viral intruders? Biochimie 83:811–817CrossRefGoogle Scholar
  68. 68.
    Bartlett AH, Park PW (2015) Proteoglycans in host–pathogen interactions: molecular mechanisms and therapeutic implications. Expert Rev Mol Med 12:e5. CrossRefGoogle Scholar
  69. 69.
    Schulze A, Gripon P, Urban S (2007) Hepatitis B virus infection initiates with a large surface protein-dependent binding to heparan sulfate proteoglycans. Hepatology 46:1759–1768. CrossRefGoogle Scholar
  70. 70.
    Sureau C, Salisse J (2013) A conformational heparan sulfate binding site essential to infectivity overlaps with the conserved hepatitis B virus a-determinant. Hepatology 57:985–994. CrossRefGoogle Scholar
  71. 71.
    Verrier ER, Colpitts CC, Bach C, Heydmann L, Weiss A, Renaud M, Durand SC, Habersetzer F, Durantel D, Abou-Jaoudé G, López Ledesma MM, Felmlee DJ, Soumillon M, Croonenborghs T, Pochet N, Nassal M, Schuster C, Brino L, Sureau C, Zeisel MB, Baumert TF (2016) A targeted functional RNA interference screen uncovers glypican 5 as an entry factor for hepatitis B and D viruses. Hepatology 63:35–48. CrossRefGoogle Scholar
  72. 72.
    Leistner CM, Gruen-Bernhard S, Glebe D (2008) Role of glycosaminoglycans for binding and infection of hepatitis B virus. Cell Microbiol 10:122–133. CrossRefGoogle Scholar
  73. 73.
    Neurath AR, Kent SBH, Strick N, Parker K (1986) Identification and chemical synthesis of a host cell receptor binding site on hepatitis B virus. Cell 46:429–436CrossRefGoogle Scholar
  74. 74.
    Neurath BAR, Strick N, Sproul P (1992) Search for hepatitis B virus cell receptors reveals binding sites for interleukin 6 on the virus envelope protein. J Exp Med 175:461–469CrossRefPubMedPubMedCentralGoogle Scholar
  75. 75.
    Pontisso P, Ruvoletto MG, Tiribelli C, Gerlich WH, Ruop A, Alberti A (1992) The preS1 domain of hepatitis B virus and IgA cross-react in their binding to the hepatocyte surface. J Gen Virol 73:2041–2045CrossRefGoogle Scholar
  76. 76.
    Ryu CJ, Cho D, Gripon P, Kim HS, Guguen-Guillouzo C, Hong HJ (2000) An 80-kilodalton protein that binds to the Pre-S1 domain of hepatitis B virus. J Virol 74:110–116CrossRefPubMedPubMedCentralGoogle Scholar
  77. 77.
    De Falco S, Ruvoletto MG, Verdoliva A, Ruvo M, Raucci A, Marino M, Senatore S, Cassani G, Alberti A, Pontisso P, Fassina G (2001) Cloning and expression of a novel hepatitis B virus-binding protein from HepG2 cells. J Biol Chem 276:36613–36623. CrossRefGoogle Scholar
  78. 78.
    Li D, Wang XZ, Ding J, Yu J-P (2005) NACA as a potential cellular target of hepatitis B virus PreS1 protein. Dig Dis Sci 50:1156–1160. CrossRefGoogle Scholar
  79. 79.
    Zhong G, Yan H, Wang H, He W, Jing Z, Qi Y, Fu L, Gao Z, Huang Y, Xu G, Feng X, Sui J, Li W (2013) Sodium taurocholate cotransporting polypeptide mediates woolly monkey hepatitis B virus infection of tupaia hepatocytes. J Virol 87:7176–7184. CrossRefPubMedPubMedCentralGoogle Scholar
  80. 80.
    Peng L, Zhao Q, Li Q, Li M, Li C, Xu T, Jing X, Zhu X, Wang Y, Li F, Liu R, Zhong C, Pan Q, Zeng B, Liao Q, Hu B, Hu Z, Huang Y, Sham P, Liu J, Xu S, Wang J, Gao Z, Wang Y (2015) The p.Ser267Phe variant in SLC10A1 is associated with resistance to chronic hepatitis B. Hepatology 61:1251–1260. CrossRefGoogle Scholar
  81. 81.
    Lee HW, Park HJ, Jin B, Dezhbord M, Kim DY, Han KH, Ryu WS, Kim S, Ahn SH (2017) Effect of S267F variant of NTCP on the patients with chronic hepatitis B. Sci Rep 7:1–7. CrossRefGoogle Scholar
  82. 82.
    An P, Zeng Z, Winkler CA (2018) The loss-of-function S267F variant in HBV receptor NTCP reduces human risk to HBV infection and disease progression. J Infect Dis. CrossRefGoogle Scholar
  83. 83.
    Hu H, Liu J, Lin Y-L, Luo W, Chu Y-J, Chang C-L, Jen C-L, Lee M-H, Lu S-N, Wang L-Y, You S-L, Yang H-I, Chen C-J (2016) The rs2296651 (S267F) variant on NTCP (SLC10A1) is inversely associated with chronic hepatitis B and progression to cirrhosis and hepatocellular carcinoma in patients with chronic hepatitis B. Gut 65:1514–1521. CrossRefGoogle Scholar
  84. 84.
    Zollner G, Wagner M, Fickert P, Silbert D, Fuchsbichler A, Zatloukal K, Denk H, Trauner M (2005) Hepatobiliary transporter expression in human hepatocellular carcinoma. Liver Int 25:367–379. CrossRefGoogle Scholar
  85. 85.
    Gripon P, Diot C, Theze N, Fourel I, Loreal O, Brechot C, Guguen-Guillouzo C (1988) Hepatitis B virus infection of adult human hepatocytes cultured in the presence of dimethyl sulfoxide. J Virol 62:4136–4143PubMedPubMedCentralGoogle Scholar
  86. 86.
    Lempp FA, Wiedtke E, Qu B, Roques P, Chemin I, Vondran FWR, Le Grand R, Grimm D, Urban S (2017) Sodium taurocholate cotransporting polypeptide is the limiting host factor of hepatitis B virus infection in macaque and pig hepatocytes. Hepatology 66:703–716CrossRefGoogle Scholar
  87. 87.
    Allweiss L, Dandri M (2016) Experimental in vitro and in vivo models for the study of human hepatitis B virus infection. J Hepatol 64:S17–S31. CrossRefGoogle Scholar
  88. 88.
    He W, Ren B, Mao F, Jing Z, Li Y, Liu Y, Peng B, Yan H, Qi Y, Sun Y, Guo J-T, Sui J, Wang F, Li W (2015) Hepatitis D virus infection of mice expressing human sodium taurocholate co-transporting polypeptide. PLoS Pathog 11:1–17. CrossRefGoogle Scholar
  89. 89.
    Lempp FA, Mutz P, Lipps C, Wirth D, Bartenschlager R, Urban S (2016) Evidence that hepatitis B virus replication in mouse cells is limited by the lack of a host cell dependency factor. J Hepatol 64:556–564. CrossRefGoogle Scholar
  90. 90.
    Burwitz BJ, Wettengel JM, Mück-Häusl MA, Ringelhan M, Ko C, Festag MM, Hammond KB, Northrup M, Bimber BN, Jacob T, Reed JS, Norris R, Park B, Moller-Tank S, Esser K, Greene JM, Wu HL, Abdulhaqq S, Webb G, Sutton WF, Klug A, Swanson T, Legasse AW, Vu TQ, Asokan A, Haigwood NL, Protzer U, Sacha JB (2017) Hepatocytic expression of human sodium-taurocholate cotransporting polypeptide enables hepatitis B virus infection of macaques. Nat Commun 8:1–10. CrossRefGoogle Scholar
  91. 91.
    Gripon P, Cannie I, Urban S (2005) Efficient inhibition of hepatitis B virus infection by acylated peptides derived from the large viral surface protein. J Virol 79:1613–1622. CrossRefPubMedPubMedCentralGoogle Scholar
  92. 92.
    Petersen J, Dandri M, Mier W, Lütgehetmann M, Volz T, von Weizsäcker F, Haberkorn U, Fischer L, Pollok J-M, Erbes B, Seitz S, Urban S (2008) Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat Biotechnol 26:335–341. CrossRefPubMedGoogle Scholar
  93. 93.
    Blank A, Markert C, Hohmann N, Carls A, Mikus G, Lehr T, Alexandrov A, Haag M, Schwab M, Urban S, Haefeli WE (2016) First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor myrcludex B. J Hepatol 65:483–489. CrossRefPubMedGoogle Scholar
  94. 94.
    Bogomolov P, Alexandrov A, Voronkova N, Macievich M, Kokina K, Petrachenkova M, Lehr T, Lempp FA, Wedemeyer H, Haag M, Schwab M, Haefeli WE, Blank A, Urban S (2016) Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study. J Hepatol 65:490–498. CrossRefGoogle Scholar
  95. 95.
    Wedemeyer H, Bogomolov P, Blank A, Allweiss L, Dandri-Petersen M, Bremer B, Voronkova N, Schöneweis K, Pathil A, Burhenne J, Haag M, Schwab M, Haefeli W-E, Wiesch JSZ, Alexandrov A, Urban S (2018) Final results of a multicenter, open-label phase 2b clinical trial to assess safety and efficacy of Myrcludex B in combination with Tenofovir in patients with chronic HBV/HDV co-infection. J Hepatol 68:S3CrossRefGoogle Scholar
  96. 96.
    König A, Döring B, Mohr C, Geipel A, Geyer J, Glebe D (2014) Kinetics of the bile acid transporter and hepatitis B virus receptor Na +/taurocholate cotransporting polypeptide (NTCP) in hepatocytes. J Hepatol 61:867–875. CrossRefGoogle Scholar
  97. 97.
    Blanchet M, Sureau C, Labonté P (2014) Use of FDA approved therapeutics with hNTCP metabolic inhibitory properties to impair the HDV lifecycle. Antivir Res 106:111–115. CrossRefGoogle Scholar
  98. 98.
    Lucifora J, Esser K, Protzer U (2013) Ezetimibe blocks hepatitis B virus infection after virus uptake into hepatocytes. Antivir Res 97:195–197. CrossRefGoogle Scholar
  99. 99.
    Azer SA, Stacey H (1993) Differential effects of Cyclosporin A on the transport of bile acids by human hepatocytes. Biochem Pharmacol 46:813–819CrossRefGoogle Scholar
  100. 100.
    Mita S, Suzuki H, Akita H, Hayashi H, Onuki R, Hofmann AF, Sugiyama Y (2006) Inhibition of bile acid transport across Na +/taurocholate cotransporting polypeptide (SLC10A1) and bile salt export pump (ABCB 11)-coexpressing LLC-PK1 cells by cholestasis-inducing drugs. Drug Metab Dispos 34:1575–1581. CrossRefPubMedGoogle Scholar
  101. 101.
    Slijepcevic D, Kaufman C, Wichers CGK, Gilglioni EH, Lempp FA, Duijst S, de Waart DR, Oude Elferink RPJ, Mier W, Stieger B, Beuers U, Urban S, van de Graaf SFJ (2015) Impaired uptake of conjugated bile acids and hepatitis B virus Pres1-binding in Na+ -taurocholate cotransporting polypeptide knockout mice. Hepatology 62:207–219. CrossRefPubMedPubMedCentralGoogle Scholar
  102. 102.
    Vaz M, Paulusma CC, Huidekoper H, De RuM, Lim C, Koster J, Ho-Mok K, Bootsma AH, Groen AK, Schaap FG, Oude Elferink RPJ, Waterham HR, Wanders RJA (2015) Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype. Hepatology 61:260–267. CrossRefPubMedGoogle Scholar
  103. 103.
    Tsukuda S, Watashi K, Hojima T, Isogawa M, Iwamoto M, Omagari K, Suzuki R, Aizaki H, Kojima S, Sugiyama M, Saito A, Tanaka Y, Mizokami M, Sureau C, Wakita T (2017) A new class of hepatitis B and D virus entry inhibitors, proanthocyanidin and its analogs, that directly act on the viral large surface proteins. Hepatology 65:1104–1116. CrossRefPubMedGoogle Scholar
  104. 104.
    Khan AG, Whidby J, Miller MT, Scarborough H, Zatorski AV, Cygan A, Price AA, Yost SA, Bohannon CD, Jacob J, Grakoui A, Marcotrigiano J (2014) Structure of the core ectodomain of the hepatitis C virus envelope glycoprotein 2. Nature 509:381–384. CrossRefPubMedPubMedCentralGoogle Scholar
  105. 105.
    Barth H, Schäfer C, Adah MI, Zhang F, Linhardt RJ, Toyoda H, Kinoshita-Toyoda A, Toida T, van Kuppevelt TH, Depla E, von Weizsäcker F, Blum HE, Baumert TF (2003) Cellular binding of hepatitis C virus envelope glycoprotein E2 requires cell surface heparan sulfate. J Biol Chem 278:41003–41012. CrossRefPubMedGoogle Scholar
  106. 106.
    Shi Q, Jiang J, Luo G (2013) Syndecan-1 serves as the major receptor for attachment of hepatitis C virus to the surfaces of hepatocytes. J Virol 87:6866–6875. CrossRefPubMedPubMedCentralGoogle Scholar
  107. 107.
    Lefevre M, Felmlee DJ, Parnot M, Baumert TF, Schuster C (2014) Syndecan 4 is involved in mediating HCV entry through interaction with lipoviral particle-associated apolipoprotein E. PLoS One 9:3–10. CrossRefGoogle Scholar
  108. 108.
    Pileri P, Uematsu Y, Campagnoli S, Galli G, Falugi F, Petracca R, Weiner AJ, Houghton M, Rosa D, Grandi G, Abrignani S (1998) Binding of hepatitis C virus to CD81. Science 282:938–942 (80-.) CrossRefPubMedGoogle Scholar
  109. 109.
    Owen DM, Huang H, Ye J, Gale M Jr (2010) Apolipoprotein E on hepatitis C virion facilitates infection through interaction with low density lipoprotein receptor. Virology 394:99–108. CrossRefGoogle Scholar
  110. 110.
    Zeisel MB, Koutsoudakis G, Schnober EK, Haberstroh A, Blum HE, Cosset F-L, Wakita T, Jaeck D, Doffoel M, Royer C, Soulier E, Schvoerer E, Schuster C, Stoll-Keller F, Bartenschlager R, Pietschmann T, Barth H, Baumert TF (2007) Scavenger receptor class B Type I is a key host factor for hepatitis C virus infection required for an entry step closely linked to CD81. Hepatology 46:1–3. CrossRefGoogle Scholar
  111. 111.
    Lupberger J, Zeisel MB, Xiao F, Thumann C, Fofana I, Zona L, Davis C, Mee CJ, Turek M, Gorke S, Royer C, Fischer B, Zahid MN, Lavillette D, Fresquet J, Cosset F-L, Rothenberg SM, Pietschmann T, Patel AH, Pessaux P, Doffoël M, Raffelsberger W, Poch O, McKeating JA, Brino L, Baumert TF (2011) EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat Med 17:589–595. CrossRefPubMedPubMedCentralGoogle Scholar
  112. 112.
    Farquhar MJ, Hu K, Harris HJ, Davis C, Brimacombe CL, Fletcher SJ, Baumert TF, Rappoport JZ, Balfe P, McKeating JA (2012) Hepatitis C virus induces CD81 and Claudin-1 endocytosis. J Virol 86:4305–4316. CrossRefPubMedPubMedCentralGoogle Scholar
  113. 113.
    Dubuisson J, Cosset F-L (2014) Virology and cell biology of the hepatitis C virus life cycle—An update. J Hepatol 61:S3–S13. CrossRefGoogle Scholar
  114. 114.
    Verrier ER, Colpitts CC, Bach C, Heydmann L, Zona L, Xiao F, Thumann C, Crouchet E, Gaudin R, Sureau C, Cosset F-L, McKeating JA, Pessaux P, Hoshida Y, Schuster C, Zeisel MB, Baumert TF (2016) Solute carrier NTCP regulates innate antiviral immune responses targeting hepatitis C virus infection of hepatocytes. Cell Rep 17:1357–1368. CrossRefPubMedPubMedCentralGoogle Scholar
  115. 115.
    Smith SE, Weston S, Kellam P, Marsh M (2014) IFITM proteins—cellular inhibitors of viral entry. Curr Opin Virol 4:71–77. CrossRefGoogle Scholar
  116. 116.
    Wilkins C, Woodward J, Lau DT-Y, Barnes A, Joyce M, McFarlane N, McKeating J, Tyrrell DL, Gale M Jr (2013) IFITM1 is a tight junction protein that inhibits hepatitis C virus entry. Hepatology 57:461–469. CrossRefGoogle Scholar
  117. 117.
    Narayana SK, Helbig KJ, Mccartney EM, Eyre NS, Bull RA, Eltahla A, Lloyd AR, Beard MR (2015) The interferon-induced transmembrane proteins, IFITM1, IFITM2, and IFITM3 inhibit hepatitis C virus entry. J Biol Chem 290:25946–25959. CrossRefPubMedPubMedCentralGoogle Scholar
  118. 118.
    Chang K-O, George DW (2007) Bile acids promote the expression of hepatitis C virus in replicon-harboring cells. J Virol 81:9633–9640. CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Nature Switzerland AG 2018

Authors and Affiliations

  1. 1.Inserm, U1110Institut de Recherche sur les Maladies Virales et HépatiquesStrasbourgFrance
  2. 2.Université de StrasbourgStrasbourgFrance
  3. 3.Division of Infection and ImmunityUniversity College LondonLondonUK
  4. 4.Institut Hospitalo-Universitaire, Pôle Hépato-digestifNouvel Hôpital CivilStrasbourgFrance

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