HBV Flashcards
What family of virus is HBV?
Hepadna
How is HBV transmitted and what is the disease pattern and latency period?
Parenteral; sexual, acute and chronic with latency of 3-6 months
What are the three particles related to HepB?
L-HBs, M-HBs, S-HBs
What type of genome does HepB have and what is associated with it/ how does it replicate
A small DNA genome (smallest of any virus) uses a reverse transcriptase to replicate its own genome. It has both positive and negative sense DNA strands with the positive being slightly larger than the negative
Size and enveloping of HBV
42nm and enveloped virus
Describe HBV incomplete double strand
Partial double stranding with a cohesive overlap that spans the 5’ regions of each strand
What is the HBcAg protein in HBV
Secreted and a good marker.
What is the polymerase attached to in HBV and how?
Covalently to the negative strand
What do PreS1 and PreS2 make up in HBV?
Make up the Pres and S polyprotein that contains the virus receptor for the infection of hepatocytes
What type of polymerase is the HBV pol?
A RT DNA dependent DNA polymerase with an RNaseH
HBxAg does what in HBV?
A small regulatory protein that stimulates gene expression and replication and protection of virally infected cells from immune cells
What cells does HBV replicate in?
Hepatocytes
Describe HBV replication
Virus fuses with cell membrane and Uncoated the DNA is removed and cccDNA (Covalently closed circular DNA - a mini chromosome indistinguishable from the host chromosome) enters the nucleus the positive sense pregenome is produced with shorted transcripts that are then translated by host ribosomes. PreS and S ℅ translationally fed into the ER whilst other proteins (P protein and capsid are translated in the nucleus for form virus particles which then combine with the components in the ER and are released
What is secreted into the blood in HBV infection?
Non infectious surface antigen particles and filaments
What is he most common route of HBV transmission and it’s incidence?
Perinatal 10% in Caucasian mothers and 50% in Asian mothers
Perinatal transmission of HBV does not occur in the placenta it occurs in the…
Labour and delivery
Percutaneous
Infection through the skin (needle stick or blood transfusion
Parenteral
Introduction into the body other than by the mouth or gut eg during sex
Perinatal
Infection during birth
Concentration of HBV in bodily fluids
High- blood, serum, wound exudates
Moderate - semen, vaginal fluid, saliva
Low/not detectable - urine, faeces, sweat, tears, breastmilk
What are the main differences in transmission between HBV and HCV?
HCV is not sexual or perinatal so often
How many of the worlds population has been infected with HBV in their lifetime?
1/3
How many people chronically infected worldwide and how many is that compared to HCV?
350 million twice as many than HCV
What do 25% of carriers of HBV develop?
Liver disease, chronic hep, cirrhosis and primary HCC?
What is the antigen for chronic HBV infection and how does carrier rates vary?
HBsAg, carrier rates vary from 0.1 to 20% depending on where in the world you are
What is the incidence of HBsAg related to?
Incidence of HBV and age of primary infection
When do most people get HBV?
When adult and they clear the infection
Global patterns of chronic HBV
High - 45% of population have lifetime risk of infection >60%, early childhood infections are common
Intermediate - 43% of global population, lifetime risk of infection 20-60%, infections in all age groups
Low -12% of global population, lifetime risk of infection
Clinical HBV features in adults
Aniceteric (not assoc with jaundice) or no disease = 60-70% Icteric disease (liver complications jaundice etc)= 20-35% Complete recovery =90% Persistent chronic disease = 2-10% Mortality rate = 0.2-0.5%
Think about and describe the acute HBV and chronic HBV infection graphs
Look and check
How many liver cancers are HBV positive and how many cases of liver cancers are caused by HBV per year?
50% and 340,000 cases
Cases of liver cancer due to HCV for year and percentage of HCV positive cancers
195,000 cases and 25%
Where are HBV specific lymphocytes detected in chronic disease?
In liver lesions and they are not enough to clear the virus, similarly with NK and NKT cells and macrophagesx
What happens to IFN in HBV?
It is deficiently produced, IFN replacement in humans only reduces viral titres and disease progression in a small number of number of HBV patients
Viral factors associated with risk of HCC in HBV carriers
Viral factors - persistently high viremia, HBeAg positivity, HBV genotype, HBV variants: mutations in the basal core promoter and in the preS region causing truncation a of the protein at the c- terminus. During regeneration after hepatic damage, HBx and preS/S genes increasingly integrate into host DNA = increased ic levels of HBx. this affects pathways such as rad and PI3K and IGFR1 and VEGF etc. (HCV persistence does not include integration and maintains itself in the er associated episode)
Host factors assoc with increased risk of HCC in HBV
Male gender (1.5-2 fold more), age, liver cirrhosis, age at primary infection, polymorphism a in genes encoding cytokines and detoxification enzymes, diabetes and obesity
Environmental factors assoc with increased of HCC in HBV carriers
Dietary exposure to aflatoxin B1 (in grains), alcohol consumption, nutritional factors (dietary iron overload, starvation)
Breakdown of HCC development in humans
Long process Chronic hepatitis (HBsAg) - liver damage - transformed liver cells - selection acting on transformed cells - outgrowth of clinal focus - malignant conversion - HCC
What miRNA is affected by HBx?
MiR181 and miR 148a
Where does HBV DNA exist?
As an episode in the form of a mini chromosome in cell nuclei
What do HBV and HCV show in terms of co infection?
Reciprocal interference is one has markers in blood and other doesn’t and vice versa
What does expression of HBV proteins stimulate in the host?
The immune response and triggers liver inflammation, some viral proteins as well as insertion of the viral DNA into liver cell genome (inducing genetic alterations) and directly interferes with cell proliferation and viability.
What are the mechanisms of HBV induced liver damage?
HBV is not cytopathic.
Hypothesis: intrahepatic antigen specific cellular immune responses initiate the process, damage is largely due to cellular and molecular effector systems - lacking deets
Non HBV HCC is associated with liver damage, describe
Cirrhosis not associated with persistent HBV infection is the major risk factor for HBV in the west. Cirrhosis can be associated with alcohol abuse and or persistent infection with other viruses particularly hepC
What are the four potential virus-specific mechanism of virus action in addition to immune/chronic inflammatory damage
1 virus integration resulting in insertional mutagenesis (IM doesn’t happen by chance/randomly)
2 effects of x gene produce (whether integrated or expressed
3 effects of genotype (not yet defined)
4 emergence of variants (mutant or otherwise) of the core promoter and pre-s region
Role of HBV X protein in the development of HCC (9)
1 viral replication
2 interference with transcription machinery
3 pro/anti apoptosis
4 genetic stability interference
5 activation/inhibition signal transduction cascades
6 transformation/ tumour promoter
7 modulation of gene expression
8 modulation of proteolytic activity
9 HBx is involved in many IC signalling pathways that are closely correlated to cell prolif and cell apoptosis
How many HBV genotype are there, what are they based on and how are they distributed?
8 based on the S protein gene
(A-H) and are geographically distributed C>B<a>E </a>
What are the possible explanations for the relationship between different genotypes and disease Phenotypes
Differences in host immune response - especially B and T cell response to HBsAg, HBcAg and HBcpreAg
Differences in the levels of viral replication
Inactivation of pro-oncogenic viral protein function
Activation of regulatory pathways, especially HBsAg and HBcAg
Modified antigenic characteristics and evasion if immune surveillance
Lack of HBeAg production, down regulation of cell cycle inhibitors, increased persistence
Antiviral resistant variants
Mutations in what genes lead to predisposition for HCC?
PreS1 and PreS2 both deletion mutants
What are the treatments of HBV
Antiviral treatments
Vaccination
Behavioural measures
So far no drugs are able to remove the cccDNA which is capable of initiation of infection so once infected always infected (if not cleared)
What is lamivudine and adefovir dipivoxil
Lamivudine is the L-enantiomer of the deoxycytidine anologur 2’3’ - deoxy-3’ thiacytidine.
Adefovir dipivoxil (hepsera) is a prodrug of adefovir which is also a nucleotide analogue.
They both target the HBV polymerase complex and causes chain termination
What HBV vaccines exist?
Plasma derived HBV vaccine consists of biochemically and bio physically inactivated HBV surface antigen (HBsAg) particles obtained from healthy chronic HBsAg carriers
Recombinant HBV is derived from HBsAg in yeast cells these vaccines have the advantage of reduction of plasma transferred virus (AIDS) complications
HBV vaccine induces protective anti-HBsAg in most individuals receiving the recommended three dose regimen
Antibody titre of >10mU/mL against HBsAg are recognised conferring protection against HBV
Why might a cure be possible for HCV but not HBV?
Because HCV exists in the episode but in HBV, proteins made from integrated virus templates may still trigger and promote CLD even if episomal DNA (incl cccDNA) is cleared
Early vaccines are:
Subvirion vaccines obtained from asymptomatic healthy carriers of HBV. HBsAg (22nm particle s ag) was harvester from the plasma of HBV carriers
1 formulin treated 2 heat inactivated 3 alum absorbed
Purification and inactivation steps removed from HBV and other infectious agents (I know agents that may not be inactivated)
Excellent safety record, no HIV seroconversion has ever been observed, no apparent side effects and no deaths. 30 million doses so far
Recombinant yeast vaccines:
Expansion of S gene in yeast leads to self-assembling 22nm particles purified from large batches of yeast cells
1 formulin treated and mixed with alum and thimerosal
Product is identical to HBV product but not properly glycosylated
Yeast product carries epitope a which induce virus neutralising antibodies. Long term efficacy yet to be firmly established but is likely to be identical to the early subunit vaccine
What has the vaccine done?
Decrease infection rates and cancer rates
In HIV positive men sex men, how effective is the vaccine?
Only 33.3-56.3% response rate in HIV + men where’s 86.5-84.4% response in HIV - men
