Download PDF
Semin Liver Dis 2005; 25: 9-19
DOI: 10.1055/s-2005-915645
Copyright © 2005 by Thieme Medical Publishers, Inc., 333 Seventh Avenue, New York, NY 10001, USA.

Molecular Virology and the Development of Resistant Mutants: Implications for Therapy

Stephen Locarnini1
  • 1Professor, Victorian Infectious Diseases Reference Laboratory, North Melbourne, Australia
Further Information

Publication History

Publication Date:
16 August 2005 (online)

    Permissions and Reprints

ABSTRACT

Two of the key events in the viral life cycle of the hepatitis B virus (HBV) involve (1) generation from genomic DNA of the covalently closed circular DNA transcriptional template and (2) reverse transcription of the viral pregenomic RNA to form the HBV DNA genome. Because the virus employs reverse transcription to copy its genome, mutant viral genomes are found frequently. Particular selection pressures, both endogenous (host immune clearance) and exogenous (vaccines and antivirals), readily select out these escape mutants. The introduction of nucleoside/nucleotide analogue therapy has seen the emergence of drug resistance as the major factor limiting drug efficacy. The development of drug resistance is not unexpected if viral replication continues in the setting of ongoing treatment, especially monotherapy. Thus, prevention of resistance requires the adoption of strategies that effectively control virus replication.

KEYWORDS

Reverse transcription - covalently closed circular DNA - viral mutants - drug resistance - vaccine escape

REFERENCES

  • 1 Chisari F, Ferrari C. Hepatitis B virus immunopathogenesis.  Annu Rev Immunol. 1995;  13 29-60
    CrossrefPubMedGoogle Scholar
  • 2 Norder H, Courouce A M, Magnius L O. Complete genomes, phylogenetic relatedness, and structural proteins of six strains of the hepatitis B virus, four of which represent two new genotypes.  Virology. 1994;  198 489-503
    CrossrefPubMedGoogle Scholar
  • 3 Stuyver L, De Gendt S, Van Geyt C et al.. A new genotype of hepatitis B virus: complete genome and phylogenetic relatedness.  J Gen Virol. 2000;  81(part 1) 67-74
    PubMedGoogle Scholar
  • 4 Ganem D, Schneider R. Hepadnaviridae: the viruses and their replication. In: Knipe DM, Howley PM Fields Virology, 4th ed. Vol. 2 Philadelphia; Lippincott-Raven 2001: 2923-2970
    Google Scholar
  • 5 De Meyer S, Gong Z, Suwandhi W, Van Pelt J, Soumillion A, Yap S. Organ and species specificity of hepatitis B virus (HBV) infection: a review of literature with a special reference to preferential attachment of HBV to human hepatocytes.  J Viral Hepatitis. 1997;  4 145-153
    CrossrefPubMedGoogle Scholar
  • 6 Rabe B, Vlachou A, Pante N, Helenius A, Kann M. Nuclear import of hepatitis B virus capsids and release of the viral genome.  Proc Natl Acad Sci USA. 2003;  100 9849-9854
    CrossrefPubMedGoogle Scholar
  • 7 Bock C T, Schranz P, Schroder C H, Zentgraf H. Hepatitis B virus genome is organized into nucleosomes in the nucleus of the infected cell.  Virus Genes. 1994;  8 215-229
    CrossrefPubMedGoogle Scholar
  • 8 Newbold J E, Xin H, Tencza M et al.. The covalently closed duplex form of the hepadnavirus genome exists in situ as a heterogeneous population of viral minochromosomes.  J Virol. 1995;  69 3350-3357
    PubMedGoogle Scholar
  • 9 Kann M, Gerlich W. Hepadnaviridae: structure and molecular virology. In: Zuckerman A, Thomas H Viral Hepatitis London; Churchill Livingstone 1998: 77-105
    Google Scholar
  • 10 Bartenschlager R, Schaller H. Hepadnaviral assembly is initiated by polymerase binding to the encapsidation signal in the viral RNA genome.  EMBO J. 1992;  11 3413-3420
    PubMedGoogle Scholar
  • 11 Zoulim F, Seeger C. Reverse transcription in hepatitis B viruses is primed by a tyrosine residue of the polymerase.  J Virol. 1994;  68 6-13
    PubMedGoogle Scholar
  • 12 Will H, Reiser W, Weimer T et al.. Replication strategy of human hepatitis B virus.  J Virol. 1987;  61 904-911
    PubMedGoogle Scholar
  • 13 Gerelsaikhan T, Tavis J E, Bruss V. Hepatitis B virus nucleocapsid envelopment does not occur without genomic DNA synthesis.  J Virol. 1996;  70 4269-4274
    PubMedGoogle Scholar
  • 14 Scaglioni P P, Melegari M, Wands J R. Posttranscriptional regulation of hepatitis B virus replication by the precore protein.  J Virol. 1997;  71 345-353
    PubMedGoogle Scholar
  • 15 Hadziyannis S. Hepatitis Be antigen negative chronic hepatitis B: from clinical recognition to pathogenesis and treatment.  Viral Hepatitis Rev. 1995;  1 7-36
    PubMedGoogle Scholar
  • 16 Hunt C M, McGill J M, Allen M I, Condreay L D. Clinical relevance of hepatitis B viral mutations.  Hepatology. 2000;  31 1037-1044
    CrossrefPubMedGoogle Scholar
  • 17 Locarnini S, Shaw T, Dean J et al.. Cellular response to conditional expression of the hepatitis B virus precore and core proteins in cultured hepatoma (Huh-7) cells.  J Clin Virol. 2005;  32 113-121
    CrossrefPubMedGoogle Scholar
  • 18 Milich D R, Jones J E, Hughes J L, Price J, Raney A K, McLachlan A. Is a function of the secreted hepatitis B e antigen to induce immunologic tolerance in utero?.  Proc Natl Acad Sci USA. 1990;  87 6599-6603
    PubMedGoogle Scholar
  • 19 Bartholomeusz A, Schaefer S. Hepatitis B virus genotypes: comparison of genotyping methods.  Rev Med Virol. 2004;  14 3-16
    CrossrefPubMedGoogle Scholar
  • 20 Lok A S, Akarca U, Greene S. Mutations in the pre-core region of hepatitis B virus serve to enhance the stability of the secondary structure of the pre-genome encapsidation signal.  Proc Natl Acad Sci USA. 1994;  91 4077-4081
    PubMedGoogle Scholar
  • 21 Le Pogam S, Yuan T, Sahu G, Chatterjee S, Shih C. Low-level secretion of human hepatitis B virus virions caused by two independent, naturally occurring mutations (P5T and L60V) in the capsid protein.  J Virol. 2000;  74 9099-9105
    CrossrefPubMedGoogle Scholar
  • 22 Lohr H F, Gerken G, Schlicht H J, Meyer zum Buschenfeld K H, Fleischer B. Low frequency of cytotoxic liver-infiltrating T lymphocytes specific for endogenous processed surface and core proteins in chronic hepatitis B.  J Infect Dis. 1993;  68 1133-1139
    PubMedGoogle Scholar
  • 23 Jung M, Pape G. Immunology of hepatitis B infection.  Lancet Infect Dis. 2002;  2 43-50
    PubMedGoogle Scholar
  • 24 Gunther S, Fischer L, Pult I, Sterneck M, Will H. Naturally occurring variants of hepatitis B virus.  Adv Virus Res. 1999;  52 25-137
    PubMedGoogle Scholar
  • 25 Akarca U S, Lok A S. Naturally occurring hepatitis B virus core gene mutations.  Hepatology. 1995;  22 50-60
    CrossrefPubMedGoogle Scholar
  • 26 Bouchard M J, Schneider R J. The enigmatic X gene of hepatitis B virus.  J Virol. 2004;  78 12725-12734
    CrossrefPubMedGoogle Scholar
  • 27 Shaw T, Locarnini S A. Preclinical aspects of lamivudine and famciclovir against hepatitis B virus.  J Viral Hepat. 1999;  6 89-106
    CrossrefPubMedGoogle Scholar
  • 28 Shaw T, Locarnini S A. Hepatic purine and pyrimidine metabolism: implications for antiviral chemotherapy of viral hepatitis.  Liver. 1995;  15 169-184
    PubMedGoogle Scholar
  • 29 Carman W F, Zanetti A R, Karayiannis P et al.. Vaccine-induced escape mutant of hepatitis B virus.  Lancet. 1990;  336 325-329
    CrossrefPubMedGoogle Scholar
  • 30 Carman W F, Trautwein C, van Deursen F J et al.. Hepatitis B virus envelope variation after transplantation with and without hepatitis B immune globulin prophylaxis.  Hepatology. 1996;  24 489-493
    PubMedGoogle Scholar
  • 31 Shaw T, Locarnini S. Entecavir for the treatment of chronic hepatitis B.  Expert Rev Anti Infect Ther. 2004;  2 853-871
    CrossrefPubMedGoogle Scholar
  • 32 Stuyver L J, Locarnini S A, Lok A et al.. Nomenclature for antiviral-resistant human hepatitis B virus mutations in the polymerase region.  Hepatology. 2001;  33 751-757
    CrossrefPubMedGoogle Scholar
  • 33 Lai C L, Dienstag J, Schiff E et al.. Prevalence and clinical correlates of YMDD variants during lamivudine therapy for patients with chronic hepatitis B.  Clin Infect Dis. 2003;  36 687-696
    CrossrefPubMedGoogle Scholar
  • 34 Leung N. Clinical experience with lamivudine.  Semin Liver Dis. 2002;  22(suppl 1) 15-21
    PubMedGoogle Scholar
  • 35 Angus P, Vaughan R, Xiong S et al.. Resistance to adefovir dipivoxil therapy associated with development of a novel mutation in the HBV polymerase.  Gastroenterology. 2003;  125 292-297
    CrossrefPubMedGoogle Scholar
  • 36 Tenney D J, Levine S M, Rose R E et al.. Clinical emergence of entecavir-resistant hepatitis B virus requires additional substitutions in virus already resistant to lamivudine.  Antimicrob Agents Chemother. 2004;  48 3498-3507
    CrossrefPubMedGoogle Scholar
  • 37 Chin R, Shaw T, Torresi J et al.. In vitro susceptibilities of wild-type or drug-resistant hepatitis B virus to (-)-beta-D-2,6-diaminopurine dioxolane and 2'-fluoro-5-methyl-beta-L-arabinofuranosyluracil.  Antimicrob Agents Chemother. 2001;  45 2495-2501
    CrossrefPubMedGoogle Scholar
  • 38 Ono-Nita S K, Kato N, Shiratori Y, Carrilho F J, Omata M. Novel nucleoside analogue MCC-478 (LY582563) is effective against wild-type or lamivudine-resistant hepatitis B virus.  Antimicrob Agents Chemother. 2002;  46 2602-2605
    CrossrefPubMedGoogle Scholar
  • 39 Levine S, Hernandez D, Yamanaka G et al.. Efficacies of entecavir against lamivudine-resistant hepatitis B virus replication and recombinant polymerases in vitro.  Antimicrob Agents Chemother. 2002;  46 2525-2532
    CrossrefPubMedGoogle Scholar
  • 40 Delaney IV W E, Locarnini S, Shaw T. Resistance of hepatitis B virus to antiviral drugs: current aspects and directions for future investigation.  Antivir Chem Chemother. 2001;  12 1-35
    PubMedGoogle Scholar
  • 41 Zollner B, Petersen J, Puchhammer-Stockl E et al.. Viral features of lamivudine resistant hepatitis B genotypes A and D.  Hepatology. 2004;  39 42-50
    CrossrefPubMedGoogle Scholar
  • 42 Bartholomeusz A, Tehan B G, Chalmers D K. Comparisons of the HBV and HIV polymerase, and antiviral resistance mutations.  Antivir Ther. 2004;  9 149-160
    PubMedGoogle Scholar
  • 43 Bartholomeusz A, Locarnini S, Ayres A et al.. Molecular modelling of hepatitis B virus polymerase and adefovir resistance identifies three clusters of mutations.  Hepatology. 2004;  40 246A
    PubMedGoogle Scholar
  • 44 Warner N, Locarnini S, Colledge D et al.. Molecular modelling of entecavir resistant mutations in the hepatitis B virus polymerase selected during therapy.  Hepatology. 2004;  40 245A
    PubMedGoogle Scholar
  • 45 Angus P, Locarnini S. Lamivudine-resistant hepatitis B virus and ongoing lamivudine therapy: stop the merry-go-round, it's time to get off!.  Antivir Ther. 2004;  9 145-148
    PubMedGoogle Scholar
  • 46 Richman D D. The impact of drug resistance on the effectiveness of chemotherapy for chronic hepatitis B.  Hepatology. 2000;  32 866-867
    CrossrefPubMedGoogle Scholar
  • 47 Okamoto H, Imai M, Kametani M, Nakamura T, Mayumi M. Genomic heterogeneity of hepatitis B virus in a 54-year-old woman who contracted the infection through materno-fetal transmission.  Jpn J Exp Med. 1987;  57 231-236
    PubMedGoogle Scholar
  • 48 Girones R, Miller R H. Mutation rate of the hepadnavirus genome.  Virology. 1989;  170 595-597
    CrossrefPubMedGoogle Scholar
  • 49 Nowak M A, Bonhoeffer S, Hill A M, Boehme R, Thomas H C, McDade H. Viral dynamics in hepatitis B virus infection.  Proc Natl Acad Sci USA. 1996;  93 4398-4402
    CrossrefPubMedGoogle Scholar
  • 50 Locarnini S, Hatzakis A, Heathcote J et al.. Management of antiviral resistance in patients with chronic hepatitis B.  Antivir Ther. 2004;  9 679-693
    PubMedGoogle Scholar
  • 51 Richman D D. The implications of drug resistance for strategies of combination antiviral chemotherapy.  Antiviral Res. 1996;  29 31-33
    CrossrefPubMedGoogle Scholar
  • 52 Thibault V, Aubron-Olivier C, Agut H, Katlama C. Primary infection with a lamivudine-resistant hepatitis B virus.  AIDS. 2002;  16 131-133
    CrossrefPubMedGoogle Scholar
  • 53 Niesters H G, De Man R A, Pas S D, Fries E, Osterhaus A D. Identification of a new variant in the YMDD motif of the hepatitis B virus polymerase gene selected during lamivudine therapy.  J Med Microbiol. 2002;  51 695-699
    PubMedGoogle Scholar
  • 54 Lok A S, Zoulim F, Locarnini S et al.. Monitoring drug resistance in chronic hepatitis B virus (HBV)-infected patients during lamivudine therapy: evaluation of performance of INNO- LiPA HBV DR assay.  J Clin Microbiol. 2002;  40 3729-3734
    CrossrefPubMedGoogle Scholar
  • 55 Zhang Y Y, Summers J. Enrichment of a precore-minus mutant of duck hepatitis B virus in experimental mixed infections.  J Virol. 1999;  73 3616-3622
    PubMedGoogle Scholar
  • 56 Zhang Y Y, Summers J. Low dynamic state of viral competition in a chronic avian hepadnavirus infection.  J Virol. 2000;  74 5257-5265
    CrossrefPubMedGoogle Scholar
  • 57 Doo E, Liang J T. Molecular anatomy and pathophysiologic implications of drug resistance in hepatitis B virus infection.  Gastroenterology. 2001;  120 1000-1008
    PubMedGoogle Scholar
  • 58 Seeger C, Mason W S. Hepatitis B virus biology.  Microbiol Mol Biol Rev. 2000;  64 51-68
    CrossrefPubMedGoogle Scholar
  • 59 Locarnini S, Birch C. Antiviral chemotherapy for chronic hepatitis B infection: lessons learned from treating HIV infected patients.  J Hepatol. 1999;  30 536-550
    CrossrefPubMedGoogle Scholar
  • 60 Colgrove R, Japour A. A combinatorial ledge: reverse transcriptase fidelity, total body viral burden, and the implications of multiple-drug HIV therapy for the evolution of antiviral resistance.  Antiviral Res. 1999;  41 45-56
    CrossrefPubMedGoogle Scholar
  • 61 Shaw T, Locarnini S. Combination chemotherapy for hepatitis B virus: the path forward?.  Drugs. 2000;  60 517-531
    PubMedGoogle Scholar

 Professor
Stephen Locarnini

Victorian Infectious Diseases Reference Laboratory

10 Wreckyn Street, North Melbourne

Victoria 3051, Australia

Email: stephen.locarnini@mh.org.au

      >