Lecture 14 (8B) - Chronic Viral Hepatitis Flashcards
Hepatitis B
300 million
sex
drug injection
50% of UK drug users
Hepatitis c
220 million
drugs - blood to blood
50% of drug users
40% in cairo from british injecting everyone in attempt to eradicate bilharzia
HBV replication
3 kilobases (when average gene 4-5 kilobases)
• 4 proteins
• DNA virus - can integrate into own chromosomes, use our body enzymes to replicate
• makes pieces of RNA to make DNA again
= REVERSE TRANSCRIPTASE STEP
HepB prevalence
- highest - africa, E and SE asia, N canada and greenlad
- intermediate - russia, india, medierranea, brazil, japan
- low - UK, w Europe, USA, australia, new zealand, scandanavia
HCV
- RNA virus so makes mistakes (1 mutation per 10,000 bases)
- is 10,000 bases long –> 1 mutation every new strand
- so many changes that T and B cells can’t get it because it’s changed by the time they’re made
Symptoms
liver fibrosis –> cirrhosis
ascites - fluid filled abdomen that can burst
multi-focal HCC - liver carcinoma
HBV has 2 forms
- acute - fightable
- chronic - worrying one
HepB makes you live long enough to pass it on (mom to kid)
Individuals most at risk of developing chronic hepatitis B infection
• neonatal vertical transmission • infants less than 3 years old • immunocompromised individuals - receiving chemotherapy - haemodialysis patiens - transplant recipients
Outcome of HBV infection according to age at time of infection
chronic from mom, change during puberty
• HepB smart enough to cause pandemic
• 11 years to form adult response to it
Hepatitis B natural history
- mother tolerizes, so no liver inflammation because no cells against
- teenage = switches on immune, antigens
alanine transaminase - enzyme commonly assocciated with liver - measures liver health
- immunotolerant phase
- HBsAg+
- HBeAg+ - Immunoactive phase
- HBsAg +
- HBeAg+ - Immunosurveillance phase
- HBsAg+
- HBeAg- - Immunoescape phase
- HBsAg+
- HBsAg-
HBV therapy
either:
• lamivudine + tenofovir - indefinite therapy of tablets
• pegasys - pegylate interferon - 48 weeks of injections
constant battle between immunology and hepatitis B
• low liver inflammation = no T cells from hep B
• passed from mother
• first 20 years of life - 100million per ml of blood
- phase 1
• virus changes in teen year - immune system starts trying to kill it - causes body damage
• disease reactivation in 50s
- phases 2 and 4
Hepatitis C
- transmitted by blood-blood contact
- causes slowly progressive liver fibrosis
- cirrhosis and cancer are common
- in the UK drug users are at greatest risk
- junkies virus
- not just a problem in drug users
- common in immigrant communities
- therapy is very effective
- prominent in 3rd world from poor medical practice
- viral disease - transient, self limiting
Chronic viral hepatitis
- HBV infects 400 million people worldwide
* HCV infects 180 million people worldwide
Viral defences
- INNATE IMMUNITY - type 1 interferons
- antibody response (slow)
- cytotoxic T cells (slow)
Interferon and the immune system
IFN-α • very potent virus killer • never found a person lacking it • biggest reason for virus elimination • induced by viral TLRs in infection • activates DC - kickstarting active immune response • good immune booster • successful virus must switch off IFN - Hep B and Hep C very good at this - 1 in 4 Hep B proteins devoted to killing IFN system
The interferons - production
- HBV polymerase inhibits the production of interferon
* HCV protease inhibits the production of IFN - chewed up by rigI
The interferons - effects
• HBV polymerase inhibits the actions of interferon
• HCV NS5a and E1 inhibit the effects of IFN
• both viruses encode proteins that inhibit production and effects of type I IFN
- virus ttries to make protein to kill IFN and cell tries to make IFN - race, block, rate of production
NK cells
not clear how HCV and HBV avoid NK cellls
- host genetic factors?
- right NK –> less likely to get chronic
Once a virus has avoided the innate immune response it needs to avoid the
acquired immune response (T and B cells)
• little is known how it avoids
• variable regions mutate so quickly immune system can’t get it
HBV uses different strategies to avoid the immune response at different stages of its life
• phase 1 immunotolerant
• phase 1 immunotolerant - virus not seen by immune system because it induces tolerance
- the main immune target against HBV is the HBV core protein
- E antigen induces tolerance –> no reaction
1st ATG codes precore/core, into ER –> hijacked, excretory program to excrete E that’s like core but small enough to cross placenta (E antigen)
- induced by HBeAg - crossing placcenta
- ATG starts coding for core
- other ATG begins coding for “pre-core” core
- virus hijacks protein excretory system so produces E antigen by hep
• phase 2 immunoactive
- tries to kill virus - damages liver cells
T cell or antibody kill infected cell and virus
- leads to inflammation
HBeAg
- HBV core protein is the major target for immune attack
- if HBV is acquired perinatally the disease is always chronic
- HBeAg crosses the placenta and induces tolerance
- hepB tolerizes, introduces to hepB then gets chronic infection
HBV uses different strategies to avoid the immune response at different stages of its life
• phase 2 immunoactive
• phase 2 immunoactive
- tries to kill virus - damages liver cells
T cell or antibody kill infected cell and virus
- leads to inflammation
- break tolerance –> get chronic
- the host immune response kills both the virus and the infected cells
- this leads to liver inflammation
Immune attack on HBV
phase 2 immunoactive
• T cells kill the infected cell
• antibodies kill the infected cell
•
How does HBV avoid antibodies
• block production
tolerance
• mutate viral proteins
Forming HBeAg
pre-core/core with a portion before ATG - ATG
E antigen dependent
clip portion of both
enters ER clipped
get HBeAg
• non needed for replication, affects that region
• gene to stop making target for immune system that will stop it
HBeAg
HBV can mutate the
pre-core gene to stop E antigen being made
How does HBV get around the cellular immune system?
- indcue tolerance
- block immune priming - infect dendritic cells
- mutate antiviral epitopes
- block IFN production and thereby stop HLA expression on the surface of the cell
- kills cells against itself, mutates itself
Viral hepatitis and the immune system
- HBV and HCV both cause chronic disease
- to achieve this they overcome the host defense network
- multiple defense mechanisms operate and most are improperly understood
HBV avoids cytotoxic response
- mutate pre-core to stop E antigen being made
- induce tolerance
- block immune priming - infect DC
- mutate anti-viral epitopes
- block INF-production and thereby stop HLA expression on the surface of the cell
