Hepatitis B virus (HBV) has evolved a unique life cycle that results in the production of enormous viral loads during active replication without actually killing the infected cell directly. Because HBV uses reverse transcription to copy its DNA genome, mutant viral genomes emerge frequently. Particular selection pressures, both endogenous (host immune clearance) and exogenous (vaccines and antiviral drugs), readily select out these escape mutants. Which particular viral mutations or combination of mutations directly affect the clinical outcome of infection are not known. Further studies are clearly needed to identify the pathogenic basis and clinical sequelae arising from the selection of these mutants.
KEYWORDS
Reverse transcription - covalently closed circular DNA - viral mutants - drug resistance - vaccine escape
REFERENCES
-
1
Guidotti L G, Rochford R, Chung J et al..
Viral clearance without destruction of infected cells during acute HBV infection.
Science.
1999;
284
825-829
-
2
Nayersina R, Fowler P, Guilhot S et al..
HLA A2 restricted cytotoxic T lymphocyte responses to multiple hepatitis B surface antigen epitopes during hepatitis B virus infection.
J Immunol.
1993;
150
4659-4671
-
3
Rehermann B, Fowler P, Sidney J et al..
The cytotoxic T lymphocyte response to multiple hepatitis B virus polymerase epitopes during and after acute viral hepatitis.
J Exp Med.
1995;
181
1047-1058
-
4
Penna A, Del Prete G, Cavalli A et al..
Predominant T-helper 1 cytokine profile of hepatitis B virus nucleocapsid-specific T cells in acute self-limited hepatitis B.
Hepatology.
1997;
25
1022-1027
-
5
Webster G J, Reignat S, Maini M K et al..
Incubation phase of acute hepatitis B in man: dynamic of cellular immune mechanisms.
Hepatology.
2000;
32
1117-1124
-
6
Ferrari C, Penna A, Giuberti T et al..
Intrahepatic, nucleocapsid antigen-specific T cells in chronic active hepatitis B.
J Immunol.
1987;
139
2050-2058
-
7
Barnaba V, Franco A, Alberti A et al..
Recognition of hepatitis B virus envelope proteins by liver-infiltrating T lymphocytes in chronic HBV infection.
J Immunol.
1989;
143
2650-2655
-
8
Lohr H F, Gerken G, Schlicht H J, Meryer zum Buschenfelde 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;
168
1133-1139
-
9
Jung M, Pape G.
Immunology of hepatitis B infection.
Lancet Infect Dis.
2002;
2
43-50
-
10
Guidotti L G, Chisari F V.
Cytokine-mediated control of viral infections.
Virology.
2000;
273
221-227
-
11 Ganem D, Schneider R. Hepadnaviridae: the viruses and their replication. In: Knipe DM, Howley PM Fields Virology. Philadelphia; Lippincott-Raven 2001: 2923-2970
-
12
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
-
13
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
67-74
-
14
Kann M, Bischof A, Gerlich W H.
In vitro model for the nuclear transport of the hepadnavirus genome.
J Virol.
1997;
71
1310-1316
-
15 Ganem D. Hepadnaviridae and their replication. In: Fields BN, Knipe DM, Howley PM Fields Virology, 3rd ed. Philadelphia; Raven 1996: 2703-2737
-
16
Tavis J.
The replication strategy of the Hepadanaviruses.
Viral Hepatitis Reviews.
1996;
2
205-218
-
17
Summers J, Mason W S.
Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate.
Cell.
1982;
29
403-415
-
18
Okamoto H, Imai M, Kametani M et al..
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
-
19
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
-
20
Hunt C M, McGill J M, Allen M I et al..
Clinical relevance of hepatitis B viral mutations.
Hepatology.
2000;
31
1037-1044
-
21
Gunther S, Fischer L, Pult I et al..
Naturally occurring variants of hepatitis B virus.
Adv Virus Res.
1999;
52
25-137
-
22
Akarca U S, Lok A S.
Naturally occurring hepatitis B virus core gene mutations.
Hepatology.
1995;
22
50-60
-
23
Carman W F, Zanetti A R, Karayiannis P et al..
Vaccine-induced escape mutant of hepatitis B virus.
Lancet.
1990;
336
325-329
-
24
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
-
25
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
-
26
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
-
27
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
-
28
Leung N.
Clinical experience with lamivudine.
Semin Liver Dis.
2002;
22(Suppl 1)
15-21
-
29
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
-
30
Ogata N, Fujii K, Takigawa S et al..
Novel patterns of amino acid mutations in the hepatitis B virus polymerase in association with resistance to lamivudine therapy in Japanese patients with chronic hepatitis B.
J Med Virol.
1999;
59
270-276
-
31
Bock C, Tillmann H, Torresi J et al..
HBV polymerase mutants with enhanced replication selected during lamivudine therapy result in sudden onset of liver failure.
Gastroenterology.
2002;
122
264-273
-
32
Hadziyannis S J, Papatheodoridis G V, Dimou E et al..
Efficacy of long-term lamivudine monotherapy in patients with hepatitis B e antigen-negative chronic hepatitis B.
Hepatology.
2000;
32
847-851
-
33
Papatheodoridis G V, Dimou E, Laras A et al..
Course of virologic breakthroughs under long-term lamivudine in HBeAg-negative precore mutant HBV liver disease.
Hepatology.
2002;
36
219-226
-
34
Chen R, Edwards R, Shaw T et al..
Effect of the G1896A precore mutation on drug sensitivity and replication yield of lamivudine-resistant HBV in vitro.
Hepatology.
2003;
37
27-35
-
35
Wang J H, Lu S N, Lee C M et al..
Fatal hepatic failure after emergence of the hepatitis B virus mutant during lamivudine therapy in a patient with liver cirrhosis.
Scand J Gastroenterol.
2002;
37
366-369
-
36
Liaw Y-F, Chien R-N, Yeh C-T et al..
Acute exacerbation and hepatitis B virus clearance after emergence of YMDD motif mutation during lamivudine therapy.
Hepatology.
1999;
30
567-572
-
37
De Man R A, Bartholomeusz A, Niesters H GM et al..
The sequential occurrence of viral mutations in a liver transplant recipient re-infected with hepatitis B virus: hepatitis B immune globulin escape, famciclovir non-response, followed by lamivudine resistance resulting in graft loss.
J Hepatol.
1998;
29
669-675
-
38
Soriano V.
Hepatitis B virus infection despite receiving lamivudine in one HIV-infected person.
HIV Clin Trials.
2003;
4
77-78
-
39
Ayres A, Bartholomeusz A, Lau G K et al..
Lamivudine and famciclovir resistant hepatitis B virus associated with fatal hepatic failure.
J Clin Virol.
2003;
27
111-116
-
40
Thibault V, Aubron-Olivier C, Agut H et al..
Primary infection with a lamivudine-resistant hepatitis B virus.
AIDS.
2002;
16
131-133
-
41
Shaw T, Locarnini S.
Combination chemotherapy for hepatitis B virus: the path forward?.
Drugs.
2000;
60
517-531
-
42
Locarnini S, Birch C.
Antiviral chemotherapy for chronic hepatitis B infection: Lessons learned from treating HIV infected patients.
J Hepatol.
1999;
30
536-550
-
43
Lewin S R, Ribeiro R M, Walter T et al..
Analysis of hepatitis B viral load decline under potent therapy: complex decay profiles observed.
Hepatology.
2001;
34
1012-1020
Professor
Stephen Locarnini
Victorian Infectious Diseases Reference Laboratory
10 Wreckyn Street, North Melbourne
Victoria 3051, Australia
Email: stephenlocarnini@compuserve.com
Email: stephen.locarnini@mh.org.au