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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: 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: 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