HCV 2 Flashcards
HCV treatment indications
-chronic liver inflammation
-presence of hcv rna in the blood=active infection
gola of hcv treatment
eliminate detectable ciral rna from the blood (viral clearance or sustained virological response =cure)
all early protocols for HCV treatment were based on:
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
Ribavirin
- 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
Ribavirin + peg-IFN⍺
- ~50% sustained virological response (SVR)
- But: 10-20% of patients do not complete therapy due to side effects
- $4000 USD/week
Direct acting antivirals: DAAS
facilited by out ability fo do cell cultures
-protease inhibitor
-ns5a inhibitor and polymerase inhibitor
NS3 Protease Substrate-Based
Rational Inhibitor Design
N6terminal’product’inhibiGon’is’observed’for:’
‘
‘’’’’’’’’’'’D D I V P C (Ki’=’79’μM)
Protease: NS3/4A inhibitors
select for substrate to block ns3
no cleaving of the polyproteins
-ex: boceprevir and telaprevir
boceprevir and telaprevir
- 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
polymerase: NS5B inhibitors
- 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
True or false: resistance to sofosbuvir is rare
true
NS5A inhibitirs
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
daclatasvir and ledipasvir
- 12-wk duration; pan-genotypic
- Combination therapy (IFN-free)
- ≥94% SVR for genotype 1
- high barrier to resistance
- Cost ~$80,000/course of treatment
which virus is the most mutable
hep c
Selection of hcv drug resistance
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)
genetic variation hcv
- 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
Many factors determine the treatment response
- 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
what is a barrier to hcv treatments
so expensivbe
shit healthcare
lack of education
touches more marginalized group
hard to diagnoase
True or false: HCV exists as a quasispecies
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)
WHAT ARE MICRORNA
- 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
miR-122
- Evolutionarily conserved, liver-specific microRNA
- 70% of microRNAs in the liver (66 000 copies/cell)
- Regulates cholesterol synthesis and fatty acid metabolism
mir-122 iteracts with what?
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
true or false: mir 122 downregulates hcv rna accumulation
false it promotes it
* Sequestration of miR-122 abolishes HCV RNA
accumulation
- Cell culture
- HCV-infected Chimpanzees
- HCV-infected patients
mir 122 acts as a … to protect the HCV genome from degradation
as a cap so that pyrophosphatases and nucleases can’t reach the viral rna
true or false: mir 122 alters the structure of the 5’ end of the genome
facts it like makes these weird speudoknots so that nucleases can’t reach it
true or false: mir 122 promotes the hcv translaction
true
it stabilizes the IRES
how are the IRES made in hcv
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
Single-dose administration of
RG-101(antisense miR-122 inhibitor)
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
true or false: dogs can get infected by hcv
they can: canine hepacivirus
from which animal might hcv come from
horseeee
Non-primate hepacivirus (NPHV)
- 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
true or false: lots of animals can get hcv
true even sharks
true or false: hcv might be a zoonotic virus
true
Hypotheses regarding the origin of HCV
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
true or false: hepaciviruses could be transmissible via an insect vector or airborne
true
