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Medical Virology L1-10 > HCV > Flashcards

HCV Flashcards

1
Q

Worldwide distribution of HCV

A

185 million chronic carriers 75% of cases become chronic
HCV is the leading chronic liver disease cirrhosis and HCC and the leading indication for liver transplantation in many countries

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2
Q

Risk factors of HCV

A

Frequent exposure to blood is the most important

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3
Q

HCV to acute/chronic hep

A 
Acute hepatitis (10-30%) to recovery 
Chronic hepatitis (70-90% dependent on county) --> HCC (2.5% of chronic patients) 
100 people infected 
75-85 = chronic
60-70 = CLD 
5 - 29 = cirrhosis
1 - 5 = liver cancer
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4
Q

Time frame of HCV

A

Acute hepatitis 0-24 weeks
Chronic hepatitis 24-50 years
Liver cirrhosis and HCC 10-40 years

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5
Q

When was HCV first identified?

A

1989

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6
Q

Where did the NANB hepatitis infectious agent

A

Could infect chimps and cause chronic liver disease and cirrhosis
Only 5% of people realise they have it and can go 20 years undiagnosed
Acute disease, mild compared to HBV

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7
Q

When was the HCV genome sequenced?

A

1991

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8
Q

Sources of HCV infection

A 
Sources of infections:
Injecting drug use 60% 
Sexual 15% 
Transfusion (before screening) 10% 
Occupational 4% 
T
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9
Q

How many HCV genotypes are there

A

6

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10
Q

What type of virus is HCV?

A

An RNA virus with a very plastic genome and is prone to change
Lots of research done genotype 1 (drugs etc specific to genotype) however more recent drugs against the majority of the genotypes

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11
Q

Replication of HCV

A

HCV infections are generally Parenteral
HCV spreads through the bloodstream to the liver - the primary target for replication
Viral half life is around 2-3 hours/1012 visions/ day if chronic
Liver contains the highest levels of HCV RNA
But only 5-19% of hepatocytes HCV RNA positive
1-5% of liver mononuclear cells express HCV antigens

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12
Q

The hepatic HCV innate immune response fails to mount

A

A productive immune rapidness that clears the infection. HCV has several mechanisms to evade the immune response - chronic infection

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13
Q

Therapy for HCV

A

Pegylated IFN α + ribavirun 40-50% curative

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14
Q

The HCV virion morphology

A

Associations with LDL

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15
Q

HCV infections does what to IFNL3 (IL28β)

A

Leads to polymorphisms which can influence the outcome of infection and therapy response

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16
Q

HCV genome has what elements?

A

IRES

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17
Q

Component of HCV genome and how is it transcribed?

A

As a polyprotein
C - core immediately wraps around genome, E1 & E2 - envelope protein (heavily glycosylated), p7 associates with NS2 in the membrane, NS2 - protease, NS3(A serine protease cofactor) - serine protease and a helicase, NS4B - membranous web, NS5A - ?, NS5B - RdepRpol

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18
Q

How is the HCV viral positive sense RNA genomes translated?

A

As a single polyprotein that is co and post translationly modified by host peptidases and 2 virally encoded proteases

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19
Q

What do HCV no structural proteins do?

A

They assemble as a peplication complex onto modified intracellular membranes

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20
Q

What intermediates are made in HCV

A

Anti genomic replication intermediate RNA and likely accumulation of dsRNA intermediates

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21
Q

How is HCV recognised by the immune system

A

HCV is recognised as non-self by PRRs that bind to PAMPs of the viral products - adaptive and innate immune activation (although this does not self like self)

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22
Q

What is HCV virus associated with when it leaves the cell?

A

In association with host lipoproteins so HCV is present as a lipoprotein coated virus

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23
Q

How does HCV enter into the cell

A 
Via heparin sulphate proteoglycans 
Low density lipoprotein receptor
SRBP1 - scavenger receptor class B member 1 
Claudin 1 
Occludins

Lots of receptors to help the entry of the virus into the cell. Initially receptors are not specific to the virus, no single one lets the virus into the cell but a whole group of them together.
Enters via clatherin mediated endocytosis

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24
Q

Look at the early and late events in the virus lifecycle and learn the images

A

Page 22/23 HCV

25
Q

What can be used as a selectable market in an engineered viral cDNA plasmid and what is removed?

A

Neomycin resistance

Removal of structural genes

26
Q

What’s a very virulent strain of HCV?

A

SGR-JFH1

27
Q

HCV clinical features

A 
Incubation period - 6-7 weeks 
Acute illness - mild 
Case fatality rate - low 
Chronic infection - 75-85%
Chronic hepatitis - 70% 
Cirrhosis - 10-20% 
Mortality from chronic liver disease 1-5% (occasional very aggressive strain)
28
Q

What marker can be used to view clinical response and liver damage to HCV?

A

ALT
alanine amino- transferase
Market of liver damage

29
Q

What factors promote progression or severity of chronic HCV

A 
Infection from blood transfusion 
Increase alcohol intake
Age >40 at time of infection
HIV co-infection 
Genetic background
Others? Male gender or other co-infection HBV
30
Q

In the UK HOW MANY HCC cases are caused by HCV?

A

30%

31
Q

In HCV what does HCC follow?

A

Chronic inflammation, necrosis, regeneration and cirrhosis

32
Q

In vivo the mechanisms of oncogenesis in HCV has not been discovered. How is it described in vitro

A

Core: can protect cells against apoptosis (transgenic mice expressing core developed primary liver cancer)
NS3: expression can lead to cellular transformation
NS5A: contains a transcription transactivation domain

33
Q

HCV suppresses and evades the immune system: innate:

A

In the cell Infection blocks IFNα release which normally activates the innate immune response. (No NKT cell act)
Extra cellular: HCV directly inhibits NK cells as well as DCs that promote adaptive immunity

34
Q

HCV suppresses and evades the immune system: adaptive

A

DCs are inhibited and the overall B and T cell response is weakened.
B cells: Mutant HCV strains elude antibody recognition
HCV elicits interfering antibodies that prevent binding of neutralising antibodies
T cells:
HCV directly and indirectly suppresses activation of killer T cells
HCV mutation yields epitopes that escape recognition
HCV transmission from liver cell to liver cell evades antibodies

35
Q

HCV induces what what in the innate response?

A

Interferon response and also attenuate the IFN response

36
Q

How does HCV affect the IFN response?

A

Core: inhibition of stat1 and increased expression of SOCa proteins
NS5A: General attenuation of IFN expression
inhibitors of PKR
NS3/4A cleaves the polyprotein and also cleaves MAVs and TRIF preventing IRF3 pathway activation and as a result no IFNα/β production

37
Q

What TLR does HCV bind to and what other mechanism is it recognised by?

A

TLR3 binding

And dsRNA

38
Q

Acutely infected HCV patients produces antibodies against?

A

Epitopes that are structural and non structural but most have no relevant antiviral activity and only a small number inhibit binding, entry of uncoating

39
Q

What is associated with spontaneous resolution of acute hcv?

A

Certain defined HLA I alleles
HLA -A3, -B27 and -Cw*01 - clear
HLA-B8 - persistence

40
Q

What does the protective effect of HLA-b27 require?

A

Presence of genotype specific immuno dominant CD8 T cell epitope. Thus preventing the viruses dominant role of a specific CD8 T cell response (elicited through IFNγ non cytopathic effector function)

41
Q

What may lead to HCV escape from antibody?

A

Quasispecies development

Interaction with HDL and SCARB1

42
Q

What is the role of CD4 cells in HCV infection?

A

They are central regulators
Acute infections associated with a vigorous multi-specific helper T cell response intensity, epitope specifics and cytokine profile of the T cell response during early infection appear to be predictive of viral clearance and recovery

43
Q

In acute HCV infection what type of cd4 response is there?

A

Strong multi specific and sustained associated with limited course of infection

44
Q

What HLA II are assoc with positive outcome of acute HCV?

A

DRB11101 and DRB10301

45
Q

If cd8s are depleted by antibodies in chinos what happens in HCV?

A

Persistence until HCV response is recovered and an HCV specific cd8 T cell response emerges showing cd8 cells are most like the key effectors in HCV control

46
Q

Th2 response is predominant in what type of HCV infection?

A

Chronic

47
Q

What th1 cytokines are required for HCV clearance?

A

Il2 and IFNγ

48
Q

CD8 in HCV pathogenisis (4)

A

Vigorous multi specific CTL response in acute infection
CTL epitopes identified of all viral proteins
Frequent of CTL epitopes much higher in the liver than the peripheral blood but still not enough to clear the virus in chronic infections
Balance between stronger CTL response and liver damage

49
Q

When do HCV antibodies appear?

A

7-31 weeks after infection

50
Q

What viral protein is the major target for neutralising antibodies and for vaccine?

A

HVR of E2 which has high sequence variability influenced by host immune pressure

51
Q

Are antibodies protective against HCV?

A

Difficult to tell without routine cell culture
Early response to E2 HRV may be assoc with clearance of HCV
Resolution on HCV can occur without antibody production (chimps) and seroconversion (humans)
Patients who recover do not seem to be immune from reinfection

52
Q

How does the immune response to HCV cause liver damage?

A

By immune recognition and destruction of infected hepatocytes
Persistent HCV infection triggers an active T cell response & liver lesions over time. (FasL induced apop of hepatocytes, TNFα and perforin based mechanisms of cells destruction)

53
Q

What are preferentially attracted to HCV infected livers?

A

Th1 cells - cytokines may enhance necro-inflammatory lesions

54
Q

What is the mutation rate of HCV?

A

1 in 10 euros every time it replicates

Which results in the rapid evolution of viral quasispecies

55
Q

Consensus sequence is?

A

The average sequence of all the viral quasispecies with all the varying mutations in the genome.

56
Q

If you develop a drug against a specific consensus sequence what happens?

A

There will be a shift in the viral quasispecies that exist.

57
Q

Three hypotheses as to why HCV persists

A
  1. Once a persistent infection is established, the immune response is too weak to clear the infection
  2. HCV proteins may actively suppress the immune response
  3. Viral genetic variation
58
Q

Treatment of HCV involves

A

Pegylates IFNα and ribavrin for those at risk of progression to cirrhosis

59
Q

What does the success of the anti-HCV therapeutics rely on?

A

HCV genotype, initial viral load, prior liver damage, age, gender. Patients may feel fine and then get very ill

Medical Virology L1-10 (2 decks)

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