Hepatitis delta virus: Insights into a peculiar pathogen and novel treatment options

Nature Reviews Gastroenterology and Hepatology

Volumn 13, Issue 10, 2016, Pages 580-589

  Lempp, Florian A ^a   Ni, Yi ^a,b   Urban, Stephan ^a,b  

^a UNIVERSITY HOSPITAL HEIDELBERG   (Germany)

^b Heidelberg   (Germany)

Author keywords

[No Author keywords available]

Indexed keywords

ADEFOVIR DIPIVOXIL; ANTIVIRUS AGENT; LONAFARNIB; MYRCLUDEX B; PEGINTERFERON ALPHA; REP 2139 CA; TENOFOVIR DISOPROXIL; UNCLASSIFIED DRUG; ALPHA INTERFERON; LIPOPEPTIDE; MYRCLUDEX-B; NUCLEIC ACID; PIPERIDINE DERIVATIVE; PYRIDINE DERIVATIVE;

ANTIVIRAL ACTIVITY; CELL CULTURE; DELTA AGENT HEPATITIS; DISEASE MODEL; DRUG POTENTIATION; DRUG TARGETING; HEPATITIS B; HEPATITIS DELTA VIRUS; HUMAN; MIXED INFECTION; MOLECULAR BIOLOGY; MULTICENTER STUDY (TOPIC); NONHUMAN; PATHOGENESIS; PHASE 2 CLINICAL TRIAL (TOPIC); PREVALENCE; PRIORITY JOURNAL; REVIEW; RISK FACTOR; RNA REPLICATION; SIDE EFFECT; VIRION; VIRUS GENOME; VIRUS REPLICATION; ANIMAL; CHEMISTRY; DRUG EFFECTS; HEPATITIS D, CHRONIC; HOST PATHOGEN INTERACTION; PHYSIOLOGY; ULTRASTRUCTURE;

ANIMALS; ANTIVIRAL AGENTS; CELLS, CULTURED; DISEASE MODELS, ANIMAL; HEPATITIS D, CHRONIC; HEPATITIS DELTA VIRUS; HOST-PATHOGEN INTERACTIONS; HUMANS; INTERFERON-ALPHA; LIPOPEPTIDES; NUCLEIC ACIDS; PIPERIDINES; PYRIDINES; VIRUS REPLICATION;

EID: 84983022123     PISSN: 17595045     EISSN: 17595053     Source Type: Journal    
DOI: 10.1038/nrgastro.2016.126     Document Type: Review

References (157)

1. Rizzetto, M. et al. Immunofluorescence detection of new antigen-antibody system (γ/anti-γ) associated to hepatitis B virus in liver and in serum of HBsAg carriers. Gut 18, 997-1003 (1977).
2. Rizzetto, M. et al. Incidence and significance of antibodies to delta antigen in hepatitis B virus infection. Lancet 2, 986-990 (1979).
3. Rizzetto, M. et al. Transmission of the hepatitis B virus-associated delta antigen to chimpanzees. J. Infect. Dis. 141, 590-602 (1980).
4. Rizzetto, M. et al. γ Agent: association of γ antigen with hepatitis B surface antigen and RNA in serum of γ-infected chimpanzees. Proc. Natl Acad. Sci. USA 77, 6124-6128 (1980).
5. He, L. F. et al. The size of the hepatitis delta agent. J. Med. Virol. 27, 31-33 (1989).
6. Chen, P. J. et al. Structure and replication of the genome of the hepatitis γ virus. Proc. Natl Acad. Sci. USA 83, 8774-8778 (1986).
7. Kos, A., Dijkema, R., Arnberg, A. C., van der Meide, P. H. &Schellekens, H. The hepatitis delta (γ) virus possesses a circular RNA. Nature 323, 558-560 (1986).
8. Wang, K. S. et al. Structure, sequence and expression of the hepatitis delta (γ) viral genome. Nature 323, 508-514 (1986).
9. Kuo, M. Y. et al. Molecular cloning of hepatitis delta virus RNA from an infected woodchuck liver: sequence, structure, and applications. J. Virol. 62, 1855-1861 (1988).
10. Gudima, S., Chang, J., Moraleda, G., Azvolinsky, A. &Taylor, J. Parameters of human hepatitis delta virus genome replication: the quantity, quality, and intracellular distribution of viral proteins and RNA. J. Virol. 76, 3709-3719 (2002).
11. Ryu, W. S., Netter, H. J., Bayer, M. &Taylor, J. Ribonucleoprotein complexes of hepatitis delta virus. J. Virol. 67, 3281-3287 (1993).
12. Li, W. &Urban, S. Entry of hepatitis B and hepatitis D virus into hepatocytes: basic insights and clinical implications. J. Hepatol. 64, S32-S40 (2016).
13. Verrier, E. R. et al. A targeted functional RNA interference screen uncovers glypican 5 as an entry factor for hepatitis B and D viruses. Hepatology 63, 35-48 (2016).
14. Lamas Longarela, O. et al. Proteoglycans act as cellular hepatitis delta virus attachment receptors. PLoS ONE 8, e58340 (2013).
15. Leistner, C. M., Gruen-Bernhard, S. &Glebe, D. Role of glycosaminoglycans for binding and infection of hepatitis B virus. Cell. Microbiol. 10, 122-133 (2008).
16. Schulze, A., Gripon, P. &Urban, S. Hepatitis B virus infection initiates with a large surface proteindependent binding to heparan sulfate proteoglycans. Hepatology 46, 1759-1768 (2007).
17. Sureau, C. &Salisse, J. A conformational heparan sulfate binding site essential to infectivity overlaps with the conserved hepatitis B virus A-determinant. Hepatology 57, 985-994 (2013).
18. Urban, S. Liver capsule: entry and entry inhibition of hepatitis B virus and hepatitis delta virus into hepatocytes. Hepatology 63, 633 (2016).
19. Ni, Y. et al. Hepatitis B and D viruses exploit sodium taurocholate co-transporting polypeptide for speciesspecific entry into hepatocytes. Gastroenterology 146, 1070-1083 (2014).
20. Yan, H. et al. Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 1, e00049 (2012).
21. Anwer, M. S. &Stieger, B. Sodium-dependent bile salt transporters of the SLC10A transporter family: more than solute transporters. Pflugers Arch. 466, 77-89 (2014).
22. Chou, H. C., Hsieh, T. Y., Sheu, G. T. &Lai, M. M. Hepatitis delta antigen mediates the nuclear import of hepatitis delta virus RNA. J. Virol. 72, 3684-3690 (1998).
23. Tavanez, J. P. et al. Hepatitis delta virus ribonucleoproteins shuttle between the nucleus and the cytoplasm. RNA 8, 637-646 (2002).
24. Chang, J., Nie, X., Chang, H. E., Han, Z. &Taylor, J. Transcription of hepatitis delta virus RNA by RNA polymerase II. J. Virol. 82, 1118-1127 (2008).
25. Greco-Stewart, V. S., Miron, P., Abrahem, A. &Pelchat, M. The human RNA polymerase II interacts with the terminal stem-loop regions of the hepatitis delta virus RNA genome. Virology 357, 68-78 (2007).
26. Macnaughton, T. B., Shi, S. T., Modahl, L. E. &Lai, M. M. Rolling circle replication of hepatitis delta virus RNA is carried out by two different cellular RNA polymerases. J. Virol. 76, 3920-3927 (2002).
27. Modahl, L. E., Macnaughton, T. B., Zhu, N., Johnson, D. L. &Lai, M. M. RNA-Dependent replication and transcription of hepatitis delta virus RNA involve distinct cellular RNA polymerases. Mol. Cell. Biol. 20, 6030-6039 (2000).
28. Flores, R., Owens, R. A. &Taylor, J. Pathogenesis by subviral agents: viroids and hepatitis delta virus. Curr. Opin. Virol. 17, 87-94 (2016).
29. Modahl, L. E. &Lai, M. M. Transcription of hepatitis delta antigen mRNA continues throughout hepatitis delta virus (HDV) replication: a new model of HDV RNA transcription and replication. J. Virol. 72, 5449-5456 (1998).
30. Kuo, M. Y., Sharmeen, L., Dinter-Gottlieb, G. &Taylor, J. Characterization of self-cleaving RNA sequences on the genome and antigenome of human hepatitis delta virus. J. Virol. 62, 4439-4444 (1988).
31. Wu, H. N. et al. Human hepatitis γ virus RNA subfragments contain an autocleavage activity. Proc. Natl Acad. Sci. USA 86, 1831-1835 (1989).
32. Macnaughton, T. B., Wang, Y. J. &Lai, M. M. Replication of hepatitis delta virus RNA: effect of mutations of the autocatalytic cleavage sites. J. Virol. 67, 2228-2234 (1993).
33. Reid, C. E. &Lazinski, D. W. A host-specific function is required for ligation of a wide variety of ribozymeprocessed RNAs. Proc. Natl Acad. Sci. USA 97, 424-429 (2000).
34. Sharmeen, L., Kuo, M. Y. &Taylor, J. Self-ligating RNA sequences on the antigenome of human hepatitis delta virus. J. Virol. 63, 1428-1430 (1989).
35. Hsieh, S. Y., Chao, M., Coates, L. &Taylor, J. Hepatitis delta virus genome replication: a polyadenylated mRNA for delta antigen. J. Virol. 64, 3192-3198 (1990).
36. Lo, K., Hwang, S. B., Duncan, R., Trousdale, M. &Lai, M. M. Characterization of mRNA for hepatitis delta antigen: exclusion of the full-length antigenomic RNA as an mRNA. Virology 250, 94-105 (1998).
37. Gudima, S., Wu, S. Y., Chiang, C. M., Moraleda, G. &Taylor, J. Origin of hepatitis delta virus mRNA. J. Virol. 74, 7204-7210 (2000).
38. Taylor, J. M. Hepatitis D virus replication. Cold Spring Harb. Perspect. Med. 5, a021568 (2015).
39. Sureau, C., Taylor, J., Chao, M., Eichberg, J. W. &Lanford, R. E. Cloned hepatitis delta virus cDNA is infectious in the chimpanzee. J. Virol. 63, 4292-4297 (1989).
40. Bonino, F., Heermann, K. H., Rizzetto, M. &Gerlich, W. H. Hepatitis delta virus: protein composition of delta antigen and its hepatitis B virus-derived envelope. J. Virol. 58, 945-950 (1986).
41. Chao, M., Hsieh, S. Y. &Taylor, J. Role of two forms of hepatitis delta virus antigen: evidence for a mechanism of self-limiting genome replication. J. Virol. 64, 5066-5069 (1990).
42. Luo, G. X. et al. A specific base transition occurs on replicating hepatitis delta virus RNA. J. Virol. 64, 1021-1027 (1990).
43. Polson, A. G., Bass, B. L. &Casey, J. L. RNA editing of hepatitis delta virus antigenome by dsRNAadenosine deaminase. Nature 380, 454-456 (1996).
44. Wong, S. K. &Lazinski, D. W. Replicating hepatitis delta virus RNA is edited in the nucleus by the small form of ADAR1. Proc. Natl Acad. Sci. USA 99, 15118-15123 (2002).
45. Hartwig, D. et al. Interferon-α stimulation of liver cells enhances hepatitis delta virus RNA editing in early infection. J. Hepatol. 41, 667-672 (2004).
46. Hartwig, D. et al. The large form of ADAR 1 is responsible for enhanced hepatitis delta virus RNA editing in interferon-α-stimulated host cells. J. Viral Hepat. 13, 150-157 (2006).
47. Glenn, J. S., Taylor, J. M. &White, J. M. In vitrosynthesized hepatitis delta virus RNA initiates genome replication in cultured cells. J. Virol. 64, 3104-3107 (1990).
48. Kuo, M. Y. P., Chao, M. &Taylor, J. Initiation of replication of the human hepatitis delta virus genome from cloned DNA: role of delta antigen. J. Virol. 63, 1945-1950 (1989).
49. Alves, C., Freitas, N. &Cunha, C. Characterization of the nuclear localization signal of the hepatitis delta virus antigen. Virology 370, 12-21 (2008).
50. Cao, D., Haussecker, D., Huang, Y. &Kay, M. A. Combined proteomic-RNAi screen for host factors involved in human hepatitis delta virus replication. RNA 15, 1971-1979 (2009).
51. Lee, C. H., Chang, S. C., Wu, C. H. &Chang, M. F. A novel chromosome region maintenance 1-independent nuclear export signal of the large form of hepatitis delta antigen that is required for the viral assembly. J. Biol. Chem. 276, 8142-8148 (2001).
52. O'Malley, B. &Lazinski, D. W. Roles of carboxylterminal and farnesylated residues in the functions of the large hepatitis delta antigen. J. Virol. 79, 1142-1153 (2005).
53. Glenn, J. S., Watson, J. A., Havel, C. M. &White, J. M. Identification of a prenylation site in delta virus large antigen. Science 256, 1331-1333 (1992).
54. Otto, J. C. &Casey, P. J. The hepatitis delta virus large antigen is farnesylated both in vitro and in animal cells. J. Biol. Chem. 271, 4569-4572 (1996).
55. Hwang, S. B. &Lai, M. M. Isoprenylation masks a conformational epitope and enhances trans-dominant inhibitory function of the large hepatitis delta antigen. J. Virol. 68, 2958-2964 (1994).
56. Hwang, S. B. &Lai, M. M. Isoprenylation mediates direct protein-protein interactions between hepatitis large delta antigen and hepatitis B virus surface antigen. J. Virol. 67, 7659-7662 (1993).
57. Komla-Soukha, I. &Sureau, C. A tryptophan-rich motif in the carboxyl terminus of the small envelope protein of hepatitis B virus is central to the assembly of hepatitis delta virus particles. J. Virol. 80, 4648-4655 (2006).
58. Macnaughton, T. B. &Lai, M. M. Genomic but not antigenomic hepatitis delta virus RNA is preferentially exported from the nucleus immediately after synthesis and processing. J. Virol. 76, 3928-3935 (2002).
59. Freitas, N., Cunha, C., Menne, S. &Gudima, S. O. Envelope proteins derived from naturally integrated hepatitis B virus DNA support assembly and release of infectious hepatitis delta virus particles. J. Virol. 88, 5742-5754 (2014).
60. Lempp, F. A. &Urban, S. Generation of a cell line that supports the full lifecycle of hepatitis delta virus [poster P181]. J. Viral Hepat. 22, 109-110 (2015).
61. Gudima, S., Meier, A., Dunbrack, R., Taylor, J. &Bruss, V. Two potentially important elements of the hepatitis B virus large envelope protein are dispensable for the infectivity of hepatitis delta virus. J. Virol. 81, 4343-4347 (2007).
62. Sureau, C., Guerra, B. &Lee, H. The middle hepatitis B virus envelope protein is not necessary for infectivity of hepatitis delta virus. J. Virol. 68, 4063-4066 (1994).
63. Sureau, C., Guerra, B. &Lanford, R. E. Role of the large hepatitis B virus envelope protein in infectivity of the hepatitis delta virion. J. Virol. 67, 366-372 (1993).
64. Urban, S., Bartenschlager, R., Kubitz, R. &Zoulim, F. Strategies to inhibit entry of HBV and HDV into hepatocytes. Gastroenterology 147, 48-64 (2014).
65. Watanabe, T. et al. Involvement of host cellular multivesicular body functions in hepatitis B virus budding. Proc. Natl Acad. Sci. USA 104, 10205-10210 (2007).
66. Gripon, P. et al. Infection of a human hepatoma cell line by hepatitis B virus. Proc. Natl Acad. Sci. USA 99, 15655-15660 (2002).
67. Wieland, S. F. The chimpanzee model for hepatitis B virus infection. Cold Spring Harb. Perspect. Med. 5, a021469 (2015).
68. Dandri, M. &Lütgehetmann, M. Mouse models of hepatitis B and delta virus infection. J. Immunol. Methods 410, 39-49 (2014).
69. Bissig, K. D. et al. Human liver chimeric mice provide a model for hepatitis B and C virus infection and treatment. J. Clin. Invest. 120, 924-930 (2010).
70. Lütgehetmann, M. et al. Humanized chimeric uPA mouse model for the study of hepatitis B and D virus interactions and preclinical drug evaluation. Hepatology 55, 685-694 (2012).
71. Ponzetto, A. et al. Transmission of the hepatitis B virus-associated γ agent to the eastern woodchuck. Proc. Natl Acad. Sci. USA 81, 2208-2212 (1984).
72. Netter, H. J., Kajino, K. &Taylor, J. M. Experimental transmission of human hepatitis delta virus to the laboratory mouse. J. Virol. 67, 3357-3362 (1993).
73. Li, H. et al. HBV life cycle is restricted in mouse hepatocytes expressing human NTCP. Cell. Mol. Immunol. 11, 175-183 (2014).
74. Yan, H. et al. Molecular determinants of hepatitis B and D virus entry restriction in mouse sodium taurocholate cotransporting polypeptide. J. Virol. 87, 7977-7991 (2013).
75. Lempp, F. A. et al. 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 (2016).
76. Giersch, K. et al. Persistent hepatitis D virus monoinfection in humanized mice is efficiently converted by hepatitis B virus to a productive co-infection. J. Hepatol. 60, 538-544 (2014).
77. He, W. et al. Hepatitis D virus infection of mice expressing human sodium taurocholate co-transporting polypeptide. PLoS Pathog. 11, e1004840 (2015).
78. Winer, B. Y. &Ploss, A. Determinants of hepatitis B and delta virus host tropism. Curr. Opin. Virol. 13, 109-116 (2015).
79. Giersch, K. et al. Hepatitis Delta co-infection in humanized mice leads to pronounced induction of innate immune responses in comparison to HBV mono-infection. J. Hepatol. 63, 346-353 (2015).
80. Lutgehetmann, M. et al. In vivo proliferation of hepadnavirus-infected hepatocytes induces loss of covalently closed circular DNA in mice. Hepatology 52, 16-24 (2010).
81. Wedemeyer, H. &Manns, M. P. Epidemiology, pathogenesis and management of hepatitis D: update and challenges ahead. Nat. Rev. Gastroenterol. Hepatol. 7, 31-40 (2010).
82. Gaeta, G. B. et al. Chronic hepatitis D: a vanishing disease? An Italian multicenter study. Hepatology 32, 824-827 (2000).
83. Smedile, A. et al. Epidemiologic patterns of infection with the hepatitis B virus-associated delta agent in Italy. Am. J. Epidemiol. 117, 223-229 (1983).
84. Degertekin, H., Yalcin, K., Yakut, M. &Yurdaydin, C. Seropositivity for delta hepatitis in patients with chronic hepatitis B and liver cirrhosis in Turkey: a meta-analysis. Liver Int. 28, 494-498 (2008).
85. Cross, T. J. et al. The increasing prevalence of hepatitis delta virus (HDV) infection in South London. J. Med. Virol. 80, 277-282 (2008).
86. Heidrich, B. et al. Virological and clinical characteristics of delta hepatitis in Central Europe. J. Viral Hepat. 16, 883-894 (2009).
87. Gish, R. G. et al. Coinfection with hepatitis B and D: epidemiology, prevalence and disease in patients in Northern California. J. Gastroenterol. Hepatol. 28, 1521-1525 (2013).
88. Kushner, T., Serper, M. &Kaplan, D. E. Delta hepatitis within the Veterans Affairs medical system in the United States: prevalence, risk factors, and outcomes. J. Hepatol. 63, 586-592 (2015).
89. Kucirka, L. M. et al. Prevalence, correlates, and viral dynamics of hepatitis delta among injection drug users. J. Infect. Dis. 202, 845-852 (2010).
90. El Bouzidi, K. et al. Hepatitis delta virus testing, epidemiology and management: a multicentre crosssectional study of patients in London. J. Clin. Virol. 66, 33-37 (2015).
91. Manesis, E. K. et al. Prevalence and clinical course of hepatitis delta infection in Greece: a 13-year prospective study. J. Hepatol. 59, 949-956 (2013).
92. Hao, L. J., Li, L., Zhang, Y. Y. &Song, P. H. Hepatitis D virus infection in liver tissues of patients with hepatitis B in China. Chin. Med. J. (Engl.) 105, 204-208 (1992).
93. Rizzetto, M. &Ciancio, A. Epidemiology of hepatitis D. Semin. Liver Dis. 32, 211-219 (2012).
94. Braga, W. S. et al. Hepatitis D virus infection in the Western Brazilian Amazon-far from a vanishing disease. Rev. Soc. Bras. Med. Trop. 45, 691-695 (2012).
95. Fonseca, J. C. et al. Prevalence of infection with hepatitis delta virus (HDV) among carriers of hepatitis B surface antigen in Amazonas State, Brazil. Trans. R. Soc. Trop. Med. Hyg. 82, 469-471 (1988).
96. Viana, S., Paraná, R., Moreira, R. C., Compri, A. P. &Macedo, V. High prevalence of hepatitis B virus and hepatitis D virus in the western Brazilian Amazon. Am. J. Trop. Med. Hyg. 73, 808-814 (2005).
97. Fattovich, G., Bortolotti, F. &Donato, F. Natural history of chronic hepatitis B: special emphasis on disease progression and prognostic factors. J. Hepatol. 48, 335-352 (2008).
98. Fattovich, G. et al. Influence of hepatitis delta virus infection on morbidity and mortality in compensated cirrhosis type B. The European Concerted Action on Viral Hepatitis (Eurohep). Gut 46, 420-426 (2000).
99. Rosenblum, L. et al. Sexual practices in the transmission of hepatitis B virus and prevalence of hepatitis delta virus infection in female prostitutes in the United States. JAMA 267, 2477-2481 (1992).
100. Wu, J. C. et al. Evidence of transmission of hepatitis D virus to spouses from sequence analysis of the viral genome. Hepatology 22, 1656-1660 (1995).
101. François-Souquière, S., Makuwa, M., Bisvigou, U. &Kazanji, M. Epidemiological and molecular features of hepatitis B and hepatitis delta virus transmission in a remote rural community in central Africa. Infect. Genet. Evol. 39, 12-21 (2016).
102. Niro, G. A. et al. Intrafamilial transmission of hepatitis delta virus: molecular evidence. J. Hepatol. 30, 564-569 (1999).
103. Ramia, S. &Bahakim, H. Perinatal transmission of hepatitis B virus-associated hepatitis D virus. Ann. Inst. Pasteur Virol. 139, 285-290 (1988).
104. Yurdaydin, C., Idilman, R., Bozkaya, H. &Bozdayi, A. M. Natural history and treatment of chronic delta hepatitis. J. Viral Hepat. 17, 749-756 (2010).
105. Negro, F. Hepatitis D virus coinfection and superinfection. Cold Spring Harb. Perspect. Med. 4, a021550 (2014).
106. Guilhot, S. et al. Expression of the hepatitis delta virus large and small antigens in transgenic mice. J. Virol. 68, 1052-1058 (1994).
107. Verme, G. et al. A histological study of hepatitis delta virus liver disease. Hepatology 6, 1303-1307 (1986).
108. Pugnale, P., Pazienza, V., Guilloux, K. &Negro, F. Hepatitis delta virus inhibits alpha interferon signaling. Hepatology 49, 398-406 (2009).
109. Lunemann, S. et al. Effects of HDV infection and pegylated interferon α treatment on the natural killer cell compartment in chronically infected individuals. Gut 64, 469-482 (2015).
110. Lunemann, S. et al. Compromised function of natural killer cells in acute and chronic viral hepatitis. J. Infect. Dis. 209, 1362-1373 (2014).
111. Nisini, R. et al. Human CD4+ T-cell response to hepatitis delta virus: identification of multiple epitopes and characterization of T-helper cytokine profiles. J. Virol. 71, 2241-2251 (1997).
112. Grabowski, J. et al. Hepatitis D virus-specific cytokine responses in patients with chronic hepatitis delta before and during interferon alfa-treatment. Liver Int. 31, 1395-1405 (2011).
113. Su, C. W. et al. Genotypes and viremia of hepatitis B and D viruses are associated with outcomes of chronic hepatitis D patients. Gastroenterology 130, 1625-1635 (2006).
114. Casey, J. L. et al. Hepatitis B virus (HBV)/hepatitis D virus (HDV) coinfection in outbreaks of acute hepatitis in the Peruvian Amazon basin: the roles of HDV genotype III and HBV genotype F. J. Infect. Dis. 174, 920-926 (1996).
115. Gomes-Gouvea, M. S. et al. Hepatitis B virus and hepatitis delta virus genotypes in outbreaks of fulminant hepatitis (Labrea black fever) in the western Brazilian Amazon region. J. Gen. Virol. 90, 2638-2643 (2009).
116. Lee, C. M., Bih, F. Y., Chao, Y. C., Govindarajan, S. &Lai, M. M. Evolution of hepatitis delta virus RNA during chronic infection. Virology 188, 265-273 (1992).
117. Rizzetto, M. et al. Treatment of chronic delta hepatitis with alpha-2 recombinant interferon. J. Hepatol. 3, S229-S233 (1986).
118. Hughes, S. A., Wedemeyer, H. &Harrison, P. M. Hepatitis delta virus. Lancet 378, 73-85 (2011).
119. Wranke, A., Heidrich, B., Hardtke, S. &Wedemeyer, H. Current management of HBV/HDV coinfection and future perspectives. Curr. Hepatol. Rep. 14, 284-292 (2015).
120. Wedemeyer, H. et al. Peginterferon plus adefovir versus either drug alone for hepatitis delta. N. Engl. J. Med. 364, 322-331 (2011).
121. Heidrich, B. et al. Late HDV RNA relapse after peginterferon alpha-based therapy of chronic hepatitis delta. Hepatology 60, 87-97 (2014).
122. Wedemeyer, H. et al. Prolonged therapy of hepatitis delta for 96 weeks with PEG-IFNa-2a plus tenofovir or placebo does not prevent HDV RNA relapse: the HIDIT-2 study. Presented at the International Liver Congress 2014 http://hepatitis-delta.org/assets/ DownloadPage/000000/2014-04-HIDIT-II-EASLHomepage. pdf (2014).
123. Wedemeyer, H. et al. Prolonged therapy of hepatitis delta for 96 weeks with pegylated-interferon-α-2a plus tenofovir or placebo does not prevent HDV RNA relapse: the HIDIT-2 study [abstract]. J. Hepatol. 60, S2-S3 (2014).
124. Lai, M. M. RNA replication without RNA-dependent RNA polymerase: surprises from hepatitis delta virus. J. Virol. 79, 7951-7958 (2005).
125. Yen, L., Magnier, M., Weissleder, R., Stockwell, B. R. &Mulligan, R. C. Identification of inhibitors of ribozyme self-cleavage in mammalian cells via high-throughput screening of chemical libraries. RNA 12, 797-806 (2006).
126. Chang, J. &Taylor, J. M. Susceptibility of human hepatitis delta virus RNAs to small interfering RNA action. J. Virol. 77, 9728-9731 (2003).
127. Wooddell, C. I. et al. Hepatocyte-targeted RNAi therapeutics for the treatment of chronic hepatitis B virus infection. Mol. Ther. 21, 973-985 (2013).
128. Yuen, M. F. et al. ARC-520 produces deep and durable knockdown of viral antigens and DNA in a phase II study in patients with chronic hepatitis B [abstract LB-9]. Hepatology 62, 1385A (2015).
129. Meier, A., Mehrle, S., Weiss, T. S., Mier, W. &Urban, S. Myristoylated PreS1-domain of the hepatitis B virus L-protein mediates specific binding to differentiated hepatocytes. Hepatology 58, 31-42 (2013).
130. Schieck, A. et al. Hepatitis B virus hepatotropism is mediated by specific receptor recognition in the liver and not restricted to susceptible hosts. Hepatology 58, 43-53 (2013).
131. Koh, C. et al. Oral prenylation inhibition with lonafarnib in chronic hepatitis D infection: a proof-of-concept randomised, double-blind, placebo-controlled phase 2A trial. Lancet Infect. Dis. 15, 1167-1174 (2015).
132. Yurdaydin, C. et al. Optimizing the prenylation inhibitor lonafarnib using ritonavir boosting in patients with chronic delta hepatitis [oral presentation O118]. J. Hepatol. 62 (Suppl. 2), S252 (2015).
133. Koh, C. et al. Prenylation inhibition with lonafarnib decreases hepatitis D levels in humans [poster 1860]. Hepatology 60, 1092A (2014).
134. Bazinet, M. et al. REP 2139 monotherapy and combination therapy with pegylated interferon: safety and potent reduction of HBsAg and HDV RNA in Caucasian patients with chronic HBV/HDV co-infection [oral presentation HDV2 O-09]. J. Viral Hepat. 22, 5-6 (2015).
135. Poutay, D. et al. Nucleic acid polymers are efficient in blocking hepatitis delta virus entry in vitro [poster P177]. J. Viral Hepat. 22, 107 (2015).
136. Bazinet, M. et al. Update on the safety and efficacy of REP 2139 mono-therapy and subsequent combination therapy with pegylated interferon alpha-2a in chronic HBV/HDV co-infection in Caucasian patients [abstract]. Hepatology 62, 222A (2015).
137. Bogomolov, P. et al. A proof-of-concept Phase 2a clinical trial with HBV/HDV entry inhibitor Myrcludex B [abstract]. Hepatology 60, 1279A-1280A (2014).
138. Blank, A. et al. First-in-human application of the novel hepatitis B and hepatitis D virus entry inhibitor Myrcludex B. J. Hepatol. http://dx.doi.org/10.1016/ j.jhep.2016.04.013 (2016).
139. Bogomolov, P. et al. Treatment of chronic hepatitis D with the entry inhibitor myrcludex B: first results of a phase Ib/IIa study. J. Hepatol. http://dx.doi.org/ 10.1016/j.jhep.2016.04.016 (2016).
140. Yust-Katz, S. et al. Phase 1/1b study of lonafarnib and temozolomide in patients with recurrent or temozolomide refractory glioblastoma. Cancer 119, 2747-2753 (2013).
141. Rizzetto, M. &Ciancio, A. The prenylation inhibitor, lonafarnib: a new therapeutic strategy against hepatitis delta. Lancet Infect. Dis. 15, 1119-1120 (2015).
142. Bordier, B. B. et al. A prenylation inhibitor prevents production of infectious hepatitis delta virus particles. J. Virol. 76, 10465-10472 (2002).
143. Bordier, B. B. et al. In vivo antiviral efficacy of prenylation inhibitors against hepatitis delta virus. J. Clin. Invest. 112, 407-414 (2003).
144. Berndt, N., Hamilton, A. D. &Sebti, S. M. Targeting protein prenylation for cancer therapy. Nat. Rev. Cancer 11, 775-791 (2011).
145. Palsuledesai, C. C. &Distefano, M. D. Protein prenylation: enzymes, therapeutics, and biotechnology applications. ACS Chem. Biol. 10, 51-62 (2015).
146. Offensperger, W. B., Offensperger, S., Walter, E., Blum, H. E. &Gerok, W. Suramin prevents duck hepatitis B virus infection in vivo. Antimicrob. Agents Chemother. 37, 1539-1542 (1993).
147. Poutay, D. et al. Nucleic acid polymers are efficient in blocking hepatitis delta virus entry in vitro [abstract LP26]. J. Hepatol. 62 (Suppl. 2), S276 (2015).
148. Replicor. Conference presentations http://replicor.com/ wp-content/uploads/2016/05/Poster-FRI-105-EASL-2016.pdf (2016).
149. Gripon, P., Cannie, I. &Urban, S. Efficient inhibition of hepatitis B virus infection by acylated peptides derived from the large viral surface protein. J. Virol. 79, 1613-1622 (2005).
150. Petersen, J. et al. Prevention of hepatitis B virus infection in vivo by entry inhibitors derived from the large envelope protein. Nat. Biotechnol. 26, 335-341 (2008).
151. Schulze, A., Schieck, A., Ni, Y., Mier, W. &Urban, S. Fine mapping of pre-S sequence requirements for hepatitis B virus large envelope protein-mediated receptor interaction. J. Virol. 84, 1989-2000 (2010).
152. Nkongolo, S. et al. Cyclosporin A inhibits hepatitis B and hepatitis D virus entry by cyclophilin-independent interference with the NTCP receptor. J. Hepatol. 60, 723-731 (2014).
153. Haag, M. et al. Quantitative bile acid profiling by liquid chromatography quadrupole time-of-flight mass spectrometry: monitoring hepatitis B therapy by a novel Na+-taurocholate cotransporting polypeptide inhibitor. Anal. Bioanal. Chem. 407, 6815-6825 (2015).
154. Slijepcevic, D. et al. Impaired uptake of conjugated bile acids and hepatitis B virus preS1-binding in Na+-taurocholate cotransporting polypeptide knockout mice. Hepatology 62, 207-219 (2015).
155. Vaz, F. M. et al. Sodium taurocholate cotransporting polypeptide (SLC10A1) deficiency: conjugated hypercholanemia without a clear clinical phenotype. Hepatology 61, 260-267 (2015).
156. Makino, S. et al. Molecular cloning and sequencing of a human hepatitis delta (γ) virus RNA. Nature 329, 343-346 (1987).
157. Nassal, M. HBV cccDNA: viral persistence reservoir and key obstacle for a cure of chronic hepatitis B. Gut 64, 1972-1984 (2015).