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Molecular Basis of Disease > Hepatitis B virus > Flashcards

Hepatitis B virus Flashcards

1
Q

What are the two strategies currently used to treat HBV?

A

Boosting immunity of the host via interferon alpha

Inhibiting the replication of the virus via polymerase inhibitors

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2
Q

Examples of polymerase inhibitors

A

Nucleoside/nucleotide analogue chain terminators

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3
Q

Pitfalls of polymerase inhibitors

A

Have little effect on antigen or cccDNA levels

Viruses have developed resistance in long term therapy

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4
Q

Why is the disadvantage of long term therapy?

A

They have high financial costs

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5
Q

What is the definition of HBV cure?

A

Loss of HBV antigens in the blood

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6
Q

Treatment goals for HBV therapy

A

Absence of HBV DNA in the plasma following therapy

Loss of HBV antigens

HBV antigen seroconversion

Loss of cccDNA

Reduction in liver complications

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7
Q

Barriers and potential targets of resolution of chronic HBV infection

A

cccDNA reservoir

Integration

Dysfunctional NK responses

Dysfunctional T-cell responses

Insufficient B-cell responses

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8
Q

What do novel strategies targeting HBV rely on?

A

Either the host or the virus

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9
Q

List the ways of targeting the virus

A

Viral entry

cccDNA

Endonucleases

Capsids

Antigen secretion

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10
Q

Describe a drug that targets viral entry as a HBV treatment

A

Myrcludex B

Synthetic peptide derived from the Pre-S1 HBV

Binds to the NTCP receptor preventing the entry of the virus

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11
Q

What are mechanisms of targeting cccDNA?

A

Epigenetic silencing of cccDNA by IFN-a

cccDNA depletion by PEG-IFN-2a and entecavir

cccDNA degradation by LTbR activation

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12
Q

Drug that inhibits antigen secretion

A

Tetrahydro-tetrazolo-pyrimidine

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13
Q

What can be done to inhibit endonucleases?

A

Target zinc finger nucleases

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14
Q

List novel strategies targeting the host

A

Combining polymerase inhibitors and IFN-a therapy

Oral TLR7 agonist

NK cells

Checkpoint inhibitors and co-stimulation

Vaccines

Modified T cells

Targeting B cells

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15
Q

What is important in order to tackle HBV infection

A

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

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16
Q

What happens to the immune response in chronic HBV?

A

The innate and adaptive immune responses are defective

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17
Q

How is the immune response defective in chronic HBV infection?

A

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

18
Q

How is combining polymerase inhibitors and IFN-a an efficient therapy in HBV?

A

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

19
Q

What do polymerase inhibitors target?

A

The intracellular effects of the HBV virus in cells

20
Q

What does IFN therapy target?

A

The defective immune cells

21
Q

What is TLR7?

A

Molecule expressed by pDCs and B cells

Activated by ssRNA and small molecules

Part of the innate immune system

22
Q

How is TLR7 involved in the innate immune system?

A

Act on Myd88, which acts on IRF7 and NF-kB

Release IFN-a and pro-inflammatory cytokines

23
Q

Example of TLR7 agonist

A

GS-9620

Acts on the TLR7 to alleviate symptoms

24
Q

How are NK cells involved in HBV?

A

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

25
Q

How are NK cells specifically targeted in HBV therapy?

A

NK cells kill HBV-specific T cells by TRAIL-mediated NK cell killing

There is a recovery of antiviral T cells following NK depletion

26
Q

Examples of co-inhibitory signals in checkpoints of antiviral T cell production

A

PD-1

CTLA-4

Tim-3

Lag-3

27
Q

Examples of co-stimulatory signals in checkpoints of antiviral T cells production

A

41BB

IL-12

28
Q

How can checkpoint inhibitors be used as HBV therapy?

A

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

29
Q

What is the relationship between Tregs and HBV viral load?

A

Treg populaiton increases with the viral load

30
Q

Example of checkpoint inhibition

A

PDL1/2 blockade

31
Q

What is checkpoint inhibition normally combined with?

A

IL-12

Optimises the HBV-specific CD8 T cell recovery in vivo

32
Q

How did the Tarmogen vaccine increase the immunity of individuals to HBV?

A

Increased CD8 T-helper population

Decreased the Treg population

Increased the Th17 popultion

Increased the antiviral effector function of CD4+ cells

33
Q

What therapy is combined with vaccines to increase efficacy of treatment?

A

PD-1/PD-L1 blockade

34
Q

What indicates the maturation of T cells?

A

Maturation

35
Q

How can T cells be engineered?

A

Vectors

36
Q

How are the engineered T cells effective at targeting HBV?

A

They are redirected to specifically target HBV and influence the specificity of existing T cells by TCR gene transfer

37
Q

What do regulatory B cells release?

A

IL-10

38
Q

Why are regulatory B cells a target for HBV therapy?m

A

Regulatory B cells inhibit HBV-specific T and NK cells

39
Q

How are B cells targeted in HBV therapy?

A

Reduce their number

40
Q

Describe the drugs that can be combined to provide a potentially HBV curative regimen

A

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

Molecular Basis of Disease (28 decks)

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