MM

 mm
• Pump the surface antigens
• First stepp top produce both HBeAg and HBsAg mm that doesn’t contain any
• Acute – eventually produce antibodies so acute DNA = exhaust immune
• Chronic: 1. no immune damage and lack of HBC-specific T cells 2. virus level comptrolled with 3. zero response to chronic
conversion of S so virus continuously produce S so no antibody production control infection
• HBV has ways to trigger innate immune response to trigger adaptive immunity • Receptor-mediated
endocytosis = clathrin-
• Liver sometimes ignore some pathogens from gut where from hepatic portal vein where tolerised so mediated endocytosis
HBV also hijak via this method (prevent over immunisation) • Partially positive strand
• Antigen-presentation is damped in liver – tolerising liver environment – not much immune response need to be repaired and
• Form perforin enzyme to kill pathogen-onfected cell completed in step 3-4 
this makes cccDNA (mini
• If know where or how T cell got dysregulated or upset, can revert it
chromosome for HBV
• PD1 is the pathway for virus – can be based around for treatment DNA)
• Virus can block PD1 pathway so no interaction with T cell so can prevent inhibitory signal by the co- • Trapped within nucleus so
factors?? can’t be seen for cccDNA
• Amplification loop for 7b
• Treatment needs to be continuous – as or not cccDNA will start being made again step
• E antigen & surface
• Unless touching cccDNA – no cure just suppress replication
antigen produced and
MM secreted a lot in the serum
• Reduce viral infection then kick the immune response start at the end of cycle

• Mild chronic – live

without knowing
• If don’t convert e+ into e-
then will have the severe
cirrhosis
HEPATITIS VIRUS STUDY
Clinical Scenario Of Infection Prevention
• Viral infection that targets the liver • Prophylactic HBV vaccine (1982)
• Approximately 296 million people living with chronic • Requires at least 3 doses for approximately 95% efficacy = Compliance is poor
HBV • WHO recommends ALL infants to receive a dose at birth, preferably within 24 hours
• Young infants get infected & born by infected mothers in • Given to at-risk groups in UK & universal infant vaccination programme for HBV in
Asia side (Thailand, China) most countries
• 1.5 million new infections yearly • ONLY 36% coverage in countries with prevalence >8% (2006) & ineffective in
• 820,000 deaths in 2019 – cirrhosis / hepatocellular 5~15% of vaccinated children born to a HBV+ mother
carcinoma (primary liver cancer, HCC) • Worldwide < 5 years of age prevalence
• Approximately 1% of HBV+ individuals (2.7 million • 1.3% down from 4.7% in the pre-vaccination era
worldwide) infected with HIV • Can use drug, used to treat HBV, for HIV when co-infected
• Approximately 10.5% of people living with HBV aware
of their infection BUT ONLY 22% are on treatment
Global
History Of HBV Distribution Of
• 1965 – HBV discovered by Dr.Baruch Blumberg NIH (Nobel Prize in
Physiology and Medicine 1976) Chronic HBV
• 1967 – Australia antigen associated with hepatitis B
• 1969~1972 – chronic HBV infection linked to development of liver
cancer
• 1972~1982 – first vaccine developed to protect against HBV
• 1977 – discovery of delta antigen, discovery of HDV Global
• 1989 – HCV cloned from human serum
• 1998 – first direct-acting antiviral (lamivudine) for chronic HBV
Distribution Of
infection HBV Genotypes
• Blumberg & colleagues discovered HBV as abundant protein in the • Genotype varies depending
serum of an Australian aboriginal – ‘Australia antigen’ on region of infection
• HBV DNA found in ancient human remains • Satellite virus, HDV, can
• *hard to propagate in vitro = hard to study only exist with the
background of HBV
HEPATITIS VIRUS
Overview
• Hepadnaviridae family
1. Hepatotropism – should only be classified if infecting hepatocytes
2. Relatively strict species specificity (narrow host range)
3. Capacity to cause acute/chronic infection with viremia and antigenemia
• 10 genotypes (A-J) – differences in genome sequence; 4 major subtypes – adw, ayw, adr, ayr
• Non-cytopathic = Cause little or no direct damage to the hepatocyte [immune response to virus causes the issue]
• 42nm: outer envelope made of HBsAg (lipid layer) surrounding a nucleocapsid core of virus
• Small: partially double stranded DNA (approximately 3.2 kb in length – rcDNA)
• Compact: 4 overlapping frame-shifted open reading frames (ORF) – encoding 7 proteins
• Pregenomic RNA (= template for reverse transcription into relax circular DNA (rcDNA) within the nucleocapsid) – complete circular
negative strand & partial positive strand
• Synthesis of the core protein (C) and HBV polymerase (P)
• mRNA’s producing large, middle, small HBeAg surface antigen on lipid layer (preS – presurface domain /S – S most dominantly
expressed)
• X protein (X gene)
• Antigenicity
• All 3 envelope proteins are highly immunogenic & induce anti-HBs immunity (B cell humoral immunity)
• Structural viral proteins = Induce T cell responses (CD8 T cells & CTL cellular immunity)
STRUCTURE
• Core antigen is nuclear
capsid
• Different start codons =
Different polymerase for
transcription (4 types)
• E antigen = Give rise to
viral persistence
NOMENCLATURE OF HEPATITIS VIRUS
 1.
LIFE CYCLE 1 2.
3.
 Viruses have 1 goal – copying themselves giving rise to IDENTICAL
4.
progeny
Simplified Life Cycle 1 5.
1. Viral entry 6. Encapsidation
• HBV bind L-HBsAg to NTCP receptor (bile acid transporter) = HBV enters • pgRNA & template for core/pol = Template for DNA
hepatocytes synthesis by reverse transcriptase
• Requires low affinity interaction with heparin sulphate proteoglycans to • pgRNA encapsidation into nucleocapsid containing
initiate initial binding and transferrin receptors partially standard rcDNA with polymerase attached
2. Uncoating & rcDNA nuclear import • RNA to DNA conversion
• Internalisation – clathrin-mediated endocytosis 7. Maturation
• Removal of viral envelope and nucleocapsid • VIRION ASSEMBLY:
• Viral rcDNA transported into the nucleus via nuclear pores Maturing nucleocapsid traffic to the ER;
3. Conversion of rcDNA into cccDNA Enveloped by budding through the ER membrane
• Completion/Repair of partially stranded plus strand (not fully understood) where HBsAg are localised before budding from
• Nuclear rcDNA conversion by viral polymerase into covalently closed hepatocyte membrane;
circular (ccc) DNA Via Golgi
• cccDNA = Transcription template for all viral mRNAs by host RNA • GENOME AMPLIFICATION
polymerase II Early in infection, maturing capsids can be shuttled
4. INCLUDED WITHIN STEP 3 back to nucleus to replenish pool of cccDNA
5. Translation of viral mRNAs 8. Release of viral antigens
• Viral mRNAs exported to cytoplasm  Viral mRNAs translated into various • Pre-C peptide transported to ER, trimmed, secreted as
HBV viral proteins pre-core antigen (HBsAg)
• Transcripts are polyadenylated for transport out of nucleus • Infected cell secretes non-infectious particles devoid of
• TRANSLATED PROTEINS: capsid and nucleic acids – empty HBsAg particles
1. Viral nucleocapsid and pre-core antigen (C, pre-C) detectable in serum (<104 ~ >109 / mL)
2. Polymerase (P) • Function of HBeAg is unknown
3. Envelope (L, M, S) • BUT Seroconversion from HBeAg+ to HBeAg- is a
4. X protein marker of reduced viral replication
5. pgRNA (3.5 kb species) spanning entire genome
LIFE CYCLE 2
Simplified Life Cycle 2
LIVER DISEASE
Spectrum Of Liver Disease Chronic HBV Infection
After HBV Infection CLINICAL PHASE DEVELOPMENT
• HBeAg & HBsAg production
Excess production of soluble and secreted proteins;
Diverts anti-Hs neutralisation of virions
• Lack of induction of an innate immune response
• Hepatotropic
• Dyregulates / Dysfunctional adaptive immune
response
• Persistence / Stability of cccDNA
Acute HBV Infection
CLINICAL PHASE
CHRONIC LIVER DISEASE DEVELOPMENT 1
Evasion Of Innate Immunity – as stealth virus Dysregulated / Dysfunctional Adaptive Immune Response
• Pattern recognition receptors (PPRs) culminating in • T cells are critical for control of HBV
induction of an antiviral IFN response • Recognise infected hepatocytes/cancerous cells 
(upregulation of 100’s ISGs)  HBV is invisible to Production of soluble mediators (cytokines, IFNg/TNFa)
PPRs of innate system  Lack of hepatic  Non-cytolytically kill them
expression of IFN and IFN-stimulated genes • Can kill cell / mediate clearance of virus by non-cytolytic
(ISGs) compared to HCV, associated with a strong methods (granzyme B elimination)
IFN response • Mechanism of immune failure
• Remains poorly understood why host innate • Pro-apoptotic Bim expression
immune responses Organ
fail to recognise • Lack CD3z expression
Immunological – liverHBV infection • TRAILR death R expression
• Processes over 30% of the total blood supply in 1 minute
• Receives antigen-rick blood from the portal vein • IL12 rescue of Tex
• Exposed to wide range of dietary and commensal products • MDSCs, low arginine
• First line of defence against blood borne pathogens • Metabolic dysfunction
• Exploited by viruses/tumours • PDL1-PD-1 signalling
• PD-1-PDL1 NK-mediated T cell inhibition
CHRONIC LIVER DISEASE DEVELOPMENT 2
Role of cccDNA / Removal & Dilution Of cccDNA
• cccDNA (viral minichromosome) is vital to HBV
persistence (molecular reservoir)
• cccDNA as the only transcriptional template for all
viral RNAs
• Nuclear location: hides replication intermediates
from the cellular machinery
• Unaffected by current therapies
• Direct targeting of cccDNA for
silencing/degradation/lethal mutation for HBV cure
TREATMENT
 RARELY ACHIEVE CURE as they only suppress/stop replication
 LIFELONG: cost, compliance, resistance, toxicity
Chronic HBV Infection
• Can treat with nucleos(t)ide analogues (NUCs)
(tenofovoir, entecavir)
• Pegylated IFNα – direct acting antiviral BUT
augments cell mediated immunity = various targets
Antivirals In Development
• ENTRY INHIBITORS
Myrcludex B – preS1 domain prevents HBV
entry;
Cyclosporin – inhibits function of NTCP
• ELIMINATION OF CCCDNA
IFNα and LTbR agonist – upregulates
APOBEC3A/3B which induce non-hepatotic
degradation of cccDNA;
CRISPR/Cas9 – targets mutations in cccDNA
• DAA (DIRECT ACTING ANTIVIRALS)
Inhibits viral enzymatic activity OR viral protein
function;
Prodrugs of tenofovir
• CORE ALLOSTERIC MODULATORS
Interferes with encapsidation process = Targets
HBc protein = Prevent mature capsid formation
• RNA INTERFERENCE (RNAi)
Delivery of small interfering RNAs to infected
hepatocytes
HEPATITIS D VIRUS (HDV) – satellite virus of HBV
 15~20 million HBV+ patients are co-infected with HDV
 Chronic HDV infection = Most severe form of viral hepatitis – accelerating
chronic HBV progression to cirrhosis/HCC
 Only treatment currently available is pegIFNα (efficient in 20~35% of
patients)
 Smallest virus known to infect humans
 Uses the same entry receptors as HBV BUT Requires HBV envelope (L;
HBsAg) for infectivity = Can’t propagate without HBV
 HDV virions composed of outer lipoprotein envelope made of HBsAg &
inner ribonucleoprotein struction, in which HDV genome resides (circular
RNA; 1.7 kb in length)
 Simultaneous infection with HBV (co-infection) OR Superimposed on
chronic HBV patients (superinfection)
 Vaccine for HBV protects against HDV