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MIMM 324 > HCV 2 > Flashcards

HCV 2 Flashcards

1
Q

HCV treatment indications

A

-chronic liver inflammation
-presence of hcv rna in the blood=active infection

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2
Q

gola of hcv treatment

A

eliminate detectable ciral rna from the blood (viral clearance or sustained virological response =cure)

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3
Q

all early protocols for HCV treatment were based on:

A

all early protocols for HCV treatment were based on IFN-⍺ administered by injection
- Modified (pegylated) form slows elimination (1/week)
* Treatments are for 24-48 weeks, hey had to do the treatments multiple times a week
* Severe side effects:
- Flu-like symptoms, depression, anxiety, restlessness, rashes,
insomnia, loss of appetite, anemia, etc.
* 30-40% of patients respond to peg-IFN⍺ alone

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4
Q

Ribavirin

A
  • Synthetic nucleoside
  • looks like guanine (pseudobase)
  • Side effects:
  • Anemia, teratogenic, fatigue,
    headache, insomnia, nausea, anorexia,
    etc.
  • Broadly antiviral, not effective against HCV
    when given alone
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5
Q

Ribavirin + peg-IFN⍺

A
  • ~50% sustained virological response (SVR)
  • But: 10-20% of patients do not complete therapy due to side effects
  • $4000 USD/week
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6
Q

Direct acting antivirals: DAAS

A

facilited by out ability fo do cell cultures
-protease inhibitor
-ns5a inhibitor and polymerase inhibitor

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7
Q

NS3 Protease Substrate-Based
Rational Inhibitor Design

A

N6terminal’product’inhibiGon’is’observed’for:’
‘
‘’’’’’’’’’'’D D I V P C (Ki’=’79’μM)

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8
Q

Protease: NS3/4A inhibitors

A

select for substrate to block ns3
no cleaving of the polyproteins
-ex: boceprevir and telaprevir

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9
Q

boceprevir and telaprevir

A
  • Boceprevir and Telaprevir (FDA approved 2011)
  • used in combination with
    peg-IFN⍺/RBV
  • Significant side effects
  • Specific for genotype 1
  • Sustained response rates in 50-70%
  • HCV is highly mutable!
  • viral resistance can (quickly) emerge
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10
Q

polymerase: NS5B inhibitors

A
  • Sofosbuvir (FDA approved 2013)
  • Nucleoside inhibitor (U analog)
  • Mechanism: chain termination
  • 12-wk duration; pan-genotypic
    ‣ ≥90% SVR for genotype 1, ~82% SVR for genotype 4
  • Cost: ~$80,000/course of treatment
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11
Q

True or false: resistance to sofosbuvir is rare

A

true

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12
Q

NS5A inhibitirs

A

NS5A: Phosphoprotein, roles in inhibition of antiviral responses, RNA replication (interacts with 3’ end of the viral RNA and NS5B) and assembly
-precise mechanisms not clear
-ex: daclatasvir and ledipasvir

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13
Q

daclatasvir and ledipasvir

A
  • 12-wk duration; pan-genotypic
  • Combination therapy (IFN-free)
  • ≥94% SVR for genotype 1
  • high barrier to resistance
  • Cost ~$80,000/course of treatment
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14
Q

which virus is the most mutable

A

hep c

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15
Q

Selection of hcv drug resistance

A

Viral Turnover: 10 ^11-10^12 viruses/day x 10^-5 -10 ^-4 pol error rate x 104 nt

Base Variants: each base can mutate to 3 other (10^4 nt genome)

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16
Q

genetic variation hcv

A
  • HCV exists as a mixture of
    populations of genetically distinct,
    but closely related, virions in every
    patient (quasispecies)
  • Most resistant viruses are relatively
    unfit and are undetectable prior to
    therapy
17
Q

Many factors determine the treatment response

A
  • Virus: the genetic barrier is related to the number and type of mutations required to overcome the clinical activity of a regimen (mutations that decrease the viral fitness increase
    the resistance barrier)
  • Drug(s): the pharmacologic barrier is increased by higher potency and higher drug levels
  • Patient: tolerability of a regimen and patient adherence are critical to treatment success
18
Q

what is a barrier to hcv treatments

A

so expensivbe
shit healthcare
lack of education
touches more marginalized group
hard to diagnoase

19
Q

True or false: HCV exists as a quasispecies

A

true n
- resistant variants to antiviral drugs exist before treatment
- resistant variants can be selected/enriched during treatment
- drug resistance can occur during treatment with all (or any) antiviral drug
- resistance is a consequence of treatment failure (but not always the cause)

20
Q

WHAT ARE MICRORNA

A
  • Small, non-coding RNAs (20-25 nt)
  • Bind to partially complementary sites
    (seed sequences) in the 3’ end of
    mRNAs and block their translation
  • Typically turn OFF gene expression
  • Expressed in a tissue-specific
    manner
  • Regulate ~50-60% of ALL human
    genes
21
Q

miR-122

A
  • Evolutionarily conserved, liver-specific microRNA
  • 70% of microRNAs in the liver (66 000 copies/cell)
  • Regulates cholesterol synthesis and fatty acid metabolism
22
Q

mir-122 iteracts with what?

A

the 5’ utr of the hcv genome which is weird
-there are w microrna sites in proximity and this upregulates the virus when this happens where usually it should be downregulation it

23
Q

true or false: mir 122 downregulates hcv rna accumulation

A

false it promotes it
* Sequestration of miR-122 abolishes HCV RNA
accumulation
- Cell culture
- HCV-infected Chimpanzees
- HCV-infected patients

24
Q

mir 122 acts as a … to protect the HCV genome from degradation

A

as a cap so that pyrophosphatases and nucleases can’t reach the viral rna

25
Q

true or false: mir 122 alters the structure of the 5’ end of the genome

A

facts it like makes these weird speudoknots so that nucleases can’t reach it

26
Q

true or false: mir 122 promotes the hcv translaction

A

true
it stabilizes the IRES

27
Q

how are the IRES made in hcv

A

mir 122
when the virus gets in the cell, site 1 and 2 are bp and then first mir 122 gets in and makes them go flat and you get and IRES and then a second comes in and then the IRES is stabilized

28
Q

Single-dose administration of
RG-101(antisense miR-122 inhibitor)

A

Mean viral load reduction of
4.1 logs
* 6/14 patients had viral
RNA below the level of
detection
* Pan-genotypic activity
* Side effects? - lowers
cholesterol
* Unique mechanism of
targeting a host factor

29
Q

true or false: dogs can get infected by hcv

A

they can: canine hepacivirus

30
Q

from which animal might hcv come from

A

horseeee

31
Q

Non-primate hepacivirus (NPHV)

A
  • Using CHV NS3 antigen,
    screened numerous
    mammalian species
  • 35% of horses seropositive
  • Renamed CHV = Non-
    primate hepacivirus (NPHV)
  • Tentative evidence for
    etiologic role of NPHV in
    hepatitis
32
Q

true or false: lots of animals can get hcv

A

true even sharks

33
Q

true or false: hcv might be a zoonotic virus

A

true

34
Q

Hypotheses regarding the origin of HCV

A

Hypothesis #1: Single cross-species transmission event between ancestral humans and a zoonotic host
* Geographic populations
* Global pattern of HCV diversity
Hypothesis #2: Multiple independent zoonotic
transmission events
* RHVs: most genetically diverse (3 lineages, 8
clades), common ancestors with other animal
hepacivirses, intermediate or original host?
probs from rodents

35
Q

true or false: hepaciviruses could be transmissible via an insect vector or airborne

A

true

MIMM 324 (26 decks)

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