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Hepatitis B Virus
Trends in Microbiology | Microbe of The Month Special Issue: Broad Concepts in Microbiology
Hepatitis B Virus
Chiaho Shih,1,2,3,* Ching-Chun Yang,1,2 Gansukh Choijilsuren,1,2 Chih-Hsu Chang,1,3 and An-Ting Liou1 1
Institute of Biomedical Sciences (IBMS), Academia Sinica, Taipei, Taiwan Taiwan International Graduate Program (TIGP) in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan 3 Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan 2
KEY FACTS:
Virion
HBs subviral parƟcles
Heparan sulfate Na+ bile acid proteoglycan symporter
No known reservoir. HBV has a tight species barrier. Discovered by Dr Baruch Blumberg in 1967 (Nobel Laureate in 1976).
Entry Hepatocyte MulƟvesicular body
Golgi ER
The HBV genome is 3.2 kb DNA; partially double-stranded rc DNA occurs in virions, and ccc DNA occurs in the nucleus of infected hepatocytes.
Morphogenesis
rcDNA
rcDNA rcDNA TranslaƟon of HBsAg A(n) A(n) A(n)
TranscripƟon
A(n) A(n) A(n)
TranslaƟon & capsid assembly
ssDNA
A(n)
cccDNA
Viral particles are infectious, enveloped spherical virions (42 nm); there are excessive numbers of noninfectious HBs subviral particles (22 nm), and icosahedral nucleocapsids (27–32 nm).
pgRNA
Viral antigens include core (HBc), surface (HBs, Australia Ag), polymerase (pol contains a reverse transcriptase domain), and HBx. HBV animal models include the chimpanzee, bat, woodchuck, ground squirrel, and duck. DISEASE FACTS:
Hepatitis B virus (HBV) is a common worldwide blood-borne pathogen. Chronic hepatitis B can progress to an inactive carrier state, and then, in some patients, give rise to cirrhosis and cancer of the liver, leading to death. An HBV surface-antigen vaccine is effective, but treatments are currently not curative. HBV replicates via reverse transcription. Its covalently closed circular (ccc) DNA in the nucleus encodes a pregenomic RNA (pgRNA), which can be encapsidated by HBV polymerase. Reverse transcription occurs in the capsids by using the pgRNA as a template for the synthesis of single-stranded linear and then partially double-stranded relaxed circular (rc) DNA. Capsids containing a mature rc DNA genome target to the nucleus for ccc DNA synthesis. Persistent HBV infection is caused mainly by ccc DNA and immune tolerance to HBV antigens in the liver. Unlike acute infection, chronic carriers contain only a low level of HBV core-antigen-specific T cell activity, contributing to the lack of viral clearance.
Immune clearance
Immune tolerance
InacƟve carrier
HBsAg
α-HBs
HBeAg
α-HBe
TAXONOMY AND CLASSIFICATION: ORDER: Unassigned FAMILY: Hepadnaviridae GENUS: Orthohepadnavirus SPECIES: Hepatitis B virus Double-stranded DNA virus
HBV DNA
Alanine aminotransferase/ aspartate aminotransferase
20
30 40 50 HBV exposure (years)
Diagnosis relies on ELISA of serum HBs, HBe, anti-HBs, and anti-HBc, or by PCR for serum HBV DNA. Coinfection occurs less frequently with HIV, hepatitis C virus, or hepatitis D virus. During chronic infection, HBs persists for longer than 6 months. HBV can cause a wide range of diseases, including subclinical, acute, and chronic hepatitis as well as fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. Hepatitis B vaccine is safe and effective (95% efficacy). It was the first human cancer vaccine and the first recombinant vaccine.
Liver inflammaƟon
10
Transmission is blood-borne or through body fluids; HBV can be transmitted perinatally (mother-to-infant) or horizontally through close contacts.
HBV can be treated with nucleos(t)ide analogs and (PEG)-interferona ribavirin.
≥ 60
*Correspondence: [email protected] (C. Shih).
386
Trends in Microbiology, April 2018, Vol. 26, No. 4
© 2018 Elsevier Ltd. All rights reserved.
https://doi.org/10.1016/j.tim.2018.01.009
Trends in Microbiology | Microbe of The Month Resources www.who.int/mediacentre/factsheets/fs204/en/ www.hepb.org/treatment-and-management/drug-watch/ Literature 1. Blumberg, B.S. et al. (1965) A ‘new’ antigen in leukemia sera. JAMA 191, 541–546 2. Blumberg, B.S. and Millman, I. (1972) Vaccine against viral hepatitis and process (US Patent Office no. 3636191) 3. Beasley, R.P. et al. (1981) Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet 2, 1129–1133 4. Chang, M.H. (1997) Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N. Engl. J. Med. 336, 1855–1859 5. Galibert, F. et al. (1979) Nucleotide sequence of the hepatitis B virus genome (subtype ayw) cloned in E. coli. Nature 281, 646–650 6. Guidotti, L.G. et al. (1999) Viral clearance without destruction of infected cells during acute HBV infection. Science 284, 825–829 7. Summers, J. and Mason, W.S. (1982) Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate. Cell 29, 403–415 8. Sureau, C. et al. (1986) Production of hepatitis B virus by a differentiated human hepatoma cell line after transfection with cloned circular HBV DNA. Cell 47, 37–47 9. Tuttleman, J.S. et al. (1986) Formation of the pool of covalently closed circular viral DNA in hepadnavirus-infected cells. Cell 47, 451–460 10. Yan, H. et al. (2012) Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 1, e00049
Trends in Microbiology, April 2018, Vol. 26, No. 4
© 2018 Elsevier Ltd. All rights reserved.
https://doi.org/10.1016/j.tim.2018.01.009
387
Hepatitis B Virus
Chiaho Shih,1,2,3,* Ching-Chun Yang,1,2 Gansukh Choijilsuren,1,2 Chih-Hsu Chang,1,3 and An-Ting Liou1 1
Institute of Biomedical Sciences (IBMS), Academia Sinica, Taipei, Taiwan Taiwan International Graduate Program (TIGP) in Molecular Medicine, National Yang-Ming University and Academia Sinica, Taipei, Taiwan 3 Graduate Institute of Microbiology, College of Medicine, National Taiwan University, Taipei, Taiwan 2
KEY FACTS:
Virion
HBs subviral parƟcles
Heparan sulfate Na+ bile acid proteoglycan symporter
No known reservoir. HBV has a tight species barrier. Discovered by Dr Baruch Blumberg in 1967 (Nobel Laureate in 1976).
Entry Hepatocyte MulƟvesicular body
Golgi ER
The HBV genome is 3.2 kb DNA; partially double-stranded rc DNA occurs in virions, and ccc DNA occurs in the nucleus of infected hepatocytes.
Morphogenesis
rcDNA
rcDNA rcDNA TranslaƟon of HBsAg A(n) A(n) A(n)
TranscripƟon
A(n) A(n) A(n)
TranslaƟon & capsid assembly
ssDNA
A(n)
cccDNA
Viral particles are infectious, enveloped spherical virions (42 nm); there are excessive numbers of noninfectious HBs subviral particles (22 nm), and icosahedral nucleocapsids (27–32 nm).
pgRNA
Viral antigens include core (HBc), surface (HBs, Australia Ag), polymerase (pol contains a reverse transcriptase domain), and HBx. HBV animal models include the chimpanzee, bat, woodchuck, ground squirrel, and duck. DISEASE FACTS:
Hepatitis B virus (HBV) is a common worldwide blood-borne pathogen. Chronic hepatitis B can progress to an inactive carrier state, and then, in some patients, give rise to cirrhosis and cancer of the liver, leading to death. An HBV surface-antigen vaccine is effective, but treatments are currently not curative. HBV replicates via reverse transcription. Its covalently closed circular (ccc) DNA in the nucleus encodes a pregenomic RNA (pgRNA), which can be encapsidated by HBV polymerase. Reverse transcription occurs in the capsids by using the pgRNA as a template for the synthesis of single-stranded linear and then partially double-stranded relaxed circular (rc) DNA. Capsids containing a mature rc DNA genome target to the nucleus for ccc DNA synthesis. Persistent HBV infection is caused mainly by ccc DNA and immune tolerance to HBV antigens in the liver. Unlike acute infection, chronic carriers contain only a low level of HBV core-antigen-specific T cell activity, contributing to the lack of viral clearance.
Immune clearance
Immune tolerance
InacƟve carrier
HBsAg
α-HBs
HBeAg
α-HBe
TAXONOMY AND CLASSIFICATION: ORDER: Unassigned FAMILY: Hepadnaviridae GENUS: Orthohepadnavirus SPECIES: Hepatitis B virus Double-stranded DNA virus
HBV DNA
Alanine aminotransferase/ aspartate aminotransferase
20
30 40 50 HBV exposure (years)
Diagnosis relies on ELISA of serum HBs, HBe, anti-HBs, and anti-HBc, or by PCR for serum HBV DNA. Coinfection occurs less frequently with HIV, hepatitis C virus, or hepatitis D virus. During chronic infection, HBs persists for longer than 6 months. HBV can cause a wide range of diseases, including subclinical, acute, and chronic hepatitis as well as fibrosis, cirrhosis, hepatocellular carcinoma, and liver failure. Hepatitis B vaccine is safe and effective (95% efficacy). It was the first human cancer vaccine and the first recombinant vaccine.
Liver inflammaƟon
10
Transmission is blood-borne or through body fluids; HBV can be transmitted perinatally (mother-to-infant) or horizontally through close contacts.
HBV can be treated with nucleos(t)ide analogs and (PEG)-interferona ribavirin.
≥ 60
*Correspondence: [email protected] (C. Shih).
386
Trends in Microbiology, April 2018, Vol. 26, No. 4
© 2018 Elsevier Ltd. All rights reserved.
https://doi.org/10.1016/j.tim.2018.01.009
Trends in Microbiology | Microbe of The Month Resources www.who.int/mediacentre/factsheets/fs204/en/ www.hepb.org/treatment-and-management/drug-watch/ Literature 1. Blumberg, B.S. et al. (1965) A ‘new’ antigen in leukemia sera. JAMA 191, 541–546 2. Blumberg, B.S. and Millman, I. (1972) Vaccine against viral hepatitis and process (US Patent Office no. 3636191) 3. Beasley, R.P. et al. (1981) Hepatocellular carcinoma and hepatitis B virus. A prospective study of 22 707 men in Taiwan. Lancet 2, 1129–1133 4. Chang, M.H. (1997) Universal hepatitis B vaccination in Taiwan and the incidence of hepatocellular carcinoma in children. Taiwan Childhood Hepatoma Study Group. N. Engl. J. Med. 336, 1855–1859 5. Galibert, F. et al. (1979) Nucleotide sequence of the hepatitis B virus genome (subtype ayw) cloned in E. coli. Nature 281, 646–650 6. Guidotti, L.G. et al. (1999) Viral clearance without destruction of infected cells during acute HBV infection. Science 284, 825–829 7. Summers, J. and Mason, W.S. (1982) Replication of the genome of a hepatitis B-like virus by reverse transcription of an RNA intermediate. Cell 29, 403–415 8. Sureau, C. et al. (1986) Production of hepatitis B virus by a differentiated human hepatoma cell line after transfection with cloned circular HBV DNA. Cell 47, 37–47 9. Tuttleman, J.S. et al. (1986) Formation of the pool of covalently closed circular viral DNA in hepadnavirus-infected cells. Cell 47, 451–460 10. Yan, H. et al. (2012) Sodium taurocholate cotransporting polypeptide is a functional receptor for human hepatitis B and D virus. eLife 1, e00049
Trends in Microbiology, April 2018, Vol. 26, No. 4
© 2018 Elsevier Ltd. All rights reserved.
https://doi.org/10.1016/j.tim.2018.01.009
387