Transcript HBV.groupA. pcl2

Presented by Group I PCL2
MEMBERS OF GROUP
BAHIZI
Sadallah
Ug 12114376
BAMPORIKI Judith
Ug 12214657
BAYINGANA Marie Eve
Ug 12214674
BAZAMBAZA Philippe
Ug 12215192
BITUNGURAMYE Adam
Ug 12114056
BIZIMANA Anselme
UG12114504
BUGINGO JEAN Pierre
Ug 12113855
BUHOLO Jael
Ug12214676
BUSOMOKE Denys Fabrice
Ug 12113988
BYIRINGIRO Jean d’ Amour
Ug 12113049
CHOI Jaeseok
Ug12215093`
MUPIKA Meda
Ug 12214675
Content
1.
2.
3.
4.
5.
6.
7.
Introduction
Epidemiology
Pathogenesis
Clinical manifestation
Diagnosis
Treatment
Prevention
1. Introduction
 The early evolution of the Hepatitis B is difficult to est
ablish.The divergence of orthohepadnavirus occurred
~125,000 years ago. Orthohepadna viruses began to div
ersify about 25,000 years ago.
Hepatitis B Virus (HBV) is a member of the hepadnavi
rus family. It is a 42-nm enveloped virion, with an icos
ahedral nucleocapsid core containing a partially dou
ble-stranded circular DNA genome.
 Year of identification 1965
Cont…
Group
Order
Family
Genus
Species
Group
VII(dsDNART)
Unassigned
Hepadnaviridae
Orthohepadnavirus
Hepatitis B virus
The virus is divided into four
major serotypes (adr, adw, ayr, ayw) based on
antigenic epitopes present on its envelope
proteins, and into eight genotypes (A-H)
according to overall nucleotide sequence variation
of the genome
Cont…
The genome of HBV is a partially double-stranded
circular DNA molecule
 A nucleocapsid “core” protein (HBcAg, Hepatitis B
core antigen) and a longer polypeptide transcript with
a precore and core region, designated HBeAg
(Hepatitis B “e” antigen). The precore region directs
the HBeAg polypeptide toward secretion into blood,
whereas HBcAg remains in hepatocytes for the
assembly of complete virions.
Cont…
 Envelope glycoproteins (HBsAg, Hepatitis B surface
antigen), which consist of three related proteins:
large HBsAg (containing Pre-S1, Pre-S2, and S), middle
HBsAg (containing Pre-S2 and S), and small HBsAg
(containing S only).
Infected hepatocytes are capable of synthesizing
and secreting massive quantities of noninfective surface
protein (mainly small HBsAg).
Cont…
 The DNA polymerase is encoded by gene P. A
polymerase (Pol) that exhibits both DNA polymerase
activity and reverse transcriptase activity. Genomic
replication occurs via an intermediate RNA template,
through a unique replication cycle: DNA ➙ RNA ➙
DNA.
 HBx protein, which is necessary for virus replication
and may act as a transcriptional transactivator of the
viral genes and a wide variety of host genes. It has been
implicated in the pathogenesis of liver cancer in HBV
infection.
Electron microscopy of a patient's serum reveals three different
types of particles: a few 42-nm virions and many 22-nm
spheres and long filaments 22 nm wide, which are composed
of surface antigen
2. Epidemiology
There are three important modes of transmission
of HBV infection:
 Parenteral (usage of contaminated needles and
syringes, intravenous drug abuse,…)
 Perinatal(can be transmitted from carrier mothers
to their babies during the perinatal period
 Sexual(is present in semen and vaginal secretions)
Cont…
 High Endemicity: prevalence in developing regions with
large population such as South East Asia, China, subSaharan Africa and the Amazon Basin, where at least
8% of the population are HBV chronic carrier.
 Intermediate Endemicity: moderately endemic in part of
Eastern and Southern Europe, the Middle East, Japan,
and part of South America, and 2-7% are chronic carriers
 Low Endemicity: low in most developed areas, such as
North America, Northern and Western Europe and
Australia, 0.5–2% of the population are chronic carriers.
Cont…
About 5-10% of HBV infections result in chronic
carrier state. The latter may be defined as persistence of
HBsAg in the circulation for more than six months.
Carriers are of two types:
 Super carriers: They have HBeAg, high titres of HBsAg
and DNA polymerase in their blood. HBV may also be
demonstrable in their blood. Very minute amount of serum
or blood from such carriers can transmit the infection.
 Simple carriers: These are more common types of
carriers who have low level of HBsAg and no HBeAg, HBV
and DNA polymerase in the blood. They transmit the
infection only when large volumes of blood are
transferred as in blood transfusion.
3. Pathogenesis
 The virus replicates in the liver
 Viruses are released into blood circulation
 The blood become highly infectious
 5% of infected individuals fail to eliminate the virus
and become persistently infected
 T-cells response eliminates viral infected liver cells
during acute hepatitis B in more than 90%
CONT…
 Host immunological response is thought to be behind
the liver injury for the following reasons:
-The existence of HBV carriers with normal liver
histology and function
-Patient with defects in cellular immune competence
are more likely to remain chronically infected.
Cont…
The replication cycle of HBV
DNA Genomes replicated by reverse transcription
 Begins with attachment of the virion to the hepatocyte
membrane
 The exact mechanisms of virus attachment are not clear
but are thought to be mediated through the pre-S1 region
of the virion envelope
 The virion is uncoated in the hepatocyte cytoplasm and the
viral genome enters the hepatocyte nucleus
Cont..
 Nucleocapsids with the partially double stranded HBV
DNA can reenter the hepatocyte nucleus to produce
more ccc DNA or be secreted as complete virions after
coating with envelope proteins.
 The ccc DNA appears to have a long half-life and is
very resistant to antiviral therapy, accounting for the
difficulty in achieving virus clearance during
treatment of chronic hepatitis B.
Cont…
 Mutations in all regions of HBV have been found in
patients with chronic HBV infection.
 Some of these mutations, such as the precore stop
codon mutation, have been incriminated in causing
more severe liver disease
 However, these variants have also been found in
asymptomatic carriers , suggesting that the mutations
alone are not necessarily pathogenic.
Cont…
 Nevertheless, HBV mutations can potentially
modulate the severity of liver disease by altering the
level of HBV replication or the expression of
immunogenic epitopes
 The primary cause of hepatic cell destruction appears
to be the cell-mediated immune response. The cells
involved are HLA-I- restricted cytotoxic T cells, which
react specifically with the fragments of nucleocapsid
proteins, HBcAg and HBeAg, expressed on the surface
of infected hepatocytes.
Attachment, Penetration, and Uncoating
Attachment
Endocytosis
Penetration
Uncoating
Figure 13.14
Cont…
In brief of replication:
 Early phase include
 Recognition of the target cell
 Attachment
 Penetration
 Uncoating




Late phase include
Macromolecular synthesis ( transcription, DNA Genomes
replicated by reverse transcription, translation,…)
Auto assembly virus
Release of virus
Multiplication of DNA Virus of HBV
Papovavirus
1 Virion attaches to host cell
7 Virions are released
Capsid
DNA
DNA
Host cell
2 Virion penetrates
cell and its DNA is
uncoated
Cytoplasm
6 Virions mature
Capsid proteins
mRNA
5 Late translation;
capsid proteins
are synthesized
3
4
Late transcription;
DNA is replicated
Early transcription and
translation; enzymes are
synthesized
Figure 13.15
Outcome from infection in the USA
4. Clinical manifestation
 The prodromal symptoms of acute viral hepatitis:
anorexia, nausea, headache, vomiting, fatigue, fever of
39.5°–40°C and jaundice
 Upper right quadrant pain
 Some change in dark urine and pale feces
Cont…
The natural course of the disease can be followed by
serum markers
FIGURE 18-11( from Robbins &Cotran
Pathology,8th ed ) below show Sequence of
serologic markers for hepatitis B viral hepatitis
demonstrating (A) acute infection with
resolution and (B) progression to chronic
infection.
5. Diagnosis
The most important laboratory test for the detection of
HBV infection:
 Immunoassay for HBsAg is detectable in most patients
during the prodrome and acute disease and undetectable at
least 6 months
 PCR analysis where DNA can be detected
HBsAb is undetectable because it is bound in immune
complexes and DNA polymerase activity is detectable
during the incubation period and early in the disease, but
the assay is not available in most clinical laboratories
Test
Acute Disease
Window Phase
Complete
Recovery
Chronic Carrier
State
HBsAg
Positive
Negative
Negative
Positive
HBsAb
Negative
Negative
Positive
Negative
HBcAb
Positive
Positive
Positive
Positive
6. Treatment
 Acute infection
Acute infection with hepatitis B usually does not require
treatment. In rare cases, however, the infection may cause
life-threatening liver failure. Patients with liver failure due
to acute hepatitis B should be evaluated for liver
transplantation. Small studies suggest that the
drug lamivudine (Epivir) may be effective in this setting.
 Chronic infection
If a person is chronically infected with hepatitis B and has
few signs or symptoms of complications, medications
usually are not used. These patients are watched carefully
and given periodic blood tests
Cont…
The medications in current use for chronic hepatitis B
include the interferons and nucleoside/nucleotide
analogues
 Interferon-alpa
Has been used to treat hepatitis B for more than 20 years.
Interferon-alpha is a naturally occurring protein that is made in
the body by white blood cells to combat viral infections. In
addition to its direct anti-viral effects, interferon works against
the hepatitis B virus by stimulating the body's immune system to
clear the virus.
 Nucleoside/nucleotide analogues (NAs)
Are man-made chemicals that mimic the nucleosides and
nucleotides that are used for making DNA. When the virus tries
to use the analogues to make its own DNA, it is unable to make
the DNA and, therefore, cannot reproduce. Examples of these
agents include adefovir (Hepsera), entecavir
(Baraclude), lamivudine (Epivir-HBV, Heptovir, Heptodin),
telbivudine (Tyzeka) and tenofovir (Viread).
7. Prevention
 Behavior Modification
Changes in sexual practice and improved screening
measures of blood products have reduced the risk of
transfusion-associated hepatitis.
 Postexposure (Passive immunization)
Hepatitis B Immune Globulin (HBIG) is a sterile solution
of ready-made antibodies against hepatitis B is used
 newborns of mothers infected with hepatitis B
 After needlestick exposure
 After sexual exposure
 After liver transplantatio
Cont…
Preexposure (Active immunization)
Prevention of primary infection by vaccination is an
important strategy to decrease the risk of chronic HBV
infection and its subsequent complications.
The vaccine is prepared from purified HbsAg
produced in yeast. Vaccination induces a protective
anti-HBs antibody response in 95% of infants,
children, and adolescents.
A vaccine called Twinrix that contains both HBsAg
and inactivated HAV provides protection against both
hepatitis B.
Summary
Year of Family
identif
ication
1965
Genus
Hepadn Orthoh
aviridae epadna
virus
Test
Genom Genom Virion
e
e size
Envelo
pe
dsDNA
Yes
Acid(HBsAg) stable
Acute Disease
3.2 kb
Transm
ission
Window Phase
Stabilit Trans
y
missio
n
Complete Recovery
Parenta
l,
sexual
HBsAg
Positive
Negative
Negative
Chronic Carrier
State
Positive
HBsAb
Negative
Negative
Positive
Negative
HBcAb
Positive
Positive
Positive
Positive
Vertica Incuba Onset
l
tion
transm period
ission
Age
Antige
prefere ns
nce
Antibo
dies
Chroni
c
carrier
state
Chroni
c
hepatit
is,
cirrhos
is
Hepato
cellula
r
carcin
oma
Int Ye
ra s
ut
eri
ne
Young HBsAg,
adults, HBcAg,
btoddle HBeAg
rsabies,
AntiHbs,
AntiHBc,
AntiHBe
5-10%
1-5%
Yes
Pe Ye
rin s
ata
l
Ea
rly
po
st
na
tal
inf
ect
Po
ssi
ble
bu
t
rar
e
6
Insidio
weeks- us or
6
acute
months
8. Reference
 http://www.medicinenet.com
 Professor note document
 Lange Microbiology and Immunology review 10
editions
 Robbins & pathology Basic of Disease, 8 editions
 UPtoDATE 2011