CSB351Y1 Lecture Notes - Lecture 28: Hypervariable Region, Ribavirin, Ns5A
26 May 2018
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Lecture 28: Flaviviridae 3
Model Structure of HCV – 2 glycoproteins, envelope lipid, capsid proteins (encodes structural/non-structural protein)
• Structural are envelop proteins (capsid) and non structural are polymerases, protease, etc
Genomic Organization
• Polyprotei leaved y NS/5A ad NS/ protease, 5’ UTR has IRES, ’ of odig regio have CREs (variale
region, poly (U/UC) tract, x tail); HVR (hypervariable region) between E1 and E2 of structural protein section
Genotypes/Quasi-species concept (related by a similar mutation)
• 6 genotypes, subtypes broken down to Quasi species due to genetic variability (non/responsive genotypes)
- Type 1a (common), Type 4-5 (common in Africa), Type 1 and 4 (less responsive to IF treatment than 2,3,5,6)
• Properties of HCV proteins – proteins interfere with various steps of IFNa/B-induced signaling (block effectors)
• Tissue tropism and host range – hepatocytes are targets for HCV, peripheral blood mononuclear cells (PBMCs)
and bone marrow cells but replication in non-liver cells (like T and B-cell lines or embryonic kidney cells)
• HCV and B-cell non-Hadgki’s lyphoas (B-NHLs) – diverse group of blood cancers; strong evidence of
association of NHLs with HCV (molecular mechanisms not well established)
• Geographical distribution – worldwide. Combination peg-IFN-a and ribavirin treatment have efficacy in 80%
infected with genotype 2/3 but blanket cure does not exist (genotype 1 most aggressive/prevalent in America)
- 3% of world population infected with HCV but virus does not have latency – possible to eradicate
• HCV treated with pegylated interferon-a and ribavirin (combination)
• Symptoms – sometimes no symptoms (acute phase) but when they occur, fatigue, nausea, jaundice
- Chronic symptoms may not be seen until liver already damaged
HCV and HCC (hepatocellular carcinoma)
• HCV not cytopathic – liver damage due to immune-mediated mechanisms (HCV proteins to host immune to
disrupt pathogen-associated pattern recognition pathway, cellular immunoregulation and subvert activity of NK
and CD4+ and CD8+ T cells
• 80% of liver cancer caused by hepatitis (60% HBV and 40% HCV)
• HCV transmission to cancer development takes 10-50 years
• Strong association between chronic HVC infection, cirrhosis (scarring of liver) and hepatocarcinogenesis
Core and NS5A proteins
• HCV core – result in deregulation of mitosis (bind p53, key component in cell cycle arrest and apoptosis)
- Disruption in checkpoints – tumorigenesis can occur (upregulate oncogenes and downregulate tumor-
suppressor genes)
• NS5A – cell transformation, differentiation and oncogenesis (expression develops tumors)
HCV Transmission
• Blood transfusion, organ transplant, INJECTION OF DRUG USE, latrogenic, sexual, sharing personal care items,
vertical transmission (mother to child severe if mother coinfected with HIV)
• Sofosbuvir (sovaldi) – once a day pill, treats HCV genotypes 1,2,3,4 (used in combination of antiviral treatment)
- Inhibitor of NS5B RNA polymerase (transcription of viral protein)
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Document Summary
Model structure of hcv 2 glycoproteins, envelope lipid, capsid proteins (encodes structural/non-structural protein: structural are envelop proteins (capsid) and non structural are polymerases, protease, etc. Genomic organization: polyprotei(cid:374) (cid:272)leaved (cid:271)y ns(cid:1007)/5a a(cid:374)d ns(cid:1006)/(cid:1007) protease, 5" utr has ires, (cid:1007)" of (cid:272)odi(cid:374)g regio(cid:374) have (cid:1007) cres (varia(cid:271)le region, poly (u/uc) tract, x tail); hvr (hypervariable region) between e1 and e2 of structural protein section. Genotypes/quasi-species concept (related by a similar mutation: 6 genotypes, subtypes broken down to quasi species due to genetic variability (non/responsive genotypes) Combination peg-ifn-a and ribavirin treatment have efficacy in 80% infected with genotype 2/3 but blanket cure does not exist (genotype 1 most aggressive/prevalent in america) Chronic symptoms may not be seen until liver already damaged. Core and ns5a proteins: hcv core result in deregulation of mitosis (bind p53, key component in cell cycle arrest and apoptosis)
