Transcript No Slide Title

Dr. Amanj Saeed
MB.CH.B MSc PhD
Clinical virologist
Hepatitis C Virus (HCV)
Envelope
• HCV is small enveloped Core
positive sense RNA virus
• Belongs to Genus
Hepacivirus of
Flaviviridae family
• Genome is 9.6 kb.
• 6 major genotypes.
Envelope
Glycoproteins
Viral RNA (9400 nucleotides)
55-65 nm
HCV
 Hepatitis C virus (HCV) is a small, enveloped
positive strand RNA virus belong to a genus
Hepacivirus of the Flaviviridae family
 An estimated 200?? million people worldwide
are infected with HCV .
 80% of infected individuals will develop chronic
persistent infection, and of these 30% will
develop progressive liver diseases including
chronic hepatitis, cirrhosis and hepatocellular
carcinoma (HCC).
HCV
 HCV infection has a major impact on public
health, yet no vaccine is available to prevent
the infection and the antiviral therapies are
characterised by:
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limited efficacy
high cost
substantial side effects.
Core
NS4A
5’UTR
3’UTR
E1 E2
P7
NS2
NS3
NS4B
NS5A
NS5B
schematic representation of HCV genome
STRUCTURAL
GENES
+ ve ss RNA
}
Genomic organisation }
NON-STRUCTURAL
GENES
FLAVIVIRUS
HCV– receptor interaction
 E1 and E2 are essential for host cell entry by
binding to receptors and inducing fusion of the
host cell membrane
 Several cell surface molecules have been
proposed to play a role in mediating HCV
attachment and entry:

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the tetraspanin CD81
scavenger receptor class B type 1 (SRB1)
heparin sulphate (HS)
and the low density lipoprotein (LDL) receptor, claudin1 and occludin.
Epidermal growth factor Receptor
Ephrin receotor
Translation of HCV
genome
 Translation of HCV genome yields a polyprotein
precursor that is subsequently processed by
cellular and viral proteases.
 Structural proteins include (core, E1, E2, P7)
 Nonstructural proteins include: NS2, NS3, NS4A,
NS4B, NS5A, NS5B.
HCV replication
 HCV Replication proceeds via formation of
complementary minus strand RNA using a viral
genome as a template and subsequent
synthesis of plus strand
 Both these steps are dependent on NS5B (viral
RNA Dependent RNA polymerase).
HCV
 HCV genome replication is associated with a
high mutation rate and sequence diversity
which eventually results in a circulating
population of diverse but closely related HCV
variants, known as a quasispecies which
underlies the following :
 capacity to escape against immune
responses
 presence of multiple variants which facilitate
the selection of adaptive mutations.
HCV genetic diversity:
consequences
 Diagnosis
 may result in false negativity
 Pathogenicity
 are all genotypes equally dangerous?
 Treatment
 do all genotypes respond equally to therapy?
 Vaccine development
 creates problems
Models for studying HCV
pathogenesis
 Analyzing the effect of HCV on transformed cell
lines.
 transgenic technology.
 Infection with related viruses (like GBV-B)
 The best model for HCV study is using
chimpanzees (economic and moral reasons
limit the use of chimpanzee in research).
Models for studying HCV
pathogenesis
 Sub-genomic replicon systems .
 generation of an infectious clone of a genotype
2 isolate of HCV known as JFH-1 which has the
capacity to go through a full viral life cycle and
produce infectious virus in hepatocyte derived
cell lines.
Models for studying HCV
pathogenesis
 HCV pseudoparticles (HCVpp).
 Recent studies developed an experimental
system to use primary human hepatocytes as a
model for studying HCV pathogenesis
Anti-HCV POSITIVE
 Evidence of infection at some time
 Gives no indication as to when infection
occurred
 Gives no indication as to whether infection was
cleared or is still present
Anti-HCV: Negative
 No evidence of infection with HCV
 BUT - be aware of possible false negatives
 if infection very recent (window period)
 if patient immunosuppressed at time of infection
Genome Detection
 Requires amplification eg
Reverse Transcriptase
Polymerase Chain Reaction
 Technically more exacting
 Expensive
Interpretation RT/PCR
results
POSITIVE
NEGATIVE
 infectious
 not infectious
 at risk of chronic liver
 not at risk of chonic
disease
 requires liver biopsy
liver disease
 may not require
biopsy
Hepatitis C virus: routes of
transmission
 Parenteral
 Injecting drug use
 Blood/blood products
 Other needles
 Failure of infection control eg outbreaks (see refs)
 Mother-to-baby (5%)
 Sexual (?real)
CLINICAL OUTCOMES OF HCV INFECTION
ACUTE INFECTION
Usually asymptomatic
CHRONIC
INFECTION 75-85%
Infection
Resolved 15-25%
ASYMPTOMATIC, mild liver disease
20 yrs
CHRONIC INFLAMMATORY HEPATITUS
CIRRHOSIS eg 20%
5 yrs
HEPATOCELLULAR CARCINOMA
Mechanism of hepatic fibrogenesis in
HCV infected patient
Chronic inflammation and the wound healing response are
likely to be the framework within which HCV induces
hepatic fibrosis
Hepatitis C
Natural history of Hepatitis C Infection
Infection by Hepatitis C Virus
6 Months
Acute Hepatitis
(>90 % Asymptomatic)
Spontaneous recovery
(15-25%)
Chronic hepatitis
(75-85%)
Chronic active
(20%)
Treatment
Cirrhosis
(20%)
Transplantation
HCC
10-30 Years
Asymptomatic
(80%)
HCV: Natural History
Infection
Clearance – 20%
Chronic infection – 80%
Prevention of patient-to-patient HCV
transmission - screening
Blood donors – anti-HCV
Organ and tissue donors – anti-HCV
Renal units – regular anti-HCV testing
Antenatal screening – NOT currently
recommended
Needlestick transmission of
blood-borne hepatitis viruses
Infected patient
healthcare worker
Infected healthcare worker
patient
Surgeon-to-patient HCV transmission: phylogenetic evidence
HCW-to-patient transmission
of HCV: UK data
Known transmissions from 5 surgeons (1 cardiac, 2
general, 2 O&G) thus far
Protection of patients:
Guidelines??
 Known HCV RNA +ve HCWs – OUT
 Current HCWs doing EPPs encouraged to be
tested if risk factors .
 Needlestick injuries – early Rx benefit to HCW
 For HCWs entering EPP-specialties – test for HCV
infection
Diagnosis
 Test for viral antigen and Antibody (ELISA)
 Test for genome (Quantitative RNA PCR)
Treatment
 Pegylated INF-α + Ribavirin