D- virology
Hepatitis B virus
Key Features of Hepatitis B Virus
Relevance
• 250 million people infected worldwide.
• In areas of Africa and East Asia, 50% of the population may
be seropositive, 5-15% may be chronically infected (carriers).
• Carriers are 200x more likely than non-carriers to develop
primary hepatocellular carcinoma.
• 300,000 cases per year in the US; 4,000 fatalities.
70-90% of maternal-neonatal infections result in chronic
infection.
Key Features of Hepatitis B Virus
• Enveloped virion containing partial double-stranded circular
DNA genome
• Replication occurs through an RNA intermediate
• Virus encodes and carries a reverse transcriptase
• Virus encoded several antigenically and clinically predictive
important proteins
Key Features of Hepatitis B Virus
• Virus has a strict tissue tropism to the liver
• Virus infected cells produce and release large amounts of
HBsAg particles lacking DNA
• Viral DNA can integrate into the host chromosome
Hepatitis B Virion, Dane particle and HBsAG
From Murray et. al., Medical Microbiology 5th
edition, 2005, Chapter 66, published by
Mosby Philadelphia,,
Nomenclature for Hepatitis B Virus components
Transcription of Hepatitis B virus
Note: HBeAg (E) is encoded
in C region using different
start codons and is not
shown
Figure 66-6
From Murray et. al., Medical Microbiology 5th
edition, 2005, Chapter 66, published by
Mosby Philadelphia,,
The growth cycle
of Hepatitis B
virus
From Murray et. al., Medical Microbiology 5th edition, 2005,
Chapter 66, published by Mosby Philadelphia,,
Figure 66-5
Reverse transcription of
Hepadnavirus occurs with
packaging of pre-genomic RNA
Fields Virology 4th edition, 2002, Chapter 86, Lippincott, Williams and Wilkins,
2002 Fig. 86-7
Figure 86-7 The hepadnaviral reverse
transcription pathway. Pregenomic RNA (dashed
line, step 1) is capped and polyadenylated and
has a large terminal redundancy (R). The
locations of direct repeats 1 and 2 (DR1 and
DR2) are shown as correspondingly numbered
boxes, and the e stem-loops are indicated.
Pregenomic RNA packaging into cores is initiated
by the interaction of P protein with the 5´ copy of
e. P initiates reverse transcription at the 5´ stemloop and extends negative-stranded DNA (solid
line) for 3 to 4 nucleotides (step 2a). P and the
covalently attached nascent DNA are then
transferred to the 3´ copy of DR1 (step 2b), and
the DNA is extended. During negative-stranded
elongation, pgRNA is degraded by the RNaseH
activity of P (step 3). When P reaches the 5´ end
of the template, its RNaseH activity leaves an
RNA oligomer consisting of r plus DR1
sequences (step 4). This RNA oligomer is
translocated and annealed to DR2, where it
primes positive-stranded DNA synthesis (lower
solid line, step 5). Positive-stranded elongation
proceeds to the 5´ end of the negative-stranded
DNA template, including the sequences denoted
as r. Because complementary r sequences are
found at the 3´ end of negative-strandeds DNA, a
second homology-mediated template transfer
can now circularize the genome. The positive
strand is then extended for a variable length
(step 6) to yield mature viral DNA.
Hepatitis B - Clinical Features
 Incubation period:
 Clinical illness (jaundice):
 Acute case-fatality rate:
 Chronic infection:
 Premature mortality from
chronic liver disease:
Average 60-90 days
Range 45-180 days
<5 yrs, <10%
5 yrs, 30%-50%
0.5%-1%
<5 yrs, 30%-90%
5 yrs, 2%-10%
15%-25%
Prevalence of Hepatitis B carriers
Figure 66-9. Worldwide prevalence of hepatitis B carriers and primary hepatocellular carcinoma.
(Courtesy Centers for Disease Control and Prevention, Atlanta.)
From Murray et. al., Medical Microbiology 5th edition, 2005,
Chapter 66, published by Mosby Philadelphia,,
Clinical outcomes of Hepatitis B infections
Figure 66-11. Clinical outcomes of acute hepatitis B infection. (Redrawn from White DO, Fenner F:
Medical virology, ed 3, New York, 1986, Academic Press
From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 62, published by Mosby Philadelphia,,
Immunological events of acute vs. chronic HBV
infection
A) Acute
B) Chronic
From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia,,
Clinical interpretation of the Hepatitis B antigen
panel
CDC WEB site: http://www.cdc.gov/ncidod/diseases/hepatitis/b/Bserology.htm
Determinants or acute and chronic HBV
infection
Figure 66-7
From Murray et. al., Medical
Microbiology 5th edition, 2005,
Chapter 66, published by Mosby
Philadelphia,,
Prevention of Hepatitis B –prophylaxis and vaccination
The HIV and Hepatitis B Reverse Transcription Systems
Flint, S.J., Enquist, L.W. et. al., “Principles of Virology”ASM Press, 2000, Chapter 7
CDC website: http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep_d/slide_1.htm
Notes:
HDV infection can be acquired either as a co-infection with HBV or as a superinfection of persons with chronic HBV
infection. Persons with HBV-HDV co-infection may have more severe acute disease and a higher risk of fulminant
hepatitis (2%-20%) compared with those infected with HBV alone; however, chronic HBV infection appears to occur
less frequently in persons with HBV-HDV co-infection. Chronic HBV carriers who acquire HDV superinfection usually
develop chronic HDV infection. In long-term studies of chronic HBV carriers with HDV superinfection, 70%-80%
have developed evidence of chronic liver diseases with cirrhosis compared with 15%-30% of patients with chronic
HBV infection alone.
Key features of Hepatitis Delta Virus
•Single stranded, self complementary RNA,
encapsidated in HbsAg
•Small, amorphous particle
•RNA encodes one protein: delta antigen
•Replicates via RNA directed RNA synthesis, catalyzed
by host RNA polymerase II
Key features of Hepatitis Delta Virus
•Delta antigen required for replication, role unknown
•Dependent on HBV as a “helper”
•HBV provides HbsAg
•May be acquired as co-infection with HBV, or
superinfection of HBV infection
•Exacerbates HBV induced disease
Hepatitis Delta Virion
Figure 66-14
From Murray et. al., Medical
Microbiology 5th edition, 2005,
Chapter 66, published by Mosby
Philadelphia,,
Consequences of hepatitis B and delta virus
infection
Figure 66-15. Consequences of deltavirus infection. Deltavirus (d) requires the presence of
hepatitis B virus (HBV) infection. Superinfection of a person already infected with HBV (carrier)
causes more rapid, severe progression than co-infection (shorter arrow).
From Murray et. al., Medical Microbiology 5th edition, 2005, Chapter 66, published by Mosby Philadelphia.
The HDV genome
Figure 88-4 Structure of the HDV RNA Genome. The single-stranded circular RNA genome is indicated by the heavy
black continuous line. The genome has the ability to form an unbranched rod structure, in which approximately 70%
of the bases are engaged in Watson-Crick pairs with counterparts from the opposite side of the circular RNA. In this
unbranched rod structure, the region encoding HDAg (nt 1598-957) is on one side. The RNA editing site is at position
1012 in the antigenome. The region on the right-hand side contains the autocatalytic cleavage sites (ribozymes), one
in the genome (nt 686) and the other in the antigenome (nt 900). The genome binds HDAg and is transcribed by a
host DNA–dependent RNA polymerase.
Fields Virology 4th edition, 2002, Chapter 88, Lippincott, Williams and Wilkins, 2002 Fig. 88-4
CDC Website: http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep_d/slide_6.htm
Diagnosis







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A battery of serological tests are used for the diagnosis of acute and
chronic hepatitis B infection.
HBsAg - used as a general marker of infection.
HBsAb - used to document recovery and/or immunity to HBV
infection.
anti-HBc IgM - marker of acute infection.
anti-HBcIgG - past or chronic infection.
HBeAg - indicates active replication of virus and therefore
infectiveness.
Anti-Hbe - virus no longer replicating. However, the patient can still be
positive for HBsAg which is made by integrated HBV.
HBV-DNA - indicates active replication of virus, more accurate than
HBeAg especially in cases of escape mutants. Used mainly for
monitoring response to therapy.
Wong’s virology WEB site: http://virologyonline.com/presentations/hepatitis.htm
Hepatitis B acute infection
Note:
Pattern of
serological
markers
varies
depending
on
whether
the
infection if
acute or
chronic
CDC website: http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep_b/slide_3.htm
Chronic Hepatitis B infection
Notes:
In patients with chronic
HBV infection, both HBsAg
and IgG anti-HBc remain
persistently detectable,
generally for life. HBeAg is
variably present in these
patients. The presence of
HBsAg for 6 months or
more is generally indicative
of chronic infection. In
addition, a negative test for
IgM anti-HBc together with
a positive test for HBsAg in
a single serum specimen
usually indicates that an
individual has chronic HBV
infection.
http://www.cdc.gov/ncidod/diseases/hepatitis/slideset/hep_b/slide_4.htm