Download - Hepatitis C virus
Dr. Amanj SaeedMB.CH.B MSc PhD
Clinical virologist
Hepatitis C Virus (HCV)EnvelopeEnvelope
CoreCore
EnvelopeEnvelopeGlycoproteinsGlycoproteins Viral RNA (9400 nucleotides)Viral RNA (9400 nucleotides)
55-65 nm55-65 nm
• HCV is small enveloped positive sense RNA virus
• Belongs to Genus Hepacivirus of Flaviviridae family
• Genome is 9.6 kb.• 6 major genotypes.
HCVHepatitis 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).
HCVHCV infection has a major impact on public
health, yet no vaccine is available to prevent the infection and the antiviral therapies are characterised by:
limited efficacy high cost substantial side effects.
STRUCTURALGENES
NON-STRUCTURALGENES
+ ve ss RNA } Genomic organisation } FLAVIVIRUS
Core
5’UTR
E1 E2 P7 NS2 NS3
NS4A
NS4B NS5A NS5B
3’UTR
schematic representation of HCV genome
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:
the tetraspanin CD81 scavenger receptor class B type 1 (SRB1) heparin sulphate (HS) and the low density lipoprotein (LDL) receptor,
claudin-1 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).
HCVHCV 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
Diagnosismay result in false negativity
Pathogenicityare all genotypes equally dangerous?
Treatmentdo all genotypes respond equally to therapy?
Vaccine developmentcreates 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 pathogenesisSub-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 pathogenesisHCV pseudoparticles (HCVpp).Recent studies developed an experimental
system to use primary human hepatocytes as a model for studying HCV pathogenesis
Anti-HCV POSITIVEEvidence 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: NegativeNo 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 DetectionRequires amplification eg Reverse Transcriptase Polymerase Chain Reaction
Technically more exacting
Expensive
Interpretation RT/PCR results
POSITIVE
infectiousat risk of chronic
liver diseaserequires liver
biopsy
NEGATIVE
not infectious not at risk of chonic
liver diseasemay not require
biopsy
Hepatitis C virus: routes of transmissionParenteral
Injecting drug useBlood/blood productsOther needles Failure of infection control eg outbreaks (see
refs)Mother-to-baby (5%)Sexual (?real)
ACUTE INFECTIONUsually asymptomatic
CHRONICINFECTION 75-85%
InfectionResolved 15-25%
20 yrs
5 yrs
ASYMPTOMATIC, mild liver disease
CHRONIC INFLAMMATORY HEPATITUS
CIRRHOSIS eg 20%
HEPATOCELLULAR CARCINOMA
Chronic inflammation and the wound healing response are likely to be the framework within which HCV induces hepatic fibrosis
Natural history of Hepatitis C Infection
Infection by Hepatitis C Virus
Acute Hepatitis (>90 % Asymptomatic)
Chronic hepatitis(75-85%)
Cirrhosis(20%)
HCC
Spontaneous recovery(15-25%)
Chronic active(20%)
Asymptomatic(80%)
6 Mon
ths
10-30 Years
Transplantation
Hepatitis C
Treatment
Chronic infection – 80%
Clearance – 20%
Infection
Blood donors – anti-HCV
Organ and tissue donors – anti-HCV
Renal units – regular anti-HCV testing
Antenatal screening – NOT currently recommended
Infected patient healthcare worker
Infected healthcare worker patient
Surgeon-to-patient HCV transmission: phylogenetic evidence
2
Known transmissions from 5 surgeons (1 cardiac, 2 general, 2 O&G) thus far
Protection of patients:Guidelines??Known HCV RNA +ve HCWs – OUTCurrent HCWs doing EPPs encouraged to be
tested if risk factors .Needlestick injuries – early Rx benefit to HCWFor 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