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Hepatitis C and Dengue virus immunopathogenesis
Both viruses are flaviviridae viruses- first virus discovered was yellow fever virus (also the
first human virus being discovered)- helped death from YF during the building of the panama
canal
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Some of them are less closely related than other viruses in the family- they only
share 60% amino acids
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Mature Denv virion-very small genome- only about 10-11 kb
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Membrane that is
derived from the host cell
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There are 6 copies of the E protein
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Flaviviridae life cycle
replicates similarly to most viruses
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The virus is endocytosed into an endosome by
receptor mediated endocytosis
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Translation, protein production, and
assembly, then the mature viruses are released from the cell in the normal pathway
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1
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2
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3
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4
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5
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full fusion, forming a continuous opening of the virion into the cell, so the contents of the
virion can be transported into the cell
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And now the
viral DNA gets into the cytoplasm as it has made a hole in the endosome
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genome structure- HCV do not have caps, both Dengue and HCV
do not have a poly(A) tail
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Flaviviridae make one giant polyprotein (made of
10 proteins) from the genome about 3000aa long
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It is translated by the ER,
and sits in and out of the ER membrane
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inside the ER it uses signalases which cleaves all of the cleavage

sites in the ER lumen, it cannot cleave the ones in the cytoplasm because it isn't in the
cytoplasm
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NS3 works inside the membrane, not in the cytoplasm, but cleaves the proteins on the
cytoplasmic side
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you go from +ssRNA and make -ssRNA
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It makes lots of antigenome (ssRNA) strands so
they can act as templates for replication of pos later on, and later on you make less neg and
more pos to package to make new particles
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So the virus does it instead
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NS3 becomes a
helicase after dissociating with Ns2b, which means its unwinding the RNA, and it is also
involved in mRNA capping
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These are all replicating in the
cytoplasm
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The RNA gets put in a little pocket of the ER to be hidden away from the immune
system
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assemblycapsid protein packages viral RNA and buds into the ER lumen
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Therefore,
Flaviviridae are not lytic viruses (they are not released by lysis of the cell)
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Furin cleaves pre-M into M causing conformational changes in E
(making the virion look smooth instead of spiky) and matures the virus particle as it is
released from the cell
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Transmission and disease
DENV transmission and disease
● genus:flavivirus
● Four serotypes: DENV-1,2,3,4
● Tropism (target): immune cells (macrophages, dendritic cells)- can also infect
hepatocytes and endothelial cells
● Transmitted by Ae
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albopictus mosquitoes
● Acute infection, no persistence
● Most significant arbovirus infecting humans
DENV symptoms
● High fever
● Joint pain, muscle, and bone pain

● Severe headaches
● Severe pain behind the eye
● Rash and mild bleeding- eg
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HCV transmission and disease
● Genus: hepacivirus
● Tropism: liver cells (hepatocytes)
● Initial infection: mild symptoms
● Chronic infection: leading to disease
● Blood-borne transmission
HCV symptoms
Acute infection

Chronic infection

Asymptomatic 80%

Asymptomatic (early years after infection)

Symptomatic 20%
Fever, fatigue, decreased appetite, nausea
and vomiting, abdo pain, dark urine, grey
faeces, joint pain, jaundice
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It is determined
by cellular receptors for virus, other cellular factors required for replication (eg
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digestive
enzymes/bile in gut)
HCV immunopathogenesis
1) Evasion of innate immune responses (interferon induction/signalling)
2) Lack of sterilising antibody responses
–Viral mimicry: Virions mimic low-density lipoproteins to evade antibody targeting
–Viral hiding: cell-to-cell spread via tight junctions to avoid exposure to antibodies
–Shifting antigens: shifting glycosylation patterns on envelope proteins
–Re-infection can occur after treatment or spontaneous virus clearance
3) Cytotoxic immune cells are key to clinical disease progression
–Important factor in switch from acute to chronic infection
–Directly cause pathologic changes in l
HCV evasion of the interferon system
1) NS3/4a viral protease
– Cleaves RIG-I to block RIG-I-mediated interferon induction
– Cleaves MAVS to block RIG-I-mediated interferon induction
– Cleaves TRIF to block TLR3 signalling and interferon induction
– NS3 binds TBK1 to prevent binding with IRF3 and interferon induction
2) NS4b: Blocks STING to prevent interferon induction
3) NS5a
– Binds MyD88 to block TLR signalling and interferon induction
– Binds a number of ISGs (2’5’-OAS, RNaseL, PKR) to block antiviral effects
4) Core: Directly interacts with STAT1, prevents STAT1 phosphorylation and activation
5) Envelope: Binds the ISG PKR to block antiviral effects
6) Replication in membranous compartments hidden from immune sensors

Cytotoxic T cell responses drive hepatitis immunopathology
1) NK cells kill infected hepatocytes and produce cytokines
– Hepatocytes are relatively resistant to perforin- and granzyme-mediated cytotoxicity
2) CD8+ cytotoxic T cells also kill infected hepatocytes and produce cytokines
– Regulatory T cells supress CD8+cytotoxic T cells to allow long-term persistence of HCV
– Prolonged exposure to viral antigen leads to increased expression of exhaustion
markers, which reduces proliferation and degranulation, and reduced cytotoxicity
3) HCV has a high mutation rate
– Epitope evasion and escape from cytotoxic killing
•Viral persistence
•Long-term liver damage (balanced by high proliferative capacity of liver)
•Chronic inflammation leading to fibrosis and cirrhosis
DENV immunopathogenesis
1) Evasion of innate immune responses (interferon induction/signalling)
2) Antibody-dependent enhancement of DENV infection contributes to haemorrhage
– Higher replication and more severe disease in secondary infection with different serotype
DENV evasion of the interferon system
1) NS2B/3 viral protease: cleaves STING to block interferon induction
2) NS2A: reduces STAT1 phosphorylation
3) NS4A: reduces STAT1 phosphorylation
4) NS4B: reduces STAT1 phosphorylation
5) NS5: binds and degrades STAT2
6) Replication in membranous compartments hidden from immune sensors
2,3,4 work synergistically: greater effect together than alone
Sequential infection with different serotypes increases risk of haemorrhage

Enhancement of DENV replication in secondary infection
1) Non-neutralising antibodies bind DENV particle and Fc receptor
2) Enhance entry into macrophages (target cells for DENV)
3) Increased viral replication, increased viraemia, increased cytokine production
Cytokine storm leads to haemorrhage- immune disruption, immune cells make more
cytokines including TNFa which increases vasodilation, resulting in haemorrhage

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