Hepatits C virus Flashcards
(42 cards)
1
Q
What is hepatitis?
A
- inflammation of the liver
- at least 6 viruses that specifically infect and damage hepatocytes
2
Q
What are the 5 hepatitis viruses?
A
- Hepatitis A, B, C, D + E
- A, B and C are the biggest concerns for human health
- B + C can be bloodbourne
3
Q
What is the prevalence of hepatitis C virus?
A
- varies but around 1% of people are infected worldwide
- 0.3% in the UK
- 11% in Egypt - shared needles in an unrelated vaccination programme
4
Q
What are the symptoms of hepatitis C virus?
A
- 20% acute, 70% chronic
- leading cause of chronic liver diseases, cirrhosis, hepatocellular carcinoma
- can cause mild infection before liver issues - easy to transmit without knowing you have it
5
Q
What is the main risk factor for hepatitis C?
A
- frequent exposure to blood
6
Q
What is the major contributor to the health burden of HCV?
A
- only 21% of people are aware they are infected
of these onlt 62% are getting treatment
7
Q
What are the main causes of hepatitis C infection?
A
- major cause is injecting drug use
- sexual contact
- blood transfusions especially in places where screening is poorer
- occupational risk
- 10% of transmissions are of unknown origin
8
Q
How many hepatitis C genotypes are there?
A
- 8
- 30% differences between genotypes
- not full cross-reactivity means its harder to make a drug or vaccine
- genotype 1 is the most prevalent in the US and europe
9
Q
Describe the epidemiology of HCV
A
- genotype 1 in the US and europe - most research efforts have gone here due to that
- genotypw 4 is the most common in Africa
- genotypw 6 is also seen in asia
10
Q
What family of viruses does hepatitive C virus come from?
A
- flaviridae
- most in this group are spread through arthropods and or blood
- may have originally been spread my insects and then moved to humans
11
Q
Where does hepatitis C virus infect?
A
- infects the blood
- spreads through the bloodstream to the liver within 2 days in chimps
- only 5-20% of hepatocytes become positive for HCV RNA - don’t know why
12
Q
How is hepatitis C virus studied?
A
- no effective routine cell culture model
- use in vitro mammalian cell expression systems, replicons and modified cell lines
13
Q
What is the morphology of a hepatitis C virion?
A
- non enveloped
- virus has a close relationship with lipid droplets in the liver that isnt fully understood
- also associates with low density lipoproteins in the serum
- may help the virus acoid hose recognitoin by cloaking or may attach itself to LDL + HDL to hide from the immune system
14
Q
What is the organisation of the hepatitis C genome?
A
- no poly A tail but a structures 5- UTR
- one long open reading frame cleaved into mature products
- 5’ structural , 3’ host immune and replication
- glycoproteins E1 and E2 are embedded in virus surface
- NS2 cleaves the NS3 protease which cleaves the rest
15
Q
What are the 3 main drug targets for hepatitis C virus?
A
- protease
- polymerase
- NS5A - unknown function
16
Q
Why does hepatitis c virus only replicate in the liver?
A
- binds to miRNA at the 5’ end of host DNA that is essential for replication
- only liver cells have these miRNAs
17
Q
Describe the hepatitis C virus life cycle within hepatocytes
A
- virus enters via clathrin-mediated endocytosis
- RNA is translated at the ER and the polyprotein is threaded through it
- negative strand is made and is used to make more genomes
- packaged and leaves the cell
- does not destroy the cell - the cell is damaged by immune system response
18
Q
How does hepatitis C virus enter host cells?
A
- attachment factors bind to the cell surface
- may bind to lipid droplet that bind LDL receptors-
- enters the cell at tight junctions (clatherin mediated)
- difficult to study due to a large range of receptors and attachment factors being involved
19
Q
In what organisation is the hepatitis C virus polyprotein threaded into the host cell ER
A
- replication proteins on the cytoplasmic side
- E1 and E2 on the lumen side
- modification of host lipid membranes forms a membraneous web that forms an active site for virus replication
20
Q
How is HCV assembled and secreted?
A
replication complexes perturb the ER membrane and enclose the cytoplasmic side proteins. the genome assembles with the core protein and lipid droplets which allow the association of E1 and E2. the virus then buds from the ER and exits the cell likely along along with lipids
21
Q
HCV can’t just be studied by transcribing viral RNA and transferring it into cells. How must it be done?
A
- using replicons
- remove unneeded structural genes and replace with markers
- clone the viral RNA as cDNA and put in a plasmid
- introduce the plasmid into cells to replicate and then select for cells with the markers to see infection
22
Q
What are the clinical features of HCV?
A
- acute mild in 20%
- chronic hepatitis in 70%
- cirrhosis in 10-20%
- death from liver disease 1-5%
23
Q
What is the clinical response to a cute hepatitis C virus?
A
- ALT (common maker for liver damage) goes up and then back down
- T cell response initiated and then subsides
- antibodies produced after time
24
Q
What is the clinical response to chronic HCV infection?
A
- similar to acute initially but with a lower T cell response that can be undetectable
- bouts of ALT and liver damage
- the viral RNA isn’t fully cleared but the vigor of the response decreases over time
- escape mutations can occur
due to repeated exposure to host responses
25
What 5 factors can promote progression and severity of chronic HCV?
- infection being from blood transfusion
- increased alcohol intake
- age over 40 at initial infection
- HIV co infection
26
What is the link between HCV infection and hepatocellular carcinoma?
- the mechanism of oncogenesis in vivo is poorly studied but data in vitro exists
- 30% of HCCs thought to be associated with HCV infection
- chronic inflammation, necrosis, regeneration and cirrhosis -> cancer formation
- core protein found to protect cells against apoptosis in mice
- addition of viral protein NS3 can cause transformation of cells
27
How does HCV suppress the humoral immune response?
- directly inhibits NK and DCs involved in the adaptive response
- blocks the release of interferon-a in the innate response
- strains undergoing mutational escape may evade antibody detection
- virus can go directly from cell to cell to reduce detection
- can also express the activation of CD8+ T cells
- prevents binding of neutralising antibodies by producing interfering antibodies
28
How does HCV peturb the inferferon response?
- NS3 protease can cleave proteins involved in DC INF signalling and release
- core protein can inhibit STAT1 and ISG production and increase SOCS proteins
- NS5A can attenuate ISG expression and inhibit the INF response
29
How does the cellular immune response differ in acute and chornic HCV infection?
- virgerous Th1 response in acute that persists after infection
- Th2 response in chronic that doesnt produce sufficient CD8+ t cells
30
How do hepatocytes get damaged in HCV?
- immune recognition and destruction of infected cells
- persistent infection triggers T cell responses and fas ligand induced apoptosis
- leads to liver lesions
31
How is the interferon response mounted in reponse to HCV?
- virus is sensed by receptors such as TLR3 that triggers the production of IFNs and proinflammatory cytokines
- when type I and II IFNs bind their receptors they activate the IFN-simulated gene factor 3 complex that induces the expression of ISGs
32
What happens to ISGs in chronic infection?
- genes stay active when when the IFN-stimulated gene factor 3 complex isn't
- ISG15 is produced abundantly in HCV infected cells and stabilises USP18 which blocks interferon receptors and makes HCV less responsive to pegylated interferon treatment
33
The humoral response to HCV is not fully undertood. What do we know?
- antibodies are detectable for several weeks post infection but diminish over time with poor memory
- E2 protein is a major target for neutralising antibodies
- an early response to E2 may be associated with HCV clearance but resolution can occur without Ab response
34
What is pegylated INF-a treatment?
- used to be used for those at risk of progression to cirrhosis
- activates the endogenous innate immune response
- success depends on HCV genotype, prior liver damage, age, genotype and more
35
What is mutational escape?
when a pathogen such as a virus acquires genetic mutations that allow it to evade the host immune response
36
Why is hepatitis C virus prone to mutational escape?
- RNA pol has a high error rate
- may be worsened by a delaed immune ersponse
- mutations can abolish antigen recognition r
37
What are the 3 hypothesese on why HCV persists?
- insufficient primary immune response and inability to maintain a sufficient T cell response in chronic
- HCV proteins actively suppressthe immune response
- viral genetic variatoin
38
How does genetic variation affect HCV clearance?
- SNPs in genes such as IL28B increase response to treatment and speed up spontaneous and treatmend-induced clearance
- IL28B is involved in the interferon response
- CC shows a better response than TT
39
What do HCV protease inhibitors do? What are their symptoms?
- mimic NS3 cleavage sites and form a tigh, long-lived complex with the NS3 protease
- given with PEG-IFN to reduce drug resistance
- only works against genotype 1
- causes rash and anaemia
40
Why are vaccines against HCV problematic to develop? (3)
- no culture system for whole virus vaccines
- virus mutates easily
- Ab response is short lived
41
What might be a good target for HCV vaccines?
genetic vaccines that promote cellular immune response (T-cell vaccine)
42
