Hepatitis C

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Hepatitis C by Mind Map: Hepatitis C

1. Viral Disease (Metabolic disease)

1.1. Primary target = Liver

1.1.1. Functions Metabolism Carbohydrate Lipids Proteins Storage Essential nutrients Vitamins Mineral Detoxification Monitor blood contents Remove toxic substances Biosynthesis of key molecules Blood plasma components Lipid production

1.1.2. Affect Acute infection Chronic Hepatitis C (CHC) ~80% Insufficient immune response Inflammation = cell death Metabolic disorder Lipid modulation disturbances Fibrosis Many scars turn into nodules Cirrhosis Scarring prevents blood flow Fluid build up (abdomen, legs, intestines) Decrease mental function Liver transplant Hepatocellular carcinoma

1.1.3. Lipo-viro-particles (LVP) Liver specific Receptors Attachment Entry VLDL-secretory pathway & apolipoproteins Assembly Maturation

1.1.4. miRNA-122 Stabilize genome Stimulate genome translation Bind 5' end Deregulation of fatty acid metabolism

1.1.5. Membranous web Viral protein induced ER-derived membranes Replicase complexes Association with LD

1.1.6. Lipid Droplet (LD) Lipoprotein synthesis pathway (LD formation) Organelles for neutral lipid storage

1.2. Disease

1.2.1. Transmission Blood-to-Blood contact Supervised injection site Drug users Blood tranfusion Piercing Tatoos Rare vertical transmission

1.2.2. Hepatitis Liver inflammation

1.2.3. Symptoms Acute infection Typically asymptomatic Fever Fatigue Decreased apetite Upset stomach Mild abdominal pain Chronic infection (+6 months) Liver disease (fatty liver) Darkening of urine Yellow skin & eyes Death

1.2.4. Upregulation of Lipid Droplets Scaffold for replication Assembly Connect metabolic & cellular function associate with ER & mitochondria

1.3. Silent Killer

1.3.1. 33% do not know they have it

1.3.2. 25% recover without treatment Genetic factor? Gene polymorphism? No longer contagious Profile patient genome

1.3.3. Co-infection with HIV patients

1.4. Treatment

1.4.1. Check Ab, vRNA, HCV genotype

1.4.2. IFN-free treatment

1.4.3. Liver Transplant Soak liver in entry inhibitors

1.4.4. Resistance

1.4.5. Harvoni/Epclusa NS5B nucleoside RNA polymerase inhibitor NS5A inhibitor unknown function

1.4.6. Miravirsen Oligonucleotide Bind miRNA-122 Risk of cancer

1.5. Monitor

1.5.1. Degree of fibrosis Therapeutic decisions Clinical outcomes

1.5.2. Evaluating fibrosis Liver Biopsy High cost Inavasive Imaging Non-invasive FibroScan Liquid Biopsy Non-invasive Liver proteins & others

2. Viral Proteins/Genome

2.1. Six genotypes

2.1.1. HCV-1 most prevalent in North America

2.2. Structural

2.2.1. Processed by cellular proteins

2.2.2. Core Builds around LD

2.2.3. Envelope glycoprotein Heterodimer (E1/E2) E1 pH-dependent fusion peptide E2 Attachment Glycosylated

2.2.4. Ion channel Regulates intracellular pH NS1/p7

2.3. Non-structural

2.3.1. Processed by viral proteins

2.3.2. NS2 (cysteine autoprotease) Separate Structural from Non-structural

2.3.3. NS3 Soluble protein Cytosol Serine protease Cleaves MAVS (biosensor) Process NS proteins Immune evasion Helicase Required for vRNA replicaton ATPase Block protease = Block helicase

2.3.4. NS4A (co-factor) Required for NS3 function Anchor for NS3

2.3.5. NS4B Required for RC Membranous Web formation Double membrane vesicles Decrease Sterol Upregulates lipid metabolism (SREBP pathway) Favorable environment for HCV Decreases sterols Activate SREBP Increase LD amount Increases LD size

2.3.6. NS5A (phosphoprotein) Unknown function Target in Epclusa Replication & assembly Binds to RNA

2.3.7. NS5B (RNA pol)

2.3.8. NS3-NS5B is associated with Replication complex

2.4. miRNA-122

2.4.1. Liver tropism

2.4.2. Co-evolution

2.4.3. 5' UTR

2.4.4. Compare sequence of binding site with other hepaciviruses

2.4.5. Redundancy in miRNA?

2.5. Rodent & canine homologs

3. Viral Lifecycle

3.1. Lipid metabolic pathway

3.1.1. NS4B

3.1.2. Overstimulation

3.1.3. SREBP

3.1.4. Increase lipid biosynthesis promotes cholesterol intracellular storage Critical cellular event Replication Assembly Budding

3.1.5. Core/LD Promote reorganization & accumulation Assembly Release

3.2. Attachment & Entry

3.2.1. E1/E2

3.2.2. Apolipoproteins

3.2.3. Lipo-viro-proteins

3.2.4. Multiple receptors Attachment (Apolipoproteins) LDLR GAG Entry (E2) CD81 SR-B1 CLDN1 OCLN NPC1L1

3.2.5. Outside-in signaling

3.3. Endocytosis, fusion, genome release

3.3.1. E1 pH-dependent fusion

3.4. Translation and cleavage

3.4.1. miRNA-122

3.4.2. Translated in rER

3.4.3. NS2 & NS3

3.4.4. Cellular proteases

3.5. Assembly of viral proteins to form RC

3.5.1. Rearrangement of ER membrane NS4B Requires a lot of energy Depletes cholesterol SREBP maintains liver homeostasis

3.5.2. Membranous webs Double Membrane Vesicles Peak of RNA replication

3.5.3. Unknown Inside DMV Cytosolic side

3.5.4. Antiviral target

3.5.5. Replication Complex Immune evasion Concentration replication proteins Exclude host proteins

3.6. Assembly of HCV virions

3.6.1. NS5A:Core-enriched LD = Assembly platform

3.6.2. SREBP pathway

3.6.3. LD re-localization

3.7. Assembly and maturation

3.7.1. VLDL secretory pathway

3.7.2. Require apolipoproteins

3.8. Budding

4. Host-virus interactions

4.1. SREBP pathway

4.1.1. Transcription Factor SRE LDLR Lipid metabolism genes

4.1.2. Activating proteases in Golgi S1P Cleaves SREBP S2P Cleaves membrane portion Allows SREBP to go to nucleus

4.1.3. SCAP detects low cholesterol SCAP & SREBP relocate to Golgi

4.2. MAVS cleavage

4.2.1. Interferon-stimulated genes

4.3. Lipid Droplet

4.3.1. Multifunctional organelles Temporary shelter Stability of host cell Prevent detection Scaffold Lipid homeostasis Signal transduction Membrane trafficking

4.3.2. Upregulate formation

4.3.3. PLIN Evolutionary conserved Marker

4.4. Exosome

4.4.1. Impact Exosome-mediated reprogramming miRNA mRNA Gene regulation of bystander cells Exosome-mediated viral transmission Infectious HCV RNA (already primed with miRNA-122) Extrahepatic disease manifestations Receptor independent Immune evasion Exosome-associated biomarkers Biological fluid Non-invasive

4.4.2. Disease Exosome regulation (upregulated on infection) Extrahepatic disease manifestations

4.4.3. Biological fluids Urine Less complex fluid Blood Saliva Semen

4.4.4. Cargo Protein miRNA mRNA

4.4.5. Specificity depends on origin

4.4.6. Treatement Block host exosomes

4.5. ER membrane reorganization

4.6. Mitochondria sequestration

4.7. Intracellular pH regulation

5. Antivirals

5.1. DAA

5.1.1. High resistance

5.1.2. NS3 Protease inhibitor Polypeptide maturation MAVS biosensor Helicase activity

5.1.3. NS4A:NS3 Prevent anchoring of NS3 No functional NS3 Prevent NS3-dependent cleavage of NS proteins Prevent formation of ER-associated replication complexes Prevent cleavage of MAVs

5.1.4. NS4B Mislocalization prevents MW formation No replication

5.1.5. NS5A Unknown function No replication No assembly

5.1.6. NS5B Nucleoside Nucleotide that stops replication Non-nucleoside Changing conformation of protein More likely for resistance

5.2. IAA

5.2.1. Low Resistance

5.2.2. Lipid modulating drugs miRNA-122 S1P Interrupt host lipid pathways Prevent LD formation S2P Much harder target since it is in the membrane

5.2.3. TEM domain Tetraspannins are closely associated

5.2.4. Cellular proteases for structural proteins

5.2.5. Entry inhibitors

5.3. Plug drug

5.3.1. 3D enzyme model

5.3.2. Simulation of binding to active site

5.3.3. Screen FDA approved drugs

5.3.4. Natural products

5.4. Harvoni/Epclusa

5.4.1. NS5B nucleoside RNA polymerase inhibitor

5.4.2. NS5A inhibitor unknown function

5.5. Sofosbuvir

5.5.1. NS5B polymerase inhibitor

5.6. Multifunctional Proteins

5.6.1. Low concetration

5.6.2. Low toxicity

5.6.3. Cost Beneficial

5.6.4. Synergistic effect

5.7. Pangenotypic

5.8. Exosome regulation

5.8.1. Upregulated on infection

6. Leaders

6.1. Mel Krajden (BCCDC)

6.2. Michael Houghton (discovered HCV-1)

6.3. Ralf Bartenschlager

6.4. Norman Kneteman

6.5. Daniel Lamarre

6.6. Frank Chisari

6.7. Peter Sarnow

6.8. Takaji Wakita

6.9. Michael S. Brown

6.10. Joseph L. Goldstein

7. Bats

7.1. Natural Reservoir

7.2. Viral diversity

7.3. DBatVir