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

1.1.1.1. Metabolism

1.1.1.1.1. Carbohydrate

1.1.1.1.2. Lipids

1.1.1.1.3. Proteins

1.1.1.2. Storage

1.1.1.2.1. Essential nutrients

1.1.1.2.2. Vitamins

1.1.1.2.3. Mineral

1.1.1.3. Detoxification

1.1.1.3.1. Monitor blood contents

1.1.1.3.2. Remove toxic substances

1.1.1.4. Biosynthesis of key molecules

1.1.1.4.1. Blood plasma components

1.1.1.4.2. Lipid production

1.1.2. Affect

1.1.2.1. Acute infection

1.1.2.2. Chronic Hepatitis C (CHC) ~80%

1.1.2.2.1. Insufficient immune response

1.1.2.2.2. Inflammation = cell death

1.1.2.2.3. Metabolic disorder

1.1.2.2.4. Lipid modulation disturbances

1.1.2.3. Fibrosis

1.1.2.3.1. Many scars turn into nodules

1.1.2.4. Cirrhosis

1.1.2.4.1. Scarring prevents blood flow

1.1.2.4.2. Fluid build up (abdomen, legs, intestines)

1.1.2.4.3. Decrease mental function

1.1.2.4.4. Liver transplant

1.1.2.5. Hepatocellular carcinoma

1.1.3. Lipo-viro-particles (LVP)

1.1.3.1. Liver specific Receptors

1.1.3.1.1. Attachment

1.1.3.1.2. Entry

1.1.3.2. VLDL-secretory pathway & apolipoproteins

1.1.3.2.1. Assembly

1.1.3.2.2. Maturation

1.1.4. miRNA-122

1.1.4.1. Stabilize genome

1.1.4.2. Stimulate genome translation

1.1.4.3. Bind 5' end

1.1.4.4. Deregulation of fatty acid metabolism

1.1.5. Membranous web

1.1.5.1. Viral protein induced

1.1.5.2. ER-derived membranes

1.1.5.3. Replicase complexes

1.1.5.4. Association with LD

1.1.6. Lipid Droplet (LD)

1.1.6.1. Lipoprotein synthesis pathway (LD formation)

1.1.6.2. Organelles for neutral lipid storage

1.2. Disease

1.2.1. Transmission

1.2.1.1. Blood-to-Blood contact

1.2.1.1.1. Supervised injection site

1.2.1.1.2. Drug users

1.2.1.1.3. Blood tranfusion

1.2.1.1.4. Piercing

1.2.1.1.5. Tatoos

1.2.1.2. Rare vertical transmission

1.2.2. Hepatitis

1.2.2.1. Liver inflammation

1.2.3. Symptoms

1.2.3.1. Acute infection

1.2.3.1.1. Typically asymptomatic

1.2.3.1.2. Fever

1.2.3.1.3. Fatigue

1.2.3.1.4. Decreased apetite

1.2.3.1.5. Upset stomach

1.2.3.1.6. Mild abdominal pain

1.2.3.2. Chronic infection (+6 months)

1.2.3.2.1. Liver disease (fatty liver)

1.2.3.2.2. Darkening of urine

1.2.3.2.3. Yellow skin & eyes

1.2.3.2.4. Death

1.2.4. Upregulation of Lipid Droplets

1.2.4.1. Scaffold for replication

1.2.4.2. Assembly

1.2.4.3. 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

1.3.2.1. Genetic factor?

1.3.2.2. Gene polymorphism?

1.3.2.3. No longer contagious

1.3.2.4. 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

1.4.3.1. Soak liver in entry inhibitors

1.4.4. Resistance

1.4.5. Harvoni/Epclusa

1.4.5.1. NS5B nucleoside RNA polymerase inhibitor

1.4.5.2. NS5A inhibitor unknown function

1.4.6. Miravirsen

1.4.6.1. Oligonucleotide

1.4.6.2. Bind miRNA-122

1.4.6.3. Risk of cancer

1.5. Monitor

1.5.1. Degree of fibrosis

1.5.1.1. Therapeutic decisions

1.5.1.2. Clinical outcomes

1.5.2. Evaluating fibrosis

1.5.2.1. Liver Biopsy

1.5.2.1.1. High cost

1.5.2.1.2. Inavasive

1.5.2.2. Imaging

1.5.2.2.1. Non-invasive

1.5.2.2.2. FibroScan

1.5.2.3. Liquid Biopsy

1.5.2.3.1. Non-invasive

1.5.2.3.2. 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

2.2.2.1. Builds around LD

2.2.3. Envelope glycoprotein

2.2.3.1. Heterodimer (E1/E2)

2.2.3.2. E1

2.2.3.2.1. pH-dependent fusion peptide

2.2.3.3. E2

2.2.3.3.1. Attachment

2.2.3.4. Glycosylated

2.2.4. Ion channel

2.2.4.1. Regulates intracellular pH

2.2.4.2. NS1/p7

2.3. Non-structural

2.3.1. Processed by viral proteins

2.3.2. NS2 (cysteine autoprotease)

2.3.2.1. Separate Structural from Non-structural

2.3.3. NS3

2.3.3.1. Soluble protein

2.3.3.2. Cytosol

2.3.3.3. Serine protease

2.3.3.3.1. Cleaves MAVS (biosensor)

2.3.3.3.2. Process NS proteins

2.3.3.3.3. Immune evasion

2.3.3.4. Helicase

2.3.3.4.1. Required for vRNA replicaton

2.3.3.5. ATPase

2.3.3.6. Block protease = Block helicase

2.3.4. NS4A (co-factor)

2.3.4.1. Required for NS3 function

2.3.4.2. Anchor for NS3

2.3.5. NS4B

2.3.5.1. Required for RC

2.3.5.2. Membranous Web formation

2.3.5.2.1. Double membrane vesicles

2.3.5.2.2. Decrease Sterol

2.3.5.3. Upregulates lipid metabolism (SREBP pathway)

2.3.5.3.1. Favorable environment for HCV

2.3.5.3.2. Decreases sterols

2.3.5.3.3. Activate SREBP

2.3.5.4. Increase LD amount

2.3.5.5. Increases LD size

2.3.6. NS5A (phosphoprotein)

2.3.6.1. Unknown function

2.3.6.2. Target in Epclusa

2.3.6.2.1. Replication & assembly

2.3.6.3. 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

3.1.4.1. promotes cholesterol intracellular storage

3.1.4.2. Critical cellular event

3.1.4.2.1. Replication

3.1.4.2.2. Assembly

3.1.4.2.3. Budding

3.1.5. Core/LD

3.1.5.1. Promote reorganization & accumulation

3.1.5.2. Assembly

3.1.5.3. 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

3.2.4.1. Attachment (Apolipoproteins)

3.2.4.1.1. LDLR

3.2.4.1.2. GAG

3.2.4.2. Entry (E2)

3.2.4.2.1. CD81

3.2.4.2.2. SR-B1

3.2.4.2.3. CLDN1

3.2.4.2.4. OCLN

3.2.4.2.5. 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

3.5.1.1. Requires a lot of energy

3.5.1.2. Depletes cholesterol

3.5.1.3. SREBP maintains liver homeostasis

3.5.2. Membranous webs

3.5.2.1. Double Membrane Vesicles

3.5.2.2. Peak of RNA replication

3.5.3. Unknown

3.5.3.1. Inside DMV

3.5.3.2. Cytosolic side

3.5.4. Antiviral target

3.5.5. Replication Complex

3.5.5.1. Immune evasion

3.5.5.2. Concentration replication proteins

3.5.5.3. 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

4.1.1.1. SRE

4.1.1.1.1. LDLR

4.1.1.2. Lipid metabolism genes

4.1.2. Activating proteases in Golgi

4.1.2.1. S1P

4.1.2.1.1. Cleaves SREBP

4.1.2.2. S2P

4.1.2.2.1. Cleaves membrane portion

4.1.2.2.2. Allows SREBP to go to nucleus

4.1.3. SCAP detects low cholesterol

4.1.3.1. SCAP & SREBP relocate to Golgi

4.2. MAVS cleavage

4.2.1. Interferon-stimulated genes

4.3. Lipid Droplet

4.3.1. Multifunctional organelles

4.3.1.1. Temporary shelter

4.3.1.1.1. Stability of host cell

4.3.1.1.2. Prevent detection

4.3.1.2. Scaffold

4.3.1.3. Lipid homeostasis

4.3.1.4. Signal transduction

4.3.1.5. Membrane trafficking

4.3.2. Upregulate formation

4.3.3. PLIN

4.3.3.1. Evolutionary conserved

4.3.3.2. Marker

4.4. Exosome

4.4.1. Impact

4.4.1.1. Exosome-mediated reprogramming

4.4.1.1.1. miRNA

4.4.1.1.2. mRNA

4.4.1.1.3. Gene regulation of bystander cells

4.4.1.2. Exosome-mediated viral transmission

4.4.1.2.1. Infectious HCV RNA (already primed with miRNA-122)

4.4.1.2.2. Extrahepatic disease manifestations

4.4.1.2.3. Receptor independent

4.4.1.2.4. Immune evasion

4.4.1.3. Exosome-associated biomarkers

4.4.1.3.1. Biological fluid

4.4.1.3.2. Non-invasive

4.4.2. Disease

4.4.2.1. Exosome regulation (upregulated on infection)

4.4.2.2. Extrahepatic disease manifestations

4.4.3. Biological fluids

4.4.3.1. Urine

4.4.3.1.1. Less complex fluid

4.4.3.2. Blood

4.4.3.3. Saliva

4.4.3.4. Semen

4.4.4. Cargo

4.4.4.1. Protein

4.4.4.2. miRNA

4.4.4.3. mRNA

4.4.5. Specificity depends on origin

4.4.6. Treatement

4.4.6.1. 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

5.1.2.1. Protease inhibitor

5.1.2.2. Polypeptide maturation

5.1.2.3. MAVS biosensor

5.1.2.4. Helicase activity

5.1.3. NS4A:NS3

5.1.3.1. Prevent anchoring of NS3

5.1.3.2. No functional NS3

5.1.3.3. Prevent NS3-dependent cleavage of NS proteins

5.1.3.4. Prevent formation of ER-associated replication complexes

5.1.3.5. Prevent cleavage of MAVs

5.1.4. NS4B

5.1.4.1. Mislocalization prevents MW formation

5.1.4.2. No replication

5.1.5. NS5A

5.1.5.1. Unknown function

5.1.5.2. No replication

5.1.5.3. No assembly

5.1.6. NS5B

5.1.6.1. Nucleoside

5.1.6.1.1. Nucleotide that stops replication

5.1.6.2. Non-nucleoside

5.1.6.2.1. Changing conformation of protein

5.1.6.2.2. More likely for resistance

5.2. IAA

5.2.1. Low Resistance

5.2.2. Lipid modulating drugs

5.2.2.1. miRNA-122

5.2.2.2. S1P

5.2.2.2.1. Interrupt host lipid pathways

5.2.2.2.2. Prevent LD formation

5.2.2.3. S2P

5.2.2.3.1. Much harder target since it is in the membrane

5.2.3. TEM domain

5.2.3.1. 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