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MIMM 324 > 26. Hepatitis C Virus > Flashcards

26. Hepatitis C Virus Flashcards

1
Q

how was hepatitis C virus discovered?

A
  1. blood from ppl with virus
  2. extract RNA and make cDNA
  3. express in E. coli
  4. detected antigen
  5. cloned antigen to get hepatitis C
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2
Q

HCV is responsible for 40-60% of _______

A

HCV is responsible for 40-60% of chronic liver disease and is the leading cause of liver transplant

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3
Q

how many people infected with HCV become chronically infected?

A

85%

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4
Q

HCV vaccine?

A

no vaccine available –> very diverse virus with diverse sequence

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5
Q

is HCV cytopathic?

A

no, it doesn’t kill cells it just forces them to continuously make virus

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6
Q

what family of virus is HCV?

A

Flaviviridae

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7
Q

how is HCV transmitted (8)? what is the main route?

A
  1. blood transfusion (MAIN)
  2. injecting drug use
  3. high risk sexual activity
  4. health-care workers
  5. hemodialysis
  6. mother-to-child
  7. household exposures
  8. cocaine use
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8
Q

3 ways to diagnose HCV

A
  1. Serology
  2. Viral genome copies
  3. Degree of liver damage
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9
Q

describe serology to diagnose HCV

A

Enzyme immunosorbent assay –> look for anti-HCV antibodies in the blood

positive in >95% of chronically infected patients

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10
Q

describe looking at viral genome copies to diagnose HCV

A

qPCR –> look for viral RNA in the blood, sign of active infection

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11
Q

how can we assess degree of liver damage?

A

look at serum liver enzymes and fibroscan (liver inflammation/fibrosis)

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12
Q

2 consequences of HCV infection

A
  1. acute hepatitis
  2. chronic hepatitis
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13
Q

what is HCV incubation period for developing acute hepatitis?

A

6-10 weeks

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14
Q

what happens to 80% of ppl with acute HCV?

A

80% of ppl with acute HCV will have no symptoms

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15
Q

what are 7 symptoms of acute HCV?

A
  1. pain in upper right quadrant
  2. anorexia
  3. abdominal pain
  4. nausea/vomiting
  5. fever
  6. fatigue
  7. jaundice
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16
Q

2 possible results of acute hepatitis

A
  1. 15% will clear infection
  2. 85% will develop chronic HCV
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17
Q

when is hepatitis considered chronic rather than acute?

A

continuing HCV-related disease without improvement for at least 6 months

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18
Q

what percent of ppl with chronic hepatitis have no symptoms?

A

60-80%

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19
Q

what is chronic hepatitis?

A

slowly progressing lifelong infection

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20
Q

2 outcomes of chronic hepatitis and proportions

A
  1. cirrhosis and liver failure (10-20%)
  2. Hepatocellular carcinoma (3-5%)
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21
Q

when do clinical symptoms of HCV appear?

A

during liver failure

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22
Q

how many years can it take btwn infection and development of serious complications?

A

20 years may elapse between infection and development of serious complications

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23
Q

evolution of HCV treatment

A
  1. IFN
  2. IFN + PI/NI
  3. Direct acting antivirals
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24
Q

3 direct acting antivirals

A
  1. Inhibitor of NS3 protease
  2. Inhibitor of NS5B polymerase
  3. Inhibitor of NS5A
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25
Q

what family is HCV part of?

A

flavivirus

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26
Q

what genus is HCV part of?

A

hepacivirus

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27
Q

is HCV enveloped or naked?

A

enveloped

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28
Q

size of HCV, avg size of capsid

A

40-80nm, 30nm

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29
Q

what is the shape of HCV capsid?

A

SPHERICAL

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30
Q

4 characteristics of HCV genome

A
  1. +ssRNA
  2. Monopartite
  3. Linear
  4. 9.6kb
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31
Q

describe the HCV genome

A

5’ UTR has IRES, no cap
3’ UTR has folded structures

1 long ORF

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32
Q

4 HCV structural proteins

A
  1. C = core
  2. E1 = envelope glycoprotein
  3. E2 = envelope glycoprotein
  4. p7 = ion channel
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33
Q

6 non-structural proteins

A
  1. NS2 = autoprotease
  2. NS3 = protease/helicase/NTPase
  3. 4A = protease co-factor
  4. NS4B = membranous web
  5. NS5A = RNA replication
  6. NS5B = RdRP
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34
Q

is the long mRNA cleaved by host or virus proteases?

A

both

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35
Q

what is the role of NS2?

A

autoprotease that cleaves and releases the N-terminus so NS3 can cleave the other non-structure proteins

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36
Q

structure of 5’ UTR

A

6 stem loops, stem loop #4 has start codon

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37
Q

structure of 3’ UTR

A

3 stem loops near poly U region

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38
Q

HCV life cycle (6)

A
  1. binds receptor on hepatocytes
  2. fusion and uncoating
  3. translating, processing
  4. replication
  5. assembly
  6. release
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39
Q

2 models of lipo-viral particles

A
  1. two-particle model
  2. single-particle model
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40
Q

3 receptors for HCV entry

A
  1. CD81
  2. CLDN-1
  3. OCLN
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41
Q

3 co-receptors for HCV entry

A
  1. GAGs
  2. LDLR
  3. SR-BI
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42
Q

what play a prominent role in viral entry? how?

A

lipoproteins via lipoviral particles

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43
Q

what type of entry is used by HCV?

A

clathrin-mediated

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44
Q

1st step of HCV when it is in the cell

A

TRANSLATION

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45
Q

is HCV capped? how does it accomplish translation?

A

not capped –> cap-independent translation accomplished by IRES at the stem loops of 5’ UTR

46
Q

describe cap-independent translation

A

IRES binds 40S subunit of ribosome and uses only eIF2 and eIF3 –> places start codon in P site of ribosome to initiate translation

47
Q

what is miR-122?

A

acts as a cap to protect HCV from degeneration

48
Q

why is miR-122 needed?

A

normally, an uncapped 5’ end of RNA would be degraded so miR-122 prevents this

49
Q

where does polyprotein processing occur?

A

occurs within membrane complex –> all proteins remain in membrane, not soluble in cytoplasm

50
Q

what proteins do host proteases cleave?

A

structural proteins

51
Q

what forms the replication complex? (4)

A
  1. NS3 + NS4A
  2. NS4B
  3. NS5A
  4. NS5B
52
Q

role of NS3 and NS4A

A

NS3 acts as helicase and NS4A is cofactor for NS3

53
Q

role of NS4B

A

membrane reorganization

54
Q

3 roles of NS5A

A

phosphoprotein, RNA replication, and assembly

55
Q

role of NS5B

A

RdRP

56
Q

where does HCV RNA replication occur?

A

on membranous webs

57
Q

5 functions of membranous webs

A
  1. physical support
  2. compartmentalization
  3. protection
  4. tethering of RNA from unwinding
  5. retention of negative strand
58
Q

where do membranous webs derive from?

A

ER

59
Q

3 structures that membranous webs derive from?

A
  1. lipid droplets
  2. double membrane vesicles
  3. multi-membrane vesicles
60
Q

what protein induces membranous webs?

A

NS4B

61
Q

describe pores at membranous webs

A

lipid vesicles contain pores that allow transport of HCV RNA in/out –> the pores have nuclear pore components redirected to form pores

62
Q

topology of NS5B

A

Right hand

63
Q

initiation of RdRP

A

de novo

64
Q

in vitro, what initiates NS5B?

A

GTP is the initiating NTP in vitro

65
Q

what does NS5B require for its function?

A

divalent metal ions

66
Q

describe the replication rate of NS5B and consequence

A

replication rate = 10^12 particles/day but has no proof-reading activity –> ERROR PRONE, therefore many genetic variants

67
Q

describe virion assembly (3)

A
  1. replicated +RNA in membrane vesicles merges with capsid proteins associated with lipid droplets
  2. capsid-bound RNA associates with envelope proteins
  3. lipoprotein machinery to bud
68
Q

what type of protein is p7?

A

viroporin

69
Q

what is a viroporin?

A

ion channel that promotes pH-mediated maturation AND the release of infectious viral particles from the cell

70
Q

2 indications for HCV treatment?

A
  1. liver disease/liver inflammation
  2. presence of HCV RNA in the blood
71
Q

goal of HCV treatment

A

eliminate detectable viral RNA from the blood

72
Q

what was the first approved HCV therapy?

A

IFN-alpha injection

73
Q

modified IFN-alpha treatment?

A

pegylated form which slows elimination so only 1 injection per week is needed

74
Q

why do you need treatment nurses for IFN-alpha?

A

severe side effects

75
Q

8 side effects of IFN-alpha

A
  1. flu-like symptoms
  2. depression
  3. anxiety
  4. restlessness
  5. rashes
  6. insomnia
  7. loss of appetite
  8. anemia
76
Q

what % of patients respond to peg-IFNalpha

A

30-40% respond to peg-IFNalpha alone

77
Q

what is ribavarin?

A

synthetic nucleoside that mimics guanosine

78
Q

how does ribavarin work? 3 consequences

A

pairs with cytidine and uridine

  1. Inhibition of IMDPH
  2. inhibition of RdRP (weak)
  3. RNA mutagenesis
79
Q

7 side effects of ribavarin

A
  1. anemia
  2. teratogenic
  3. fatigue
  4. headache
  5. insomnia
  6. nausea
  7. anorexia
80
Q

efficacy of ribavarin

A

only a broad antivirial –> not effective against HCV when alone

81
Q

results of ribavarin and peg-IFNalpha given together

A

50% sustained virological response

but 10-20% don’t complete therapy due to side effects

82
Q

3 major classes of direct acting antivirals

A
  1. protease inhibitors
  2. NS5A inhibitors
  3. polymerase inhibiters
83
Q

2 protease inhibitors

A
  1. boceprevir
  2. telaprevir
84
Q

protease inhibitors are used in combination with:

A

peg-IFNalpha/ribavirin

85
Q

2 problems with protease inhibitors?

A
  1. severe side effects
  2. viral resistance can quickly emerge
86
Q

3 types of polymerase inhibitors

A
  1. benzimidazole indole derivatives
  2. non-nucleoside analogues
  3. nucleoside analogues
87
Q

diff btwn non-nucleoside and nucleoside analogues

A

non-nucleoside analogues –> don’t bind in active site

nucleoside analogues –> bind in active site

88
Q

example of nucleoside analogue

A

sofosbuvir

89
Q

mechanism of sofosbuvir

A

U analog –> nucleotide inhibitor leads to chain termination

90
Q

duration of sofosbuvir treatment

A

12 weeks

91
Q

does sofosbuvir work on multiple types of HCV?

A

> 90% sustained virological response for genotype 1

82% sustained virological response for genotype 4

92
Q

describe sofosbuvir as a prodrug

A

has protected phosphate group so can easily become NTP

93
Q

sofosbuvir course of treatment

A

viral load quickly decreases to low level when treatment begins

stop treatment, rebounds with diff sequence that reduces drug potency

94
Q

2 possible mechanisms of NS5A inhibitors?

A
  1. affecting RNA binding
  2. protein-protein interactions
95
Q

2 types of NS5A inhibitors

A
  1. daclatasvir
  2. ledipasvir
96
Q

does NS5A inhibitor work across specific HCV genotypes or many?

A

works across many genotypes

97
Q

what gives best results of NS5A inhibitors?

A

combination therapy of daclatasvir and ledipasvir

98
Q

difference btwn genotype and subtype

A

genotypes differ by 30-35%

subtypes differ by 10-30%

99
Q

3 implications of HCV being genetically diverse

A
  1. immune response
  2. disease progression
  3. treatment/drug resistance
100
Q

2 ways that HCV drug resistance occurs

A
  1. viral turnover
  2. base variants
101
Q

describe the viral turnover of HCV contributing to genetic diversity

A

many viruses produced per day + high pol error rate + long genome = diversity

102
Q

how many HCV mutations/day can we expect with single mutation? double mutation?

A

9x10^9 new genomes/day with 1 mutation

5x10^8 new genomes/day with 2 mutations

103
Q

describe base variants contributing to HCV diversity

A

each base can mutate to 3 other bases –> on a long genome this is a lot of diversity

104
Q

describe the mixture of HCV populations

A

HCV exists as a mixture of populations of genetically distinct but closely related virions in every patient –> quasispecies

105
Q

prior to therapy, what happens to most resistant viruses

A

prior to therapy, most resistant viruses are unfit and undetectable

106
Q

describe the HCV viruses along the course of treatment (3 stages)

A
  1. prior to treatment, start with lots of WT virus
  2. WT virus decreases with treatment
  3. then non-WT virus increases with treatment
107
Q

why does non-WT virus increase with treatment

A

virus type is selected based on environment

normally, non-WT virus is low

but treatment will allow non-WT type to survive

108
Q

is HCV curable?

A

yes –> over 95% SVR and RNA viral episome is eliminated

109
Q

4 reasons HCV is a quasispecies

A
  1. resistant variants to antiviral drugs exist before treatment
  2. resistant variants are selected during treatment
  3. drug resistance can occur with treatment
  4. resistance is CONSEQUENCE of treatment failure (not always the cause)
110
Q

how can treatment failure due to resistance be minimized?

A
  1. use combinations of drugs
  2. use drugs with higher barrier to resistance

MIMM 324 (37 decks)

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