Skip to main content
SpringerLink
Log in
Book cover

Gene Therapy for HIV and Chronic Infections pp 1–29Cite as

Gene Therapies for Hepatitis C Virus

  • Chapter
  • First Online:

Part of the book series: Advances in Experimental Medicine and Biology ((ASGCT,volume 848))

Abstract

Hepatitis C virus (HCV) is a leading cause of chronic hepatitis and infects approximately three to four million people per year, about 170 million infected people in total, making it one of the major global health problems. In a minority of cases HCV is cleared spontaneously, but in most of the infected individuals infection progresses to a chronic state associated with high risk to develop liver cirrhosis, hepatocellular cancer, or liver failure. The treatment of HCV infection has evolved over the years. Interferon (IFN)-α in combination with ribavirin has been used for decades as standard therapy. More recently, a new standard-of-care treatment has been approved based on a triple combination with either HCV protease inhibitor telaprevir or boceprevir. In addition, various options for all-oral, IFN-free regimens are currently being evaluated. Despite substantial improvement of sustained virological response rates, some intrinsic limitations of these new direct-acting antivirals, including serious side effects, the risk of resistance development and high cost, urge the development of alternative or additional therapeutic strategies. Gene therapy represents a feasible alternative treatment. Small RNA technology, including RNA interference (RNAi) techniques and antisense approaches, is one of the potentially promising ways to investigate viral and host cell factors that are involved in HCV infection and replication. With this, newly developed gene therapy regimens will be provided to treat HCV. In this chapter, a comprehensive overview guides you through the current developments and applications of RNAi and microRNA-based gene therapy strategies in HCV treatment.

This is a preview of subscription content, log in via an institution.

Chapter
USD   29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD   84.99
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD   109.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD   109.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Learn about institutional subscriptions

Abbreviations

A1AT:

Alpha-1 anti-trypsin

AAV:

Adeno-associated viruses

DAA:

Directly acting antiviral agents

HCC:

Hepatocellular cancer

HCV:

Hepatitis C virus

IFN-α:

Interferon α

IRES:

Internal ribosome entry site

LDL-R:

Low-density lipoprotein receptor

LNA:

Locked nucleic acid

miRNA:

micro RNA

NS:

Non-structural

ORF:

Open reading frame

RdRp:

RNA-dependent RNA polymerase

RISC:

RNA induced silencing complex

RNAi:

RNA interference

scAAV:

Self-complementary adeno-associated viruses

shRNA:

Short hairpin RNA

siRNA:

Short interference RNA

SVR:

Sustained virological response

UTR:

Untranslated region

References

  1. Ray R. Progress toward development of a hepatitis C vaccine with broad shoulders. Sci Transl Med. 2011;3(94):94ps33.

    CAS  PubMed  Google Scholar 

  2. Lagging LM, Meyer K, Owens RJ, Ray R. Functional role of hepatitis C virus chimeric glycoproteins in the infectivity of pseudotyped virus. J Virol. 1998;72(5):3539–46.

    CAS  PubMed Central  PubMed  Google Scholar 

  3. Garrone P, Fluckiger A-C, Mangeot PE, Gauthier E, Dupeyrot-Lacas P, Mancip J, et al. A prime-boost strategy using virus-like particles pseudotyped for HCV proteins triggers broadly neutralizing antibodies in macaques. Sci Transl Med. 2011;3(94):94ra71.

    CAS  PubMed  Google Scholar 

  4. Zeuzem S, Buti M, Ferenci P, Sperl J, Horsmans Y, Cianciara J, et al. Efficacy of 24 weeks treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C infected with genotype 1 and low pretreatment viremia. J Hepatol. 2006;44(1):97–103.

    CAS  PubMed  Google Scholar 

  5. Davis GL, Wong JB, McHutchison JG, Manns MP, Harvey J, Albrecht J. Early virologic response to treatment with peginterferon alfa-2b plus ribavirin in patients with chronic hepatitis C. Hepatology. 2003;38(3):645–52.

    CAS  PubMed  Google Scholar 

  6. Sarbah SA, Younossi ZM. Hepatitis C: an update on the silent epidemic. J Clin Gastroenterol. 2000;30(2):125–43.

    CAS  PubMed  Google Scholar 

  7. Sarin S, Kumar M. Natural history of HCV infection. Hepatol Int. 2012;6(4):684–95.

    Google Scholar 

  8. Ryder SD. Progression of hepatic fibrosis in patients with hepatitis C: a prospective repeat liver biopsy study. Gut. 2004;53(3):451–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  9. Nakano T, Lau GMG, Lau GML, Sugiyama M, Mizokami M. An updated analysis of hepatitis C virus genotypes and subtypes based on the complete coding region. Liver Int. 2012;32(2):339–45.

    CAS  PubMed  Google Scholar 

  10. Lamarre D, Anderson PC, Bailey M, Beaulieu P, Bolger G, Bonneau P, et al. An NS3 protease inhibitor with antiviral effects in humans infected with hepatitis C virus. Nature. 2003;426(6963):186–9.

    CAS  PubMed  Google Scholar 

  11. Njoroge FG, Chen KX, Shih N-Y, Piwinski JJ. Challenges in modern drug discovery: a case study of boceprevir, an HCV protease inhibitor for the treatment of hepatitis C virus infection. Acc Chem Res. 2008;41(1):50–9.

    CAS  PubMed  Google Scholar 

  12. Gao M, Nettles RE, Belema M, Snyder LB, Nguyen VN, Fridell RA, et al. Chemical genetics strategy identifies an HCV NS5A inhibitor with a potent clinical effect. Nature. 2010;465(7294):96–100.

    CAS  PubMed  Google Scholar 

  13. Chatel-Chaix L, Baril M, Lamarre D. Hepatitis C virus NS3/4A protease inhibitors: a light at the end of the tunnel. Viruses. 2010;2(8):1752–65.

    CAS  PubMed Central  PubMed  Google Scholar 

  14. Chou R, Hartung D, Rahman B, Wasson N, Cottrell EB, Fu R. Comparative effectiveness of antiviral treatment for hepatitis C virus infection in adults: a systematic review. Ann Intern Med. 2013;158(2):114–23.

    PubMed  Google Scholar 

  15. Flego M, Ascione A, Cianfriglia M, Vella S. Clinical development of monoclonal antibody-based drugs in HIV and HCV diseases. BMC Med. 2013;11(1):4.

    PubMed Central  PubMed  Google Scholar 

  16. Fire A, Xu S, Montgomery MK, Kostas SA, Driver SE, Mello CC. Potent and specific genetic interference by double-stranded RNA in Caenorhabditis elegans. Nature. 1998;391(6669):806–11.

    CAS  PubMed  Google Scholar 

  17. Choo QL, Richman KH, Han JH, Berger K, Lee C, Dong C, et al. Genetic organization and diversity of the hepatitis C virus. Proc Natl Acad Sci. 1991;88(6):2451–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  18. Tsukiyama-Kohara K, Iizuka N, Kohara M, Nomoto A. Internal ribosome entry site within hepatitis C virus RNA. J Virol. 1992;66(3):1476–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  19. Lindenbach BD, Rice CM. Unravelling hepatitis C virus replication from genome to function. Nature. 2005;436(7053):933–8.

    CAS  PubMed  Google Scholar 

  20. Penin F, Dubuisson J, Rey FA, Moradpour D, Pawlotsky J-M. Structural biology of hepatitis C virus. Hepatology. 2004;39(1):5–19.

    CAS  PubMed  Google Scholar 

  21. Penin F, Brass V, Appel N, Ramboarina S, Montserret R, Ficheux D, et al. Structure and function of the membrane anchor domain of hepatitis C virus nonstructural protein 5A. J Biol Chem. 2004;279(39):40835–43.

    CAS  PubMed  Google Scholar 

  22. Giannini C, Brechot C. Hepatitis C virus biology. Cell Death Differ. 2003;10(S1):S27–38.

    CAS  PubMed  Google Scholar 

  23. Selby MJ, Choo Q-L, Berger K, Kuo G, Glazer E, Eckart M, et al. Expression, identification and subcellular localization of the proteins encoded by the hepatitis C viral genome. J Gen Virol. 1993;74(6):1103–13.

    CAS  PubMed  Google Scholar 

  24. Lohmann V, Körner F, Koch JO, Herian U, Theilmann L, Bartenschlager R. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science. 1999;285(5424):110–3.

    CAS  PubMed  Google Scholar 

  25. Harada S, Watanabe Y, Takeuchi K, Suzuki T, Katayama T, Takebe Y, et al. Expression of processed core protein of hepatitis C virus in mammalian cells. J Virol. 1991;65(6):3015–21.

    CAS  PubMed Central  PubMed  Google Scholar 

  26. Takeuchi K, Kubo Y, Boonmar S, Watanabe Y, Katayama T, Choo Q-L, et al. The putative nucleocapsid and envelope protein genes of hepatitis C virus determined by comparison of the nucleotide sequences of two isolates derived from an experimentally infected chimpanzee and healthy human carriers. J Gen Virol. 1990;71(12):3027–33.

    CAS  PubMed  Google Scholar 

  27. Griffin SDC, Beales LP, Clarke DS, Worsfold O, Evans SD, Jaeger J, et al. The p7 protein of hepatitis C virus forms an ion channel that is blocked by the antiviral drug, Amantadine. FEBS Lett. 2003;535(1–3):34–8.

    CAS  PubMed  Google Scholar 

  28. Pavlović D, Neville DCA, Argaud O, Blumberg B, Dwek RA, Fischer WB, et al. The hepatitis C virus p7 protein forms an ion channel that is inhibited by long-alkyl-chain iminosugar derivatives. Proc Natl Acad Sci. 2003;100(10):6104–8.

    PubMed Central  PubMed  Google Scholar 

  29. Okamoto K, Moriishi K, Miyamura T, Matsuura Y. Intramembrane proteolysis and endoplasmic reticulum retention of hepatitis C virus core protein. J Virol. 2004;78(12):6370–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  30. Lemberg MK, Martoglio B. Requirements for signal peptide peptidase-catalyzed intramembrane proteolysis. Mol Cell. 2002;10(4):735–44.

    CAS  PubMed  Google Scholar 

  31. Bartenschlager R, Ahlborn-Laake L, Mous J, Jacobsen H. Kinetic and structural analyses of hepatitis C virus polyprotein processing. J Virol. 1994;68(8):5045–55.

    CAS  PubMed Central  PubMed  Google Scholar 

  32. Pallaoro M, Lahm A, Biasiol G, Brunetti M, Nardella C, Orsatti L, et al. Characterization of the hepatitis C virus NS2/3 processing reaction by using a purified precursor protein. J Virol. 2001;75(20):9939–46.

    CAS  PubMed Central  PubMed  Google Scholar 

  33. Simmonds P, Bukh J, Combet C, Deléage G, Enomoto N, Feinstone S, et al. Consensus proposals for a unified system of nomenclature of hepatitis C virus genotypes. Hepatology. 2005;42(4):962–73.

    CAS  PubMed  Google Scholar 

  34. Farci P. New insights into the HCV quasispecies and compartmentalization. Semin Liver Dis. 2011;31(04):356–74.

    CAS  PubMed  Google Scholar 

  35. Smith DB, Mellor J, Jarvis LM, Davidson F, Kolberg J, Urdea M, et al. Variation of the hepatitis C virus 5′ non-coding region: implications for secondary structure, virus detection and typing. J Gen Virol. 1995;76(7):1749–61.

    CAS  PubMed  Google Scholar 

  36. Okamoto H, Kurai K, Okada S-I, Yamamoto K, Lizuka H, Tanaka T, et al. Full-length sequence of a hepatitis C virus genome having poor homology to reported isolates: comparative study of four distinct genotypes. Virology. 1992;188(1):331–41.

    CAS  PubMed  Google Scholar 

  37. Kato N, Hijikata M, Ootsuyama Y, Nakagawa M, Ohkoshi S, Sugimura T, et al. Molecular cloning of the human hepatitis C virus genome from Japanese patients with non-A, non-B hepatitis. Proc Natl Acad Sci. 1990;87(24):9524–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  38. Okamoto H, Okada S, Sugiyama Y, Kurai K, Iizuka H, Machida A, et al. Nucleotide sequence of the genomic RNA of hepatitis C virus isolated from a human carrier: comparison with reported isolates for conserved and divergent regions. J Gen Virol. 1991;72(11):2697–704.

    CAS  PubMed  Google Scholar 

  39. Sakamoto M, Akahane Y, Tsuda F, Tanaka T, Woodfield DG, Okamoto H. Entire nucleotide sequence and characterization of a hepatitis C virus of genotype V/3a. J Gen Virol. 1994;75(7):1761–8.

    CAS  PubMed  Google Scholar 

  40. Bartosch B, Dubuisson J, Cosset F-L. Infectious hepatitis C virus pseudo-particles containing functional E1–E2 envelope protein complexes. J Exp Med. 2003;197(5):633–42.

    CAS  PubMed Central  PubMed  Google Scholar 

  41. Petracca R, Falugi F, Galli G, Norais N, Rosa D, Campagnoli S, et al. Structure-function analysis of hepatitis C virus envelope-CD81 binding. J Virol. 2000;74(10):4824–30.

    CAS  PubMed Central  PubMed  Google Scholar 

  42. Kapadia SB, Barth H, Baumert T, McKeating JA, Chisari FV. Initiation of hepatitis C virus infection is dependent on cholesterol and cooperativity between CD81 and scavenger receptor B type I. J Virol. 2007;81(1):374–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  43. Barth H, Schäfer C, Adah MI, Zhang F, Linhardt RJ, Toyoda H, et al. Cellular binding of hepatitis C virus envelope glycoprotein E2 requires cell surface heparan sulfate. J Biol Chem. 2003;278(42):41003–12.

    CAS  PubMed  Google Scholar 

  44. Agnello V, Ábel G, Elfahal M, Knight GB, Zhang Q-X. Hepatitis C virus and other Flaviviridae viruses enter cells via low density lipoprotein receptor. Proc Natl Acad Sci. 1999;96(22):12766–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  45. Pöhlmann S, Zhang J, Baribaud F, Chen Z, Leslie GJ, Lin G, et al. Hepatitis C virus glycoproteins interact with DC-SIGN and DC-SIGNR. J Virol. 2003;77(7):4070–80.

    PubMed Central  PubMed  Google Scholar 

  46. Gardner JP, Durso RJ, Arrigale RR, Donovan GP, Maddon PJ, Dragic T, et al. L-SIGN (CD 209L) is a liver-specific capture receptor for hepatitis C virus. Proc Natl Acad Sci. 2003;100(8):4498–503.

    CAS  PubMed Central  PubMed  Google Scholar 

  47. Evans MJ, von Hahn T, Tscherne DM, Syder AJ, Panis M, Wolk B, et al. Claudin-1 is a hepatitis C virus co-receptor required for a late step in entry. Nature. 2007;446(7137):801–5.

    CAS  PubMed  Google Scholar 

  48. Meertens L, Bertaux C, Cukierman L, Cormier E, Lavillette D, Cosset F-L, et al. The tight junction proteins claudin-1, -6, and -9 are entry cofactors for hepatitis C virus. J Virol. 2008;82(7):3555–60.

    CAS  PubMed Central  PubMed  Google Scholar 

  49. Zheng A, Yuan F, Li Y, Zhu F, Hou P, Li J, et al. Claudin-6 and claudin-9 function as additional coreceptors for hepatitis C virus. J Virol. 2007;81(22):12465–71.

    CAS  PubMed Central  PubMed  Google Scholar 

  50. Liu S, Kuo W, Yang W, Liu W, Gibson GA, Dorko K, et al. The second extracellular loop dictates Occludin-mediated HCV entry. Virology. 2010;407(1):160–70.

    CAS  PubMed Central  PubMed  Google Scholar 

  51. Sourisseau M, Michta ML, Zony C, Israelow B, Hopcraft SE, Narbus CM, et al. Temporal analysis of hepatitis C virus cell entry with occludin directed blocking antibodies. PLoS Pathog. 2013;9(3):e1003244.

    CAS  PubMed Central  PubMed  Google Scholar 

  52. Liu S, Yang W, Shen L, Turner JR, Coyne CB, Wang T. Tight junction proteins claudin-1 and occludin control hepatitis C virus entry and are downregulated during infection to prevent superinfection. J Virol. 2009;83(4):2011–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  53. Ploss A, Evans MJ, Gaysinskaya VA, Panis M, You H, de Jong YP, et al. Human occludin is a hepatitis C virus entry factor required for infection of mouse cells. Nature. 2009;457(7231):882–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  54. Sainz B, Barretto N, Martin DN, Hiraga N, Imamura M, Hussain S, et al. Identification of the Niemann-Pick C1-like 1 cholesterol absorption receptor as a new hepatitis C virus entry factor. Nat Med. 2012;18(2):281–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  55. Lupberger J, Zeisel MB, Xiao F, Thumann C, Fofana I, Zona L, et al. EGFR and EphA2 are host factors for hepatitis C virus entry and possible targets for antiviral therapy. Nat Med. 2011;17(5):589–95.

    CAS  PubMed Central  PubMed  Google Scholar 

  56. Albecka A, Belouzard S, de Beeck AO, Descamps V, Goueslain L, Bertrand-Michel J, et al. Role of low-density lipoprotein receptor in the hepatitis C virus life cycle. Hepatology. 2012;55(4):998–1007.

    CAS  PubMed  Google Scholar 

  57. Spahn CMT, Kieft JS, Grassucci RA, Penczek PA, Zhou K, Doudna JA, et al. Hepatitis C virus IRES RNA-induced changes in the conformation of the 40S ribosomal subunit. Science. 2001;291(5510):1959–62.

    CAS  PubMed  Google Scholar 

  58. Otto GA, Puglisi JD. The pathway of HCV IRES-mediated translation initiation. Cell. 2004;119(3):369–80.

    CAS  PubMed  Google Scholar 

  59. Ji H, Fraser CS, Yu Y, Leary J, Doudna JA. Coordinated assembly of human translation initiation complexes by the hepatitis C virus internal ribosome entry site RNA. Proc Natl Acad Sci U S A. 2004;101(49):16990–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  60. Hijikata M, Mizushima H, Akagi T, Mori S, Kakiuchi N, Kato N, et al. Two distinct proteinase activities required for the processing of a putative nonstructural precursor protein of hepatitis C virus. J Virol. 1993;67(8):4665–75.

    CAS  PubMed Central  PubMed  Google Scholar 

  61. Kadaré G, Haenni AL. Virus-encoded RNA helicases. J Virol. 1997;71(4):2583–90.

    PubMed Central  PubMed  Google Scholar 

  62. Park J-S, Yang JM, Min M-K. Hepatitis C virus nonstructural protein NS4B transforms NIH3T3 cells in cooperation with the Ha-ras oncogene. Biochem Biophys Res Commun. 2000;267(2):581–7.

    CAS  PubMed  Google Scholar 

  63. Egger D, Wölk B, Gosert R, Bianchi L, Blum HE, Moradpour D, et al. Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex. J Virol. 2002;76(12):5974–84.

    CAS  PubMed Central  PubMed  Google Scholar 

  64. Gale Jr MJ, Korth MJ, Tang NM, Tan S-L, Hopkins DA, Dever TE, et al. Evidence that hepatitis C virus resistance to interferon is mediated through repression of the PKR protein kinase by the nonstructural 5A protein. Virology. 1997;230(2):217–27.

    CAS  PubMed  Google Scholar 

  65. Tan S-L, Katze MG. How hepatitis C virus counteracts the interferon response: the jury is still out on NS5A. Virology. 2001;284(1):1–12.

    CAS  PubMed  Google Scholar 

  66. Schmidt-Mende J, Bieck E, Hügle T, Penin F, Rice CM, Blum HE, et al. Determinants for membrane association of the hepatitis C virus RNA-dependent RNA polymerase. J Biol Chem. 2001;276(47):44052–63.

    CAS  PubMed  Google Scholar 

  67. Behrens S, Tomei L, De Francesco R. Identification and properties of the RNA-dependent RNA polymerase of hepatitis C virus. EMBO J. 1996;15(1):12–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  68. Randall G, Panis M, Cooper JD, Tellinghuisen TL, Sukhodolets KE, Pfeffer S, et al. Cellular cofactors affecting hepatitis C virus infection and replication. Proc Natl Acad Sci. 2007;104(31):12884–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  69. Gutshall LL, Tsai J, Del Vecchio AM, Gontarek RR, Herold KM, Sathe GM, et al. hnRNP C and polypyrimidine tract-binding protein specifically interact with the pyrimidine-rich region within the 3′NTR of the HCV RNA genome. Nucleic Acids Res. 1999;27(6):1457–63.

    PubMed Central  PubMed  Google Scholar 

  70. Pflugheber J, Fredericksen B, Sumpter R, Wang C, Ware F, Sodora DL, et al. Regulation of PKR and IRF-1 during hepatitis C virus RNA replication. Proc Natl Acad Sci. 2002;99(7):4650–5.

    CAS  PubMed Central  PubMed  Google Scholar 

  71. Choi S-H, Park K-J, Ahn B-Y, Jung G, Lai MMC, Hwang SB. Hepatitis C virus nonstructural 5B protein regulates tumor necrosis factor alpha signaling through effects on cellular IκB kinase. Mol Cell Biol. 2006;26(8):3048–59.

    CAS  PubMed Central  PubMed  Google Scholar 

  72. Ariumi Y, Kuroki M, Kushima Y, Osugi K, Hijikata M, Maki M, et al. Hepatitis C virus hijacks P-body and stress granule components around lipid droplets. J Virol. 2011;85(14):6882–92.

    CAS  PubMed Central  PubMed  Google Scholar 

  73. Salloum S, Wang H, Ferguson C, Parton RG, Tai AW. Rab18 binds to hepatitis C virus NS5A and promotes interaction between sites of viral replication and lipid droplets. PLoS Pathog. 2013;9(8):e1003513.

    CAS  PubMed Central  PubMed  Google Scholar 

  74. Bode JG, Brenndörfer ED, Karthe J, Häussinger D. Interplay between host cell and hepatitis C virus in regulating viral replication. Biol Chem. 2009;390(10):1013–32.

    CAS  PubMed  Google Scholar 

  75. Wang C, Gale Jr M, Keller BC, Huang H, Brown MS, Goldstein JL, et al. Identification of FBL2 as a geranylgeranylated cellular protein required for hepatitis C virus RNA replication. Mol Cell. 2005;18(4):425–34.

    CAS  PubMed  Google Scholar 

  76. Evans MJ, Rice CM, Goff SP. Genetic interactions between hepatitis C virus replicons. J Virol. 2004;78(21):12085–9.

    CAS  PubMed Central  PubMed  Google Scholar 

  77. Hamamoto I, Nishimura Y, Okamoto T, Aizaki H, Liu M, Mori Y, et al. Human VAP-B is involved in hepatitis C virus replication through interaction with NS5A and NS5B. J Virol. 2005;79(21):13473–82.

    CAS  PubMed Central  PubMed  Google Scholar 

  78. Foster TL, Gallay P, Stonehouse NJ, Harris M. Cyclophilin A interacts with domain II of hepatitis C virus NS5A and stimulates RNA binding in an isomerase-dependent manner. J Virol. 2011;85(14):7460–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  79. Watashi K, Ishii N, Hijikata M, Inoue D, Murata T, Miyanari Y, et al. Cyclophilin B is a functional regulator of hepatitis C virus RNA polymerase. Mol Cell. 2005;19(1):111–22.

    CAS  PubMed  Google Scholar 

  80. Okamoto T, Nishimura Y, Ichimura T, Suzuki K, Miyamura T, Suzuki T, et al. Hepatitis C virus RNA replication is regulated by FKBP8 and Hsp90. EMBO J. 2006;25(20):5015–25.

    CAS  PubMed Central  PubMed  Google Scholar 

  81. Jopling CL, Yi M, Lancaster AM, Lemon SM, Sarnow P. Modulation of hepatitis C virus RNA abundance by a liver-specific MicroRNA. Science. 2005;309(5740):1577–81.

    CAS  PubMed  Google Scholar 

  82. Blackham SL, McGarvey MJ. A host cell RNA binding protein, Staufen1, has a role in hepatitis C virus replication before virus assembly. J Gen Virol. 2013;94(Pt11):2429–36.

    CAS  PubMed  Google Scholar 

  83. Gosert R, Egger D, Lohmann V, Bartenschlager R, Blum HE, Bienz K, et al. Identification of the hepatitis C virus RNA replication complex in Huh-7 cells harboring subgenomic replicons. J Virol. 2003;77(9):5487–92.

    CAS  PubMed Central  PubMed  Google Scholar 

  84. Gao L, Aizaki H, He J-W, Lai MMC. Interactions between viral nonstructural proteins and host protein hVAP-33 mediate the formation of hepatitis C virus RNA replication complex on lipid raft. J Virol. 2004;78(7):3480–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  85. Masaki T, Suzuki R, Murakami K, Aizaki H, Ishii K, Murayama A, et al. Interaction of hepatitis C virus nonstructural protein 5A with core protein is critical for the production of infectious virus particles. J Virol. 2008;82(16):7964–76.

    CAS  PubMed Central  PubMed  Google Scholar 

  86. Appel N, Zayas M, Miller S, Krijnse-Locker J, Schaller T, Friebe P, et al. Essential role of domain III of nonstructural protein 5A for hepatitis C virus infectious particle assembly. PLoS Pathog. 2008;4(3):e1000035. doi:10.1371/journal.ppat.1000035.

    PubMed Central  PubMed  Google Scholar 

  87. Neveu G, Barouch-Bentov R, Ziv-Av A, Gerber D, Jacob Y, Einav S. Identification and targeting of an interaction between a tyrosine motif within hepatitis C virus core protein and AP2M1 essential for viral assembly. PLoS Pathog. 2012;8(8):e1002845.

    CAS  PubMed Central  PubMed  Google Scholar 

  88. Menzel N, Fischl W, Hueging K, Bankwitz D, Frentzen A, Haid S, et al. MAP-kinase regulated cytosolic phospholipase A2 activity is essential for production of infectious hepatitis C virus particles. PLoS Pathog. 2012;8(7):e1002829.

    CAS  PubMed Central  PubMed  Google Scholar 

  89. Huang H, Sun F, Owen DM, Li W, Chen Y, Gale M, et al. Hepatitis C virus production by human hepatocytes dependent on assembly and secretion of very low-density lipoproteins. Proc Natl Acad Sci. 2007;104(14):5848–53.

    CAS  PubMed Central  PubMed  Google Scholar 

  90. Icard V, Diaz O, Scholtes C, Perrin-Cocon L, Ramière C, Bartenschlager R, et al. Secretion of hepatitis C virus envelope glycoproteins depends on assembly of apolipoprotein B positive lipoproteins. PLoS One. 2009;4(1):e4233.

    PubMed Central  PubMed  Google Scholar 

  91. Benga WJA, Krieger SE, Dimitrova M, Zeisel MB, Parnot M, Lupberger J, et al. Apolipoprotein E interacts with hepatitis C virus nonstructural protein 5A and determines assembly of infectious particles. Hepatology. 2010;51(1):43–53.

    CAS  PubMed  Google Scholar 

  92. André P, Komurian-Pradel F, Deforges S, Perret M, Berland JL, Sodoyer M, et al. Characterization of low- and very-low-density hepatitis C virus RNA-containing particles. J Virol. 2002;76(14):6919–28.

    PubMed Central  PubMed  Google Scholar 

  93. Gentzsch J, Brohm C, Steinmann E, Friesland M, Menzel N, Vieyres G, et al. Hepatitis C virus p7 is critical for capsid assembly and envelopment. PLoS Pathog. 2013;9(5):e1003355.

    CAS  PubMed Central  PubMed  Google Scholar 

  94. Calistri A, Salata C, Parolin C, Palù G. Role of multivesicular bodies and their components in the egress of enveloped RNA viruses. Rev Med Virol. 2009;19(1):31–45.

    CAS  PubMed  Google Scholar 

  95. Corless L, Crump CM, Griffin SDC, Harris M. Vps4 and the ESCRT-III complex are required for the release of infectious hepatitis C virus particles. J Gen Virol. 2010;91(2):362–72.

    CAS  PubMed  Google Scholar 

  96. Ramakrishnaiah V, Thumann C, Fofana I, Habersetzer F, Pan Q, de Ruiter PE, et al. Exosome-mediated transmission of hepatitis C virus between human hepatoma Huh7.5 cells. Proc Natl Acad Sci. 2013;110(32):13109–13.

    CAS  PubMed Central  PubMed  Google Scholar 

  97. Watanabe T, Sorensen EM, Naito A, Schott M, Kim S, Ahlquist P. Involvement of host cellular multivesicular body functions in hepatitis B virus budding. Proc Natl Acad Sci. 2007;104(24):10205–10.

    CAS  PubMed Central  PubMed  Google Scholar 

  98. Booth AM, Fang Y, Fallon JK, Yang J-M, Hildreth JEK, Gould SJ. Exosomes and HIV Gag bud from endosome-like domains of the T cell plasma membrane. J Cell Biol. 2006;172(6):923–35.

    CAS  PubMed Central  PubMed  Google Scholar 

  99. Gousset K, Ablan SD, Coren LV, Ono A, Soheilian F, Nagashima K, et al. Real-time visualization of HIV-1 GAG trafficking in infected macrophages. PLoS Pathog. 2008;4(3):e1000015.

    PubMed Central  PubMed  Google Scholar 

  100. Pelchen-Matthews A, Kramer B, Marsh M. Infectious HIV-1 assembles in late endosomes in primary macrophages. J Cell Biol. 2003;162(3):443–55.

    CAS  PubMed Central  PubMed  Google Scholar 

  101. Craven RC, Harty RN, Paragas J, Palese P, Wills JW. Late domain function identified in the vesicular stomatitis virus M protein by use of rhabdovirus-retrovirus chimeras. J Virol. 1999;73(4):3359–65.

    CAS  PubMed Central  PubMed  Google Scholar 

  102. Kolesnikova L, Berghöfer B, Bamberg S, Becker S. Multivesicular bodies as a platform for formation of the Marburg virus envelope. J Virol. 2004;78(22):12277–87.

    CAS  PubMed Central  PubMed  Google Scholar 

  103. Perez M, Craven RC, de la Torre JC. The small RING finger protein Z drives arenavirus budding: implications for antiviral strategies. Proc Natl Acad Sci. 2003;100(22):12978–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  104. Lai C-K, Jeng K-S, Machida K, Lai MMC. Hepatitis C virus egress and release depend on endosomal trafficking of core protein. J Virol. 2010;84(21):11590–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  105. Seeff LB. Natural history of chronic hepatitis C. Hepatology. 2002;36(5B):s35–46.

    PubMed  Google Scholar 

  106. Wakita T, Pietschmann T, Kato T, Date T, Miyamoto M, Zhao Z, et al. Production of infectious hepatitis C virus in tissue culture from a cloned viral genome. Nat Med. 2005;11(7):791–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  107. Dustin LB, Rice CM. Flying under the radar: the immunobiology of hepatitis C. Annu Rev Immunol. 2007;25(1):71–99.

    CAS  PubMed  Google Scholar 

  108. Manns MP, Pockros PJ, Norkrans G, Smith CI, Morgan TR, Häussinger D, et al. Long-term clearance of hepatitis C virus following interferon α-2b or peginterferon α-2b, alone or in combination with ribavirin. J Viral Hepat. 2013;20(8):524–9.

    CAS  PubMed  Google Scholar 

  109. Jesudian AB, Jacobson IM. Telaprevir for chronic hepatitis C virus infection. Clin Liver Dis. 2013;17(1):47–62.

    PubMed  Google Scholar 

  110. Jacobson IM, McHutchison JG, Dusheiko G, Di Bisceglie AM, Reddy KR, Bzowej NH, et al. Telaprevir for previously untreated chronic hepatitis C virus infection. N Engl J Med. 2011;364(25):2405–16.

    CAS  PubMed  Google Scholar 

  111. Ghany MG, Nelson DR, Strader DB, Thomas DL, Seeff LB. An update on treatment of genotype 1 chronic hepatitis C virus infection: 2011 practice guideline by the American Association for the Study of Liver Diseases. Hepatology. 2011;54(4):1433–44.

    PubMed Central  PubMed  Google Scholar 

  112. Hézode C, Forestier N, Dusheiko G, Ferenci P, Pol S, Goeser T, et al. Telaprevir and peginterferon with or without ribavirin for chronic HCV infection. N Engl J Med. 2009;360(18):1839–50.

    PubMed  Google Scholar 

  113. Bacon BR, Gordon SC, Lawitz E, Marcellin P, Vierling JM, Zeuzem S, et al. Boceprevir for previously treated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1207–17.

    CAS  PubMed Central  PubMed  Google Scholar 

  114. Poordad F, McCone J, Bacon BR, Bruno S, Manns MP, Sulkowski MS, et al. Boceprevir for untreated chronic HCV genotype 1 infection. N Engl J Med. 2011;364(13):1195–206.

    CAS  PubMed Central  PubMed  Google Scholar 

  115. Zeuzem S, Andreone P, Pol S, Lawitz E, Diago M, Roberts S, et al. Telaprevir for retreatment of HCV infection. N Engl J Med. 2011;364(25):2417–28.

    CAS  PubMed  Google Scholar 

  116. Garcia-Retortillo M, Forns X. Prevention and treatment of hepatitis C virus recurrence after liver transplantation. J Hepatol. 2004;41(1):2–10.

    PubMed  Google Scholar 

  117. Feliu A, Gay E, García-Retortillo M, Saiz JC, Forns X. Evolution of hepatitis C virus quasispecies immediately following liver transplantation. Liver Transpl. 2004;10(9):1131–9.

    PubMed  Google Scholar 

  118. De Bruijne J, Weegink CJ, Jansen PLM, Reesink HW. New developments in the antiviral treatment of hepatitis C. Vox Sang. 2009;97(1):1–12.

    PubMed  Google Scholar 

  119. Scheel TKH, Rice CM. Understanding the hepatitis C virus life cycle paves the way for highly effective therapies. Nat Med. 2013;19(7):837–49.

    CAS  PubMed Central  PubMed  Google Scholar 

  120. Pan Q, Henry S, Metselaar H, Scholte B, Kwekkeboom J, Tilanus H, et al. Combined antiviral activity of interferon-α and RNA interference directed against hepatitis C without affecting vector delivery and gene silencing. J Mol Med. 2009;87(7):713–22.

    CAS  PubMed Central  PubMed  Google Scholar 

  121. Pan QW, Henry SD, Scholte BJ, Tilanus HW, Janssen HL, van der Laan LJ. New therapeutic opportunities for hepatitis C based on small RNA. World J Gastroenterol. 2007;13(33):4431–6.

    CAS  PubMed  Google Scholar 

  122. Paddison PJ, Caudy AA, Hannon GJ. Stable suppression of gene expression by RNAi in mammalian cells. Proc Natl Acad Sci U S A. 2002;99(3):1443–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  123. Paddison PJ, Caudy AA, Bernstein E, Hannon GJ, Conklin DS. Short hairpin RNAs (shRNAs) induce sequence-specific silencing in mammalian cells. Genes Dev. 2002;16(8):948–58.

    CAS  PubMed Central  PubMed  Google Scholar 

  124. Engels BM, Hutvagner G. Principles and effects of microRNA-mediated post-transcriptional gene regulation. Oncogene. 2006;25(46):6163–9.

    CAS  PubMed  Google Scholar 

  125. Carmell MA, Xuan Z, Zhang MQ, Hannon GJ. The Argonaute family: tentacles that reach into RNAi, developmental control, stem cell maintenance, and tumorigenesis. Genes Dev. 2002;16(21):2733–42.

    CAS  PubMed  Google Scholar 

  126. Hammond SM, Boettcher S, Caudy AA, Kobayashi R, Hannon GJ. Argonaute2, a link between genetic and biochemical analyses of RNAi. Science. 2001;293(5532):1146–50.

    CAS  PubMed  Google Scholar 

  127. Tur-Kaspa R, Teicher L, Levine BJ, Skoultchi AI, Shafritz DA. Use of electroporation to introduce biologically active foreign genes into primary rat hepatocytes. Mol Cell Biol. 1986;6(2):716–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  128. Leibiger B, Leibiger I, Sarrach D, Zühlke H. Expression of exogenous DNA in rat liver cells after liposome-mediated transfection in vivo. Biochem Biophys Res Commun. 1991;174(3):1223–31.

    CAS  PubMed  Google Scholar 

  129. Lewis DL, Hagstrom JE, Loomis AG, Wolff JA, Herweijer H. Efficient delivery of siRNA for inhibition of gene expression in postnatal mice. Nat Genet. 2002;32(1):107–8.

    CAS  PubMed  Google Scholar 

  130. McCaffrey AP, Meuse L, Pham T-TT, Conklin DS, Hannon GJ, Kay MA. Gene expression: RNA interference in adult mice. Nature. 2002;418(6893):38–9.

    CAS  PubMed  Google Scholar 

  131. Wooddell CI, Van Hout CV, Reppen T, Lewis DL, Herweijer H. Long-term RNA interference from optimized siRNA expression constructs in adult mice. Biochem Biophys Res Commun. 2005;334(1):117–27.

    CAS  PubMed  Google Scholar 

  132. Blaese RM, Culver K, Miller A, Carter C, Fleisher T, Clerici M, et al. T lymphocyte-directed gene therapy for ADA-SCID: initial trial results after 4 years. Science. 1995;270(5235):475–80.

    CAS  PubMed  Google Scholar 

  133. Lehrman S. Virus treatment questioned after gene therapy death. Nature. 1999;401(6753):517–8.

    CAS  PubMed  Google Scholar 

  134. Baum C, Modlich U, Göhring G, Schlegelberger B. Concise review: managing genotoxicity in the therapeutic modification of stem cells. Stem Cells. 2011;29(10):1479–84.

    CAS  PubMed  Google Scholar 

  135. Ginn SL, Alexander IE, Edelstein ML, Abedi MR, Wixon J. Gene therapy clinical trials worldwide to 2012—an update. J Gene Med. 2013;15(2):65–77.

    CAS  PubMed  Google Scholar 

  136. Chowdhury J, Grossman M, Gupta S, Chowdhury N, Baker Jr J, Wilson J. Long-term improvement of hypercholesterolemia after ex vivo gene therapy in LDLR-deficient rabbits. Science. 1991;254(5039):1802–5.

    CAS  PubMed  Google Scholar 

  137. Kay MA, Baley P, Rothenberg S, Leland F, Fleming L, Ponder KP, et al. Expression of human alpha 1-antitrypsin in dogs after autologous transplantation of retroviral transduced hepatocytes. Proc Natl Acad Sci. 1992;89(1):89–93.

    CAS  PubMed Central  PubMed  Google Scholar 

  138. Kay MA, Li Q, Liu T-J, Leland F, Toman C, Finegold M, et al. Hepatic gene therapy: persistent expression of human α1-antitrypsin in mice after direct gene delivery in vivo. Hum Gene Ther. 1992;3(6):641–7.

    CAS  PubMed  Google Scholar 

  139. Kaleko M, Garcia JV, Miller AD. Persistent gene expression after retroviral gene transfer into liver cells in vivo human gene therapy. Hum Gene Ther. 1991;2(1):27–32.

    CAS  PubMed  Google Scholar 

  140. Ferry N, Duplessis O, Houssin D, Danos O, Heard JM. Retroviral-mediated gene transfer into hepatocytes in vivo. Proc Natl Acad Sci. 1991;88(19):8377–81.

    CAS  PubMed Central  PubMed  Google Scholar 

  141. Rettinger SD, Kennedy SC, Wu X, Saylors RL, Hafenrichter DG, Flye MW, et al. Liver-directed gene therapy: quantitative evaluation of promoter elements by using in vivo retroviral transduction. Proc Natl Acad Sci. 1994;91(4):1460–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  142. Cunningham SC, Dane AP, Spinoulas A, Alexander IE. Gene delivery to the juvenile mouse liver using AAV2/8 vectors. Mol Ther. 2008;16(6):1081–8.

    CAS  PubMed  Google Scholar 

  143. Dariel A, Nguyen TH, Pichard V, Schmitt F, Aubert D, Ferry N, et al. A new surgical approach to improve gene transfer in liver using lentiviral vectors. J Pediatr Surg. 2009;44(3):517–22.

    PubMed  Google Scholar 

  144. Rettinger SD, Ponder KP, Saylors RL, Kennedy SC, Hafenrichter DC, Flye MW. In vivo hepatocyte transduction with retrovirus during in-flow occlusion. J Surg Res. 1993;54(5):418–25.

    CAS  PubMed  Google Scholar 

  145. Curiel DT, Agarwal S, Wagner E, Cotten M. Adenovirus enhancement of transferrin-polylysine-mediated gene delivery. Proc Natl Acad Sci. 1991;88(19):8850–4.

    CAS  PubMed Central  PubMed  Google Scholar 

  146. Cristiano RJ, Smith LC, Woo SL. Hepatic gene therapy: adenovirus enhancement of receptor-mediated gene delivery and expression in primary hepatocytes. Proc Natl Acad Sci. 1993;90(6):2122–6.

    CAS  PubMed Central  PubMed  Google Scholar 

  147. Curiel DT, Wagner E, Matt Cotten M, Birnstiel ML, Agarwal S, Li C-M, et al. High-efficiency gene transfer mediated by adenovirus coupled to DNA–polylysine complexes. Hum Gene Ther. 1992;3(2):147–54.

    CAS  PubMed  Google Scholar 

  148. Schulick AH, Vassalli G, Dunn PF, Dong G, Rade JJ, Zamarron C, et al. Established immunity precludes adenovirus-mediated gene transfer in rat carotid arteries. Potential for immunosuppression and vector engineering to overcome barriers of immunity. J Clin Invest. 1997;99(2):209–19.

    CAS  PubMed Central  PubMed  Google Scholar 

  149. Uprichard SL, Boyd B, Althage A, Chisari FV. Clearance of hepatitis B virus from the liver of transgenic mice by short hairpin RNAs. Proc Natl Acad Sci U S A. 2005;102(3):773–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  150. Sakamoto N, Tanabe Y, Yokota T, Satoh K, Sekine-Osajima Y, Nakagawa M, et al. Inhibition of hepatitis C virus infection and expression in vitro and in vivo by recombinant adenovirus expressing short hairpin RNA. J Gastroenterol Hepatol. 2008;23(9):1437–47.

    CAS  PubMed  Google Scholar 

  151. Crowther C, Ely A, Hornby J, Mufamadi S, Salazar F, Marion P, et al. Efficient inhibition of hepatitis B virus replication in vivo, using polyethylene glycol-modified adenovirus vectors. Hum Gene Ther. 2008;19(11):1325–31.

    CAS  PubMed  Google Scholar 

  152. Lu S, Cullen BR. Adenovirus VA1 noncoding RNA can inhibit small interfering RNA and MicroRNA biogenesis. J Virol. 2004;78(23):12868–76.

    CAS  PubMed Central  PubMed  Google Scholar 

  153. Andersson MG, Haasnoot PCJ, Xu N, Berenjian S, Berkhout B, Akusjärvi G. Suppression of RNA interference by adenovirus virus-associated RNA. J Virol. 2005;79(15):9556–65.

    CAS  PubMed Central  PubMed  Google Scholar 

  154. Ruiz R, Witting SR, Saxena R, Morral N. Robust hepatic gene silencing for functional studies using helper-dependent adenoviral vectors human gene therapy. Hum Gene Ther. 2009;20(1):87–94.

    CAS  PubMed Central  PubMed  Google Scholar 

  155. Witting SR, Brown M, Saxena R, Nabinger S, Morral N. Helper-dependent adenovirus-mediated short hairpin RNA expression in the liver activates the interferon response. J Biol Chem. 2008;283(4):2120–8.

    CAS  PubMed  Google Scholar 

  156. Weindler FW, Heilbronn R. A subset of herpes simplex virus replication genes provides helper functions for productive adeno-associated virus replication. J Virol. 1991;65(5):2476–83.

    CAS  PubMed Central  PubMed  Google Scholar 

  157. Grimm D, Kay MA. From virus evolution to vector revolution: use of naturally occurring serotypes of adeno-associated virus (AAV) as novel vectors for human gene therapy. Curr Gene Ther. 2003;3:281–304.

    CAS  PubMed  Google Scholar 

  158. Manno CS, Arruda VR, Pierce GF, Glader B, Ragni M, Rasko J, et al. Successful transduction of liver in hemophilia by AAV-Factor IX and limitations imposed by the host immune response. Nat Med. 2006;12(3):342–7.

    CAS  PubMed  Google Scholar 

  159. Nakai H, Fuess S, Storm TA, Muramatsu S-I, Nara Y, Kay MA. Unrestricted hepatocyte transduction with adeno-associated virus serotype 8 vectors in mice. J Virol. 2005;79(1):214–24.

    CAS  PubMed Central  PubMed  Google Scholar 

  160. McCarty DM, Monahan PE, Samulski RJ. Self-complementary recombinant adeno-associated virus (scAAV) vectors promote efficient transduction independently of DNA synthesis. Gene Ther. 2001;8(16):1248–54.

    CAS  PubMed  Google Scholar 

  161. Hacein-Bey-Abina S, Von Kalle C, Schmidt M, McCormack MP, Wulffraat N, Leboulch P, et al. LMO2-associated clonal T cell proliferation in two patients after gene therapy for SCID-X1. Science. 2003;302(5644):415–9.

    CAS  PubMed  Google Scholar 

  162. Maetzig T, Galla M, Baum C, Schambach A. Gammaretroviral vectors: biology, technology and application. Viruses. 2011;3(6):677–713.

    PubMed Central  PubMed  Google Scholar 

  163. Modlich U, Navarro S, Zychlinski D, Maetzig T, Knoess S, Brugman MH, et al. Insertional transformation of hematopoietic cells by self-inactivating lentiviral and gammaretroviral vectors. Mol Ther. 2009;17(11):1919–28.

    CAS  PubMed Central  PubMed  Google Scholar 

  164. Montini E, Cesana D, Schmidt M, Sanvito F, Bartholomae C, Ranzani M, et al. The genotoxic potential of retroviral vectors is strongly modulated by vector design and integration site selection in a mouse model of HSC gene therapy. J Clin Invest. 2009;119(4):964–75.

    CAS  PubMed Central  PubMed  Google Scholar 

  165. Henry SD, van der Wegen P, Metselaar HJ, Tilanus HW, Scholte BJ, van der Laan LJW. Simultaneous targeting of HCV replication and viral binding with a single lentiviral vector containing multiple RNA interference expression cassettes. Mol Ther. 2006;14(4):485–93.

    CAS  PubMed  Google Scholar 

  166. Khokhar A, Noorali S, Sheraz M, Mahalingham K, Pace DG, Khanani MR, et al. Computational analysis to predict functional role of hsa-miR-3065-3p as an antiviral therapeutic agent for treatment of triple infections: HCV, HIV-1, and HBV. Libyan J Med. 2012;7:19774.

    PubMed  Google Scholar 

  167. Henry S, Pan Q, van der Laan L. Production of multicopy shRNA lentiviral vectors for antiviral therapy. Methods Mol Biol. 2011;721:313–32.

    CAS  PubMed  Google Scholar 

  168. Zhang J, Rossi J. Strategies in designing multigene expression units to downregulate HIV-1. Methods Mol Biol. 2010;623:123–36.

    CAS  PubMed  Google Scholar 

  169. Smith AD, Sumazin P, Xuan Z, Zhang MQ. DNA motifs in human and mouse proximal promoters predict tissue-specific expression. Proc Natl Acad Sci. 2006;103(16):6275–80.

    CAS  PubMed Central  PubMed  Google Scholar 

  170. Smith AD, Sumazin P, Zhang MQ. Tissue-specific regulatory elements in mammalian promoters. Mol Syst Biol. 2007;3:73.

    PubMed Central  PubMed  Google Scholar 

  171. Hu Y, Ren X, Wang H, Ma Y, Wang L, Shen Y, et al. Liver-specific expression of an exogenous gene controlled by human apolipoprotein A-I promoter. Int J Pharm. 2010;398(1–2):161–4.

    CAS  PubMed  Google Scholar 

  172. Schmitt F, Remy S, Dariel A, Flageul M, Pichard V, Boni S, et al. Lentiviral vectors that express UGT1A1 in liver and contain miR-142 target sequences normalize hyperbilirubinemia in Gunn rats. Gastroenterology. 2010;139(3):999–1007.e2.

    CAS  PubMed  Google Scholar 

  173. Pinkert CA, Ornitz DM, Brinster RL, Palmiter RD. An albumin enhancer located 10 kb upstream functions along with its promoter to direct efficient, liver-specific expression in transgenic mice. Genes Dev. 1987;1(3):268–76.

    CAS  PubMed  Google Scholar 

  174. Hafenrichter DG, Ponder KP, Rettinger SD, Kennedy SC, Wu X, Saylors RS, et al. Liver-directed gene therapy: evaluation of liver specific promoter elements. J Surg Res. 1994;56(6):510–7.

    CAS  PubMed  Google Scholar 

  175. Hayashi Y, Mori Y, Janssen OE, Sunthornthepvarakul T, Weiss RE, Takeda K, et al. Human thyroxine-binding globulin gene: complete sequence and transcriptional regulation. Mol Endocrinol. 1993;7(8):1049–60.

    CAS  PubMed  Google Scholar 

  176. Yan Z, Yan H, Ou H. Human thyroxine binding globulin (TBG) promoter directs efficient and sustaining transgene expression in liver-specific pattern. Gene. 2012;506(2):289–94.

    CAS  PubMed  Google Scholar 

  177. DiPersio CM, Jackson DA, Zaret KS. The extracellular matrix coordinately modulates liver transcription factors and hepatocyte morphology. Mol Cell Biol. 1991;11(9):4405–14.

    CAS  PubMed Central  PubMed  Google Scholar 

  178. Gatfield D, Le Martelot G, Vejnar CE, Gerlach D, Schaad O, Fleury-Olela F, et al. Integration of microRNA miR-122 in hepatic circadian gene expression. Genes Dev. 2009;23(11):1313–26.

    CAS  PubMed Central  PubMed  Google Scholar 

  179. Esau C, Davis S, Murray SF, Yu XX, Pandey SK, Pear M, et al. MiR-122 regulation of lipid metabolism revealed by in vivo antisense targeting. Cell Metab. 2006;3(2):87–98.

    CAS  PubMed  Google Scholar 

  180. Waidmann O, Bihrer V, Pleli T, Farnik H, Berger A, Zeuzem S, et al. Serum microRNA-122 levels in different groups of patients with chronic hepatitis B virus infection. J Viral Hepat. 2012;19(2):e58–65.

    CAS  PubMed  Google Scholar 

  181. Morita K, Taketomi A, Shirabe K, Umeda K, Kayashima H, Ninomiya M, et al. Clinical significance and potential of hepatic microRNA-122 expression in hepatitis C. Liver Int. 2011;31(4):474–84.

    CAS  PubMed  Google Scholar 

  182. Yoshikawa T, Takata A, Otsuka M, Kishikawa T, Kojima K, Yoshida H, et al. Silencing of microRNA-122 enhances interferon-α signaling in the liver through regulating SOCS3 promoter methylation. Sci Rep. 2012;2:637. doi:10.1038/srep00637.

    PubMed Central  PubMed  Google Scholar 

  183. Harrington KJ, Linardakis E, Vile RG. Transcriptional control: an essential component of cancer gene therapy strategies? Adv Drug Deliv Rev. 2000;44(2–3):167–84.

    CAS  PubMed  Google Scholar 

  184. Geisler A, Jungmann A, Kurreck J, Poller W, Katus HA, Vetter R, et al. microRNA122-regulated transgene expression increases specificity of cardiac gene transfer upon intravenous delivery of AAV9 vectors. Gene Ther. 2011;18(2):199–209.

    CAS  PubMed  Google Scholar 

  185. Qiao C, Yuan Z, Li J, He B, Zheng H, Mayer C, et al. Liver-specific microRNA-122 target sequences incorporated in AAV vectors efficiently inhibits transgene expression in the liver. Gene Ther. 2011;18(4):403–10.

    CAS  PubMed Central  PubMed  Google Scholar 

  186. Inagaki K, Fuess S, Storm TA, Gibson GA, McTiernan CF, Kay MA, et al. Robust systemic transduction with AAV9 vectors in mice: efficient global cardiac gene transfer superior to that of AAV8. Mol Ther. 2006;14(1):45–53.

    CAS  PubMed Central  PubMed  Google Scholar 

  187. Zincarelli C, Soltys S, Rengo G, Rabinowitz JE. Analysis of AAV serotypes 1-9 mediated gene expression and tropism in mice after systemic injection. Mol Ther. 2008;16(6):1073–80.

    CAS  PubMed  Google Scholar 

  188. Qi Y, Liu X, Li H, Shenoy V, Li Q, Hauswirth WW, et al. Selective tropism of the recombinant adeno-associated virus 9 serotype for rat cardiac tissue. J Gene Med. 2010;12(1):22–34.

    CAS  PubMed  Google Scholar 

  189. Li W, Asokan A, Wu Z, Van Dyke T, DiPrimio N, Johnson JS, et al. Engineering and selection of shuffled AAV genomes: a new strategy for producing targeted biological nanoparticles. Mol Ther. 2008;16(7):1252–60.

    CAS  PubMed Central  PubMed  Google Scholar 

  190. Pacak C, Sakai Y, Thattaliyath B, Mah C, Byrne B. Tissue specific promoters improve specificity of AAV9 mediated transgene expression following intra-vascular gene delivery in neonatal mice. Genet Vaccines Ther. 2008;6(1):13.

    PubMed Central  PubMed  Google Scholar 

  191. Bish LT, Morine K, Sleeper MM, Sanmiguel J, Wu D, Gao G, et al. Adeno-associated virus (AAV) serotype 9 provides global cardiac gene transfer superior to AAV1, AAV6, AAV7, and AAV8 in the mouse and rat. Hum Gene Ther. 2008;19(12):1359–68.

    CAS  PubMed Central  PubMed  Google Scholar 

  192. Pollock R, Clackson T. Dimerizer-regulated gene expression. Curr Opin Biotechnol. 2002;13(5):459–67.

    CAS  PubMed  Google Scholar 

  193. Chen S-J, Johnston J, Sandhu A, Bish LT, Hovhannisyan R, Jno-Charles O, et al. Enhancing the utility of adeno-associated virus gene transfer through inducible tissue-specific expression. Hum Gene Ther Methods. 2013;24(4):270–8.

    CAS  PubMed Central  PubMed  Google Scholar 

  194. Ng TI, Mo H, Pilot-Matias T, He Y, Koev G, Krishnan P, et al. Identification of host genes involved in hepatitis C virus replication by small interfering RNA technology. Hepatology. 2007;45(6):1413–21.

    CAS  PubMed  Google Scholar 

  195. Supekova L, Supek F, Lee J, Chen S, Gray N, Pezacki JP, et al. Identification of human kinases involved in hepatitis C virus replication by small interference RNA library screening. J Biol Chem. 2008;283(1):29–36.

    CAS  PubMed  Google Scholar 

  196. Pan Q, de Ruiter PE, von Eije KJ, Smits R, Kwekkeboom J, Tilanus HW, et al. Disturbance of the microRNA pathway by commonly used lentiviral shRNA libraries limits the application for screening host factors involved in hepatitis C virus infection. FEBS Lett. 2011;585(7):1025–30.

    CAS  PubMed  Google Scholar 

  197. Garaigorta U, Heim MH, Boyd B, Wieland S, Chisari FV. Hepatitis C virus (HCV) induces formation of stress granules whose proteins regulate HCV RNA replication and virus assembly and egress. J Virol. 2012;86(20):11043–56.

    CAS  PubMed Central  PubMed  Google Scholar 

  198. Yi Z, Pan T, Wu X, Song W, Wang S, Xu Y, et al. Hepatitis C virus co-opts Ras-GTPase-activating protein-binding protein 1 for its genome replication. J Virol. 2011;85(14):6996–7004.

    CAS  PubMed Central  PubMed  Google Scholar 

  199. Xue Q, Ding H, Liu M, Zhao P, Gao J, Ren H, et al. Inhibition of hepatitis C virus replication and expression by small interfering RNA targeting host cellular genes. Arch Virol. 2007;152(5):955–62.

    CAS  PubMed  Google Scholar 

  200. Isken O, Baroth M, Grassmann CW, Weinlich S, Ostareck DH, Ostareck-Lederer A, et al. Nuclear factors are involved in hepatitis C virus RNA replication. RNA. 2007;13(10):1675–92.

    CAS  PubMed Central  PubMed  Google Scholar 

  201. Zhang Z, Harris D, Pandey VN. Genome replication and regulation of viral gene expression: the FUSE binding protein is a cellular factor required for efficient replication of hepatitis C virus. J Virol. 2008;82(12):5761–73.

    CAS  PubMed Central  PubMed  Google Scholar 

  202. Stenvang Jepsen J, Sørensen MD, Wengel J. Locked nucleic acid: a potent nucleic acid analog in therapeutics and biotechnology. Oligonucleotides. 2004;14(2):130–46.

    Google Scholar 

  203. Válóczi A, Hornyik C, Varga N, Burgyán J, Kauppinen S, Havelda Z. Sensitive and specific detection of microRNAs by northern blot analysis using LNA-modified oligonucleotide probes. Nucleic Acids Res. 2004;32(22):e175.

    PubMed Central  PubMed  Google Scholar 

  204. el-Awady M, el-Din N, el-Garf W, Youssef S, Omran M, el-Abd J, et al. Antisense oligonucleotide inhibition of hepatitis C virus genotype 4 replication in HepG2 cells. Cancer Cell Int. 2006;6:18.

    PubMed Central  PubMed  Google Scholar 

  205. Wei B, Wei Y, Zhang K, Wang J, Xu R, Zhan S, et al. Development of an antisense RNA delivery system using conjugates of the MS2 bacteriophage capsids and HIV-1 TAT cell penetrating peptide. Biomed Pharmacother. 2009;63(4):313–8.

    CAS  PubMed  Google Scholar 

  206. Lanford RE, Hildebrandt-Eriksen ES, Petri A, Persson R, Lindow M, Munk ME, et al. Therapeutic silencing of MicroRNA-122 in primates with chronic hepatitis C virus infection. Science. 2010;327(5962):198–201.

    CAS  PubMed Central  PubMed  Google Scholar 

  207. Janssen HLA, Reesink HW, Lawitz EJ, Zeuzem S, Rodriguez-Torres M, Patel K, et al. Treatment of HCV infection by targeting MicroRNA. N Engl J Med. 2013;368(18):1685–94.

    CAS  PubMed  Google Scholar 

  208. de Jong YP, Jacobson IM. Antisense therapy for hepatitis C virus infection. J Hepatol. 2014;60(1):227–8.

    PubMed  Google Scholar 

  209. Tsai W-C, Hsu S-D, Hsu C-S, Lai T-C, Chen S-J, Shen R, et al. MicroRNA-122 plays a critical role in liver homeostasis and hepatocarcinogenesis. J Clin Invest. 2012;122(8):2884–97.

    CAS  PubMed Central  PubMed  Google Scholar 

  210. S-h H, Wang B, Kota J, Yu J, Costinean S, Kutay H, et al. Essential metabolic, anti-inflammatory, and anti-tumorigenic functions of miR-122 in liver. J Clin Invest. 2012;122(8):2871–83.

    Google Scholar 

  211. Lieberman J, Sarnow P. Micromanaging hepatitis C virus. N Engl J Med. 2013;368(18):1741–3.

    CAS  PubMed  Google Scholar 

  212. Randall G, Chen L, Panis M, Fischer AK, Lindenbach BD, Sun J, et al. Silencing of USP18 potentiates the antiviral activity of interferon against hepatitis C virus infection. Gastroenterology. 2006;131(5):1584–91.

    CAS  PubMed  Google Scholar 

  213. Okamoto H, Kojima M, Okada S, Yoshizawa H, Iizuka H, Tanaka T, et al. Genetic drift of hepatitis C virus during an 8.2-year infection in a chimpanzee: variability and stability. Virology. 1992;190(2):894–9.

    CAS  PubMed  Google Scholar 

  214. Novina CD, Murray MF, Dykxhoorn DM, Beresford PJ, Riess J, Lee S-K, et al. siRNA-directed inhibition of HIV-1 infection. Nat Med. 2002;8(7):681–6. doi:10.1038/nm725.

    CAS  PubMed  Google Scholar 

  215. Ciesek S, Steinmann E, Wedemeyer H, Manns MP, Neyts J, Tautz N, et al. Cyclosporine A inhibits hepatitis C virus nonstructural protein 2 through cyclophilin A. Hepatology. 2009;50(5):1638–45.

    CAS  PubMed  Google Scholar 

  216. Dorner M, Horwitz JA, Donovan BM, Labitt RN, Budell WC, Friling T, et al. Completion of the entire hepatitis C virus life cycle in genetically humanized mice. Nature. 2013;501(7466):237–41.

    CAS  PubMed  Google Scholar 

  217. Shulla A, Randall G. Hepatitis C virus—host interactions, replication, and viral assembly. Curr Opin Virol. 2012;2(6):725–32.

    CAS  PubMed  Google Scholar 

  218. Zein NN. Clinical significance of hepatitis C virus genotypes. Clin Microbiol Rev. 2000;13(2):223–35.

    CAS  PubMed Central  PubMed  Google Scholar 

Download references

Acknowledgements

The authors would like to thank Dr. Scot Henry, Columbia University New York, and Profs Herold Metselaar and Hugo Tilanus of the Erasmus MC-University Medical Center Rotterdam for longstanding support of our gene therapy research. This work is supported by an Erasmus MC Research Grant.

Author information

Authors and Affiliations

  1. Department of Surgery, Erasmus MC – University Medical Center Rotterdam, Room Na-619,’s, Gravendijkwal 230, 3015CE, Rotterdam, The Netherlands

    Monique M. A. Verstegen Ph.D. & Luc J. W. van der Laan Ph.D.

  2. Department of Gastroenterology and Hepatology, Erasmus MC – University Medical Center Rotterdam, Room Na-619,’s, Gravendijkwal 230, 3015CE, Rotterdam, The Netherlands

    Qiuwei Pan Ph.D.

Authors
  1. Monique M. A. Verstegen Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Qiuwei Pan Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Luc J. W. van der Laan Ph.D.
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Monique M. A. Verstegen Ph.D. .

Editor information

Editors and Affiliations

  1. University of Amsterdam, Amsterdam, The Netherlands

    Ben Berkhout

  2. The Wistar Institute, University of Pennsylvania, Philadelphia, Pennsylvania, USA

    Hildegund C.J. Ertl

  3. University of the Witwatersrand, Johannesburg, South Africa

    Marc S. Weinberg

Rights and permissions

Reprints and permissions

Copyright information

© 2015 American Society of Gene and Cell Therapy

About this chapter

Cite this chapter

Verstegen, M.M.A., Pan, Q., van der Laan, L.J.W. (2015). Gene Therapies for Hepatitis C Virus. In: Berkhout, B., Ertl, H., Weinberg, M. (eds) Gene Therapy for HIV and Chronic Infections. Advances in Experimental Medicine and Biology(), vol 848. Springer, New York, NY. https://doi.org/10.1007/978-1-4939-2432-5_1

Download citation

Publish with us

Policies and ethics

Search

Navigation