Hepatitis B virus

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Hepatitis B virus
CDC website http//www.cdc.gov/ncidod/diseases/h
epatitis/slideset/hep_b/slide_1.htm
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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.

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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

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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

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Hepatitis B Virion, Dane particle and HBsAG
From Murray et. al., Medical Microbiology 5th
edition, 2005, Chapter 66, published by Mosby
Philadelphia,,
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Nomenclature for Hepatitis B Virus components
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Transcription of Hepatitis B virus
Figure 43-1
From Engleberg, et. al., Schaechters Mechanisms
of Microbial Disease, Fourth Edition, Chapter 43,
published by Lippincott Williams Wilkins,
Philadelphia.
8
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
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Reverse transcription of Hepadnavirus occurs with
packaging of pre-genomic RNA
FIGURE 43-3 Hepatitis B virus genome replication.
1. Reverse transcription begins with the
polymerase binding to a unique stem-loop
structure, located at the 5' end of pregenomic
RNA. 2. The polymerase (P) uses one of its own
amino acids to prime synthesis and copies three
or four nucleotides derived from a bulged region
of the stem-loop structure (2a). The polymerase
then translocates to the 3' copy of direct repeat
1 (DR1), which includes nucleotides that are
complementary to those attached to the polymerase
(2b). 3. Reverse transcription is extended from
that point. As the leading front of the
polymerase copies RNA into DNA, its trailing
portion destroys the template that has already
been copied. 4. When the polymerase reaches the
5' end of the pregenomic RNA, minus-strand
synthesis is complete. The short pregenomic RNA
oligonucleotide that remains undigested is then
used to prime plus-strand DNA synthesis. That RNA
includes the 5' copy of DR1 and is translocated
to a new and complementary region near the 5' end
of the minus DNA strand termed direct repeat 2
(DR2). 5. Once the second translocation has
occurred, plus-strand synthesis begins. During
plus-strand synthesis, when the polymerase
reaches the end of the minus-strand template, a
third and final translocation event occurs. The
minus DNA strand has two small terminal
redundancies, termed ?r?. 6. The 5' copy of r is
dissociated from the plus DNA strand and replaced
with the 3' copy. That dissociation results in
the circularization of the DNA molecule and
enables further extension of the plus strand cap,
5'-terminal cap An, poly(A) tract.
From Engleberg, et. al., Schaechters Mechanisms
of Microbial Disease, Fourth Edition, Chapter 43,
published by Lippincott Williams Wilkins,
Philadelphia.
10

Hepatitis B - Clinical Features

• Incubation period Average 60-90 days
• Range 45-180 days
• Clinical illness (jaundice) lt5 yrs,
  lt10 5 yrs, 30-50
• Acute case-fatality rate 0.5-1
• Chronic infection lt5 yrs, 30-90 5 yrs,
  2-10
• Premature mortality fromchronic liver
  disease 15-25

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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,,
12
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,,
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Immunological events of acute vs. chronic HBV
infection
A) Acute
B) Chronic
From Engleberg, et. al., Schaechters Mechanisms
of Microbial Disease, Fourth Edition, Chapter 43,
published by Lippincott Williams Wilkins,
Philadelphia.
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Clinical interpretation of the Hepatitis B
antigen panel
CDC WEB site http//www.cdc.gov/ncidod/diseases/
hepatitis/b/Bserology.htm
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Determinants or acute and chronic HBV infection
From Murray et. al., Medical Microbiology 5th
edition, 2005, Chapter 66, published by Mosby
Philadelphia,,
Figure 66-7
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Prevention of Hepatitis B prophylaxis and
vaccination
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The HIV and Hepatitis B Reverse Transcription
Systems
Flint, S.J., Enquist, L.W. et. al., Principles
of VirologyASM Press, 2000, Chapter 7
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CDC website http//www.cdc.gov/ncidod/diseases/h
epatitis/slideset/hep_d/slide_1.htm
NotesHDV 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.
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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

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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

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Hepatitis Delta Virion
From Murray et. al., Medical Microbiology 5th
edition, 2005, Chapter 66, published by Mosby
Philadelphia,,
Figure 66-14
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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.
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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
DNAdependent RNA polymerase.
Fields Virology 4th edition, 2002, Chapter 88,
Lippincott, Williams and Wilkins, 2002 Fig. 88-4
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CDC Website http//www.cdc.gov/ncidod/diseases/he
patitis/slideset/hep_d/slide_6.htm
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Diagnosis

• 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.

Wongs virology WEB site http//virology-online.c
om/presentations/hepatitis.htm
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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/h
epatitis/slideset/hep_b/slide_3.htm
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Chronic Hepatitis B infection
NotesIn 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/slide
set/hep_b/slide_4.htm