Hepatitis B virus Flashcards
What are the two strategies currently used to treat HBV?
Boosting immunity of the host via interferon alpha
Inhibiting the replication of the virus via polymerase inhibitors
Examples of polymerase inhibitors
Nucleoside/nucleotide analogue chain terminators
Pitfalls of polymerase inhibitors
Have little effect on antigen or cccDNA levels
Viruses have developed resistance in long term therapy
Why is the disadvantage of long term therapy?
They have high financial costs
What is the definition of HBV cure?
Loss of HBV antigens in the blood
Treatment goals for HBV therapy
Absence of HBV DNA in the plasma following therapy
Loss of HBV antigens
HBV antigen seroconversion
Loss of cccDNA
Reduction in liver complications
Barriers and potential targets of resolution of chronic HBV infection
cccDNA reservoir
Integration
Dysfunctional NK responses
Dysfunctional T-cell responses
Insufficient B-cell responses
What do novel strategies targeting HBV rely on?
Either the host or the virus
List the ways of targeting the virus
Viral entry
cccDNA
Endonucleases
Capsids
Antigen secretion
Describe a drug that targets viral entry as a HBV treatment
Myrcludex B
Synthetic peptide derived from the Pre-S1 HBV
Binds to the NTCP receptor preventing the entry of the virus
What are mechanisms of targeting cccDNA?
Epigenetic silencing of cccDNA by IFN-a
cccDNA depletion by PEG-IFN-2a and entecavir
cccDNA degradation by LTbR activation
Drug that inhibits antigen secretion
Tetrahydro-tetrazolo-pyrimidine
What can be done to inhibit endonucleases?
Target zinc finger nucleases
List novel strategies targeting the host
Combining polymerase inhibitors and IFN-a therapy
Oral TLR7 agonist
NK cells
Checkpoint inhibitors and co-stimulation
Vaccines
Modified T cells
Targeting B cells
What is important in order to tackle HBV infection
A coordinate and integrated immune response
Where effectors like IFN-a and NK cells from the innate immune response, and CD4/CD8 T cells and B cells from the humoral immune response work together to combat the infection
What happens to the immune response in chronic HBV?
The innate and adaptive immune responses are defective
How is the immune response defective in chronic HBV infection?
HBV-specific T cells are exhausted and pro-apoptotic
NK cells of the innate immune response are faulty and produce defective IFN-y
NK cells delete HBV-specific T cells
Aberrant myeloid-derived suppressor cells inhibit T cells through nutrient deprivation
How is combining polymerase inhibitors and IFN-a an efficient therapy in HBV?
Patients have defective NK cells and cytotoxic T cells
Combining the therapies will target the intracellular effects of hepatitis
Improves the serum concentration of NK and CD8 T cells
What do polymerase inhibitors target?
The intracellular effects of the HBV virus in cells
What does IFN therapy target?
The defective immune cells
What is TLR7?
Molecule expressed by pDCs and B cells
Activated by ssRNA and small molecules
Part of the innate immune system
How is TLR7 involved in the innate immune system?
Act on Myd88, which acts on IRF7 and NF-kB
Release IFN-a and pro-inflammatory cytokines
Example of TLR7 agonist
GS-9620
Acts on the TLR7 to alleviate symptoms
How are NK cells involved in HBV?
Release IFN-a
Constitute 30% of intrahepatic lymphocytes
Cause NK-mediated liver injury
Also involved in antiviral NK activity, anti-fibrotic NK activity and NK-mediated T cell depletion
How are NK cells specifically targeted in HBV therapy?
NK cells kill HBV-specific T cells by TRAIL-mediated NK cell killing
There is a recovery of antiviral T cells following NK depletion
Examples of co-inhibitory signals in checkpoints of antiviral T cell production
PD-1
CTLA-4
Tim-3
Lag-3
Examples of co-stimulatory signals in checkpoints of antiviral T cells production
41BB
IL-12
How can checkpoint inhibitors be used as HBV therapy?
They can be used to push the balance and enhance the effect of co-stimulatory signals
Stimulates the T cells in their antiviral response
Also can push the balance and enhance the effect of co-inhibitory signals in Tregs
What is the relationship between Tregs and HBV viral load?
Treg populaiton increases with the viral load
Example of checkpoint inhibition
PDL1/2 blockade
What is checkpoint inhibition normally combined with?
IL-12
Optimises the HBV-specific CD8 T cell recovery in vivo
How did the Tarmogen vaccine increase the immunity of individuals to HBV?
Increased CD8 T-helper population
Decreased the Treg population
Increased the Th17 popultion
Increased the antiviral effector function of CD4+ cells
What therapy is combined with vaccines to increase efficacy of treatment?
PD-1/PD-L1 blockade
What indicates the maturation of T cells?
Maturation
How can T cells be engineered?
Vectors
How are the engineered T cells effective at targeting HBV?
They are redirected to specifically target HBV and influence the specificity of existing T cells by TCR gene transfer
What do regulatory B cells release?
IL-10
Why are regulatory B cells a target for HBV therapy?m
Regulatory B cells inhibit HBV-specific T and NK cells
How are B cells targeted in HBV therapy?
Reduce their number
Describe the drugs that can be combined to provide a potentially HBV curative regimen
Polymerase inhibtors first used to prevent viral spread and cccDNA re-amplification
Agents to activate antiviral immunity or relieve repression of the system
Selective agent to deplete or perturb cccDNA
Agents to inhibit other components of the HBV life cycle
