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I&I SC1 > Developments in virology > Flashcards

Developments in virology Flashcards

Lectures: -Week 2, day 4, lecture 1: Viruses as friends - Gene therapy -Week 2, day 4, lecture 4: Prevention & treatment of viral disease - Vaccines -Week 2, day 4, lecture 5: Prevention & treatment of viral disease - Antivirals & immunomodulators -Week 2, day 4, lecture 6: Viruses as friends - Oncolytic viruses

1
Q

What are nucleoside analogues?

A

Compounds analogous to nucleosides, which have their hydroxy-group swapped for another type of group

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2
Q

What do nucleoside analogues need to become active? Why?

A

Intracelllular phosphorylation to triphosphate

They need this because compounds that have a triphosphate group attach are polar and unable to pass through the cell membrane

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3
Q

How do nucleoside analogues interfere with viral replication? (2 mechanisms)

A
  1. They act as chain terminators -> no complete copy of the genetic material
  2. They interfere with the confirmation of the DNA, causing hypermutations -> produces non-replication competent virus
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4
Q

What is special about the activation of acyclovir?

A

It is activated by a thymidine kinase that is produces by herpesvirus -> only active when herpes virus is present

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5
Q

How can nucleoside analogues be specific for viruses?

A

They can be made in such a way that they only get used by viral polymerases -> only built into viral genome

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6
Q

How can non-selective nucleoside analogues be used?

A

Cancer therapy -> targets fast dividing cells

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7
Q

Which three groups of replication inhibitors can be used against viruses?

A
  1. Classic antivirals
  2. Repurposed drugs
  3. Neutralizing antibodies
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8
Q

How do neutralizing antibodies prevent viral replication?

A

Prevent virus from binding to its receptor -> prohibits entry into host cells

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9
Q

Which two different immunmodulatory strategies can be applied against a (viral) infection?

A
  1. Suppression to prevent a cytokine storm
  2. Enhancement of immune response
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10
Q

What mainly determines the duration of virus infectivity?

A

The titre of neutralizing antibodies -> a low titre means little to no neutralization of virus -> high viral load -> (often) high infectivity

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11
Q

Which patients benefit from antibody therapy in the treatment of COVID-19?

A

Immune suppressed individuals -> don’t generate a natural antibody response

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12
Q

Which three stages can be identified in the disease course of COVID-19?

A
  1. Early infection
  2. Pulmonary phase
  3. Hyperinflammatory phase
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13
Q

What are the characteristics of the early infection stage of COVID-19? (3)

A
  1. High viral replication
  2. Asymptomatic or mild/moderate symptoms
  3. High viral replication -> neutralizing antibodies are effective at this stage
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14
Q

What are the characteristics of the pulmonary phase of COVID-19? (2)

A
  1. Low(er) viral replication
  2. Pneumonia, dyspnoea, opacities on X-thorax and CT
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15
Q

What are the characteristics of the hyperinflammatory phase of COVID-19? (3)

A
  1. Cytokine storm -> strong inflammatory response, causing high mortality
  2. ARDS, sepsis, pneumonia
  3. Immunosuppressants reduce cytokine storm -> reduce mortality
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16
Q

Why is it hard to modify faulty genes by inserting replacement genes into human cells?

A

Human cells have evolved to prevent foreign genetic material from entering the cell, because this is usually a viral genome

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17
Q

How can we circumvent stategies the cell uses to prevent entry of foreign genetic material?

A

Using viruses that evade these strategies

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18
Q

Why are lentiviruses a good vector for viral gene therapy?

A

They integrate their genome into host cells -> all daugther cells will carry the fixed gene

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19
Q

What is an important characteristic of genetic defects that is required for effective gene therapy?

A

The mutation has to be recessive -> dominant mutations would still overpower the replacement gene

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20
Q

What is an important danger of treating SCID-patients with gene therapy?

A

Development of leukaemia due to viral integration in places in the genome that induce cell division

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21
Q

How can leukaemia in SCID-patients treated with viral gene therapy be prevented?

A

Vector improvement -> make sure the vector does not land in promotor regions to prevent turning on undesirable genes

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22
Q

Why is Parvovirus AAV9 a good option to treat SMA?

A

It solely targets cells in the spinal chord

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23
Q

What is the disadvantage of using parvoviruses as a vector for gene therapy? What is the solution to this?

A

Viral genome does not integrate in the host genome -> not present in daughter cells

Solution: only use this kind of virus in non-/slowly dividing tissue

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24
Q

What are the two types of viral gene therapy?

A
  1. Chromosomal gene therapy
  2. Extrachromosomal gene therapy
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25
Q

What is an example, disadvantage and advantage of chromosomal gene therapy?

A

Example: lentiviruses integrating into the host genome
Advantage: integration into host genome means that gene repair is transferred over to daughter cells
Disadvantage: leukaemic potential due to integration in host genome

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26
Q

What is an example, advantage and disadvantage of extrachromosomal gene therapy?

A

Example: parvovirus AAV9 to treat SMA
Advantage: no integration in host genome -> no leukaemic potential
Disadvantage: no integration in host genome -> does not divide into daughter cells

27
Q

What is the goal of immunization using vaccines?

A

Formation of immunological memory, allowing for a faster & stronger response

28
Q

What is the difference between active & passive immunization?

A

Active immunization generates immunological memory, passive immunization doesn’t

29
Q

What are the natural & artificial ways of active immunzation?

A

Natural: natural infection
Artificial: vaccination

30
Q

What are the natural & artificial ways of passive immunization?

A

Natural: maternal antibodies
Artificial: monoclonal antibodies

31
Q

Who don’t benefit from vaccination?

A

Can only be used in immunocompetent patients -> immunocompromised don’t benefit since they don’t generate immunological memory

32
Q

What are the benefits of passive immunization? (2)

A
  1. Can be used in immunocompromised patients
  2. Works very fast
33
Q

What are examples of passive immunization? (3)

A
  1. Maternal antibodies
  2. IVIG
  3. Monoclonal antibodies
34
Q

Which types of IVIG are available? (3)

A
  1. Homologous pooled human antibody
  2. Homologous human hyperimmmune globulins
  3. Heterologous hyperimmune serum
35
Q

What is homologous pooled human antibody? When is it used?

A

Pooled antibodies from a lot of different donors
Used in congenital immunoglobulin deficiencies to replace antibodies

36
Q

What are homologous hyperimmune globulins? When is it used?

A

Pooled IgG from selected donors with high levels of antibodies of interest
Used as post-exposure prophylaxis against various diseases

37
Q

What is heterologous hyperimmune serum? When is it used?

A

Antibodies produced in animals
Used as post-exposure prophylaxis against diseases for which there is no human antibody available

38
Q

What is the disadvantage of monoclonal antibodies when treating viral infections?

A

Monoclonals recognize specific epitopes and are therefore susceptible to resistance due to viral mutations

39
Q

When does the highest burden of morbidity/mortality from infectious diseases occur?

A

<5 years of life

40
Q

What is a problem when vaccinating very young children?

A

Presence of maternal antibodies prevents effective memory formation

41
Q

What are two important features of the immature immune system of infants?

A
  1. Less bone marrow to (rapidly) generate immune cells
  2. Incompletely mature marginal zone B-cells to protect from sepsis
42
Q

How can maternal antibodies be used to protect children from infectious diseases?

A

Vaccinating mothers leads to transfer of antibodies against certain pathogens to the child

43
Q

Who, in addition to children, can especially benefit from vaccinations? (2)

A
  1. Immunocompromised individuals
  2. Elderly
44
Q

What is the main weakness of the immune system of elderly?

A

Reduced number of functioning T-cells. T-cells that are still present are often in hyperinflammatory state.

45
Q

Against which diseases can elderly be vaccinated? (4)

A
  1. Seasonal influenza viruses
  2. Pneumococcal disease
  3. Herpes zoster
  4. SARS-CoV-2
46
Q

Why is vaccination preferred over natural infection to immunize a population? (3)

A
  1. Easier to consistenly immunize the population
  2. Side effects often milder than disease
  3. Vaccines provide a more consistent immune response compared to natural disease
47
Q

Why do people in their 30s usually get a boost of immunity to varicella zoster virus?

A

They encounter a lot of infected children

48
Q

When are people at risk of varicella zoster?

A

When they get older and immunity to VZV starts to drop

49
Q

Decreasing [antibodies/T-cells] are the biggest cause of decreasing immunity to VZV

A

T-cells

50
Q

What should a VZV-vaccine for elderly target in order to effectively increase immunity?

A

Cellular immunity, as this drops (the most) when people age

51
Q

What is an oncolytic virus?

A

Virus that specifically target cancers cells, while leaving other cells unharmed

52
Q

How do oncolytic viruses target cancer cells? (2)

A
  1. Characteristic cell surface receptors/promotors
  2. Differences in gene expression
53
Q

What are the mechanisms by which oncolytic viruses can exert anti-tumour effects? (4)

A
  1. Direct oncolysis
  2. Non-specific immune stimulation
  3. Attraction of cytotoxic T-cells
  4. Forming a vector for therapeutic genes
54
Q

How can oncolytic viruses induce non-specific immune stimulation?

A

Lysis of tumour cells provokes immune cells against other tumour cells due to spillage of intracellular tumour antigens

55
Q

What is NDV? What is its natural host?

A

Newcastle Disease Virus
Natural host = poultry

56
Q

Is NDV naturally specific to cancer cells?

A

No, oncolytic specificity needs to be built in through exploitation of defective antiviral immunity of cancer cells

57
Q

Cell lines don’t offer a reliable model for cancers. Which model system provides a more reliable model?

A

Organoids

58
Q

Why are nude mice not a good model to study the efficacy of oncolytic viruses?

A

Because they don’t have an immune system and thus can’t be used to study the interaction between the oncolytic virus & immune system

59
Q

What are the general characteristics of oncolytic viruses? (4)

A
  1. Tumour selective infection
  2. Antitumour effect
  3. Safe for patients and surrounding
  4. Artificial enhancement of efficacy and safety
60
Q

What are important characteristics of safe oncolytic viruses? (2)

A
  1. Selective towards tumour cells
  2. Don’t cause serious disease in humans or animals
61
Q

How can oncolytic viruses be naturally enhanced? (3)

A
  1. Attenuation -> higher safety
  2. Increasing virulence -> higher effectivity
  3. Arming the virus -> higher effectivity & safety
62
Q

What are characteristics of NDV that make it suitable as oncolytic virus? (4)

A
  1. Animal virus -> safe for patients
  2. Efficacy proven in clinical trials
  3. Genetic manipulation possible
  4. Increase in virulence = increase in effectivity
63
Q

What is the problem with NDV as oncolytic virus?

A

Still infectious to poultry

I&I SC1 (20 decks)

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