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MB4030 > Hepatitis C > Flashcards

Hepatitis C Flashcards

1
Q

NANB

A
  • Harvey J Alter
  • lipid enveloped virus
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2
Q

Approaches by Genelabs and Chiron to identify and isolate NANB virus

A
  • Ab titer containing number of Abs w/ affinity for various viral Ags
  • use liver tissue and plasma from infected chimp
  • use human Abs to find viral proteins (Immunoscreening)
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3
Q

HCV & HCC

A
  • chronic infection
  • liver disease: fibrosis, cirrhosis, HCC

HCC
- malignant tumour
- poor prognosis
- high levels of anti-HCV present
- genotype** 1b** have higher rates

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4
Q

HCV & Anti-D immunoglobulin

A
  • Anti-D used to treat Rhesus neg mother with Rhesus pos baby
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5
Q

Most resistant genotype of HCV to therapy

A

Genotype 1a

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6
Q

How does HCV enter?

A
  • enters liver via hepatic artery and portal vein
    (vessels that transport blood to liver)
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7
Q

Acute HCV

A

lasts from 0 to 24 wks
- often remains undetected

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8
Q

CHC

A

Chronic hepatitis C
- 70% individuals develop this

Cirrhosis and hepatoceelular carcinoma - most common causes of mortality at end stage CHC

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9
Q

Structure of HCV

A
  • envelope proteins (contains lipid bilayer)
  • positive ssRNA
  • capsid (protects nucleic acid)
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10
Q

HCV IRES

A

Internal Ribosomal Entry Site
- contains regions of dsRNA
- used by virus to bind to ribosomes and start translation

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11
Q

HCV is a ….

A

Hepacivirus

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12
Q

Where does HCV bind

A

binds to hepatocyte cell surface protein receptors and enters cell by receptor-mediated endocytosis

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13
Q

HCV receptors

A

LDLRs on basolateral hepatocyte surface

Interacts with
- CD81
- tight junction proteins (claudins, CLDN1, OCLN)

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14
Q

Where does HCV translation and replication begin

A

Cytosol

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15
Q

Innate immunity receptors involved in HCV detection

A

TLR-7: detects HCV ssRNA
TLR-3: detects **dsRNA **
RIG-1: detects **ssRNA **in cytoplasm
PKR: detects dsRNA (IRES region)

detection leads to activation of TFs…
- NFkB
- IRF3
- IRF7

and subsequent production and secretion of cytokines and IFNs… (ANTI-VIRALS)
- IFN alpha
- IFN beta
- IFNλ

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16
Q

HCV defenses

A

Sensing of HCV can activate innate antiviral defences through IFN induction in hepatocytes

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17
Q

HCV control of IFN induction and immune evasion

A

NS3-NS4A (HCV protease)

  • cleaves HCV polyprotein (liberates NS proteins)
  • blocks RIG-1 by cleaving MAVS from intracellular membranes
  • **Blocks TLR3 **by cleaving TRIF
  • with E2 protien - both block PKR activity

NET result: suboptimal innate response

18
Q

Significance of cleaved MAVS

A

patients have lower IFNs

19
Q

IFN therapy

A
  • variable
  • many patients maintain high HCV viral load
20
Q

HCV genotypes

A

2 & 3: highest IFN-a treatment response rate (70-80%)
1 & 4: curative in 40-50% cases

21
Q

ISGs

A

IFN stimulated genes

  • IFN induces expression of 100s of ISGs with antiviral and immunomodulatory activities
  • genotypes 1 &4 have high levels of ISGs in patients liver before therapy (less effect IFN response)
22
Q

Are ISGs anti-viral?

A

No

Differential induction of specific ISGs in patients with different outcomes of HCV infection

23
Q

Treatment of chronic HCV with IFNs

A

Pegylated IFN-a combined w/ ribavirin for 24-48 wks

24
Q

Sustained Virologic Response

A

undetectable level of HCV RNA, 12 wks after end of therapy
- virological surrogate for clinical cure

25
Q

Ribavirin

A

a guanosine analog used to stop viral RNA synthesis

26
Q

Why are some outcomes resolved vs chronic

A
  • HCV genotypes (1,4 not good)
  • role of host factor and genetics
  • IFNa S/E
27
Q

Genotypes 1 & 4

A

Cured with IFNs about 40-50% time

28
Q

Factors that influence therapy responses to pegylated IFN-a

A
  • viral genotype (2,3 : better clinical outcome)
  • IFNλ3,4 genotypes

*single NT polymorphism located upstream of IFNλ3 gene is predictive of HCV clearance

*individuals woth IFNλ4 are associated with decreased clearance of HCV

  • role of MHC/HLA and HCV AP to T cells

*some people inherit better MHC (more protection)

29
Q

Role of MHC/HLA and HCV AP to T cells in clearance of HCV

A

spontaneous clearance:
HLA-B27, HLA-B57, HLA-A03

30
Q

HLA-B27

A
  • immunodominant HLA-B27-restricted virus specific CD8+ T cell epitopes
  • escape from CD8 T cell response targeting this epitope is difficult
  • binding epitope located in conserved region of RNA dependant RNA polymerase NS5B (puts fitness contraints on HCVs) - high fitness cost; less likely to mutate

*epitope conserved in HCV G1 but not G3 -> not protective in HCV G3 infection

31
Q

What dictates infection outcome

A
  1. Host AP genes
  2. HCV genotype
32
Q

First direct acting antiviral drugs

A

Telaprevir
Boceprevir

*HCV protease inhibitors

33
Q

IFN free Direct acting antiviral treatments

A

HCV NS4A interacts with HCV NS3
- NS3 is a protease and cleaves polyprotein

HCV NS5A
- interacts with multiple host cell and viral proteins

NS5A
- plays multiple roles in mediating viral replication, host cell interactions, viral pathogenesis

NS5B **
- RNA Polymerase**

34
Q

Targets for DAAs

A
  1. NS3/NS4A protease
  2. NS5B Polymerase
  3. NS5A replication complex
35
Q

Simeprevir

A

PI
- once daily dose
- given with PEG-IFN + RBV

36
Q

Sofosbuvir

A

NS5B polymerase inhibitor

*resistance barrier much higher compared to PIs

37
Q

Features of IFN-free DAA regimens

A
  • 8 to 12 wks
  • excellent safetly profile
  • efficacy over 95%
38
Q

Pan-genotypic DAA therapies

A

Sofosbuvir
NS5B
Velpatasvir
NS5A inhbitor

39
Q

What drug types offer exceptional SVR across all genotypes

A

NS5A
NS5B
inhibitors

40
Q

Most difficult genotype to treat with IFNs

A

G1

MB4030 (11 decks)

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