Developments in virology

Question 1

What are nucleoside analogues?

Answer 1

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

Question 2

What do nucleoside analogues need to become active? Why?

Answer 2

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

Question 3

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

Answer 3

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

Question 4

What is special about the activation of acyclovir?

Answer 4

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

Question 5

How can nucleoside analogues be specific for viruses?

Answer 5

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

Question 6

How can non-selective nucleoside analogues be used?

Answer 6

Cancer therapy -> targets fast dividing cells

Question 7

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

Answer 7

1. Classic antivirals
2. Repurposed drugs
3. Neutralizing antibodies

Question 8

How do neutralizing antibodies prevent viral replication?

Answer 8

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

Question 9

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

Answer 9

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

Question 10

What mainly determines the duration of virus infectivity?

Answer 10

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

Question 11

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

Answer 11

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

Question 12

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

Answer 12

1. Early infection
2. Pulmonary phase
3. Hyperinflammatory phase

Question 13

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

Answer 13

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

Question 14

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

Answer 14

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

Question 15

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

Answer 15

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

Question 16

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

Answer 16

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

Question 17

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

Answer 17

Using viruses that evade these strategies

Question 18

Why are lentiviruses a good vector for viral gene therapy?

Answer 18

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

Question 19

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

Answer 19

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

Question 20

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

Answer 20

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

Question 21

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

Answer 21

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

Question 22

Why is Parvovirus AAV9 a good option to treat SMA?

Answer 22

It solely targets cells in the spinal chord

Question 23

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

Answer 23

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

Question 24

What are the two types of viral gene therapy?

Answer 24

1. Chromosomal gene therapy
2. Extrachromosomal gene therapy

Question 25

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

Answer 25

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

Question 26

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

Answer 26

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

Question 27

What is the goal of immunization using vaccines?

Answer 27

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

Question 28

What is the difference between active & passive immunization?

Answer 28

Active immunization generates immunological memory, passive immunization doesn't

Question 29

What are the natural & artificial ways of active immunzation?

Answer 29

Natural: natural infection Artificial: vaccination

Question 30

What are the natural & artificial ways of passive immunization?

Answer 30

Natural: maternal antibodies Artificial: monoclonal antibodies

Question 31

Who don't benefit from vaccination?

Answer 31

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

Question 32

What are the benefits of passive immunization? (2)

Answer 32

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

Question 33

What are examples of passive immunization? (3)

Answer 33

1. Maternal antibodies 2. IVIG 3. Monoclonal antibodies

Question 34

Which types of IVIG are available? (3)

Answer 34

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

Question 35

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

Answer 35

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

Question 36

What are homologous hyperimmune globulins? When is it used?

Answer 36

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

Question 37

What is heterologous hyperimmune serum? When is it used?

Answer 37

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

Question 38

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

Answer 38

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

Question 39

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

Answer 39

<5 years of life

Question 40

What is a problem when vaccinating very young children?

Answer 40

Presence of maternal antibodies prevents effective memory formation

Question 41

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

Answer 41

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

Question 42

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

Answer 42

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

Question 43

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

Answer 43

1. Immunocompromised individuals 2. Elderly

Question 44

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

Answer 44

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

Question 45

Against which diseases can elderly be vaccinated? (4)

Answer 45

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

Question 46

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

Answer 46

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

Question 47

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

Answer 47

They encounter a lot of infected children

Question 48

When are people at risk of varicella zoster?

Answer 48

When they get older and immunity to VZV starts to drop

Question 49

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

Answer 49

T-cells

Question 50

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

Answer 50

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

Question 51

What is an oncolytic virus?

Answer 51

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

Question 52

How do oncolytic viruses target cancer cells? (2)

Answer 52

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

Question 53

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

Answer 53

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

Question 54

How can oncolytic viruses induce non-specific immune stimulation?

Answer 54

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

Question 55

What is NDV? What is its natural host?

Answer 55

Newcastle Disease Virus Natural host = poultry

Question 56

Is NDV naturally specific to cancer cells?

Answer 56

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

Question 57

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

Answer 57

Organoids

Question 58

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

Answer 58

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

Question 59

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

Answer 59

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

Question 60

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

Answer 60

1. Selective towards tumour cells 2. Don't cause serious disease in humans or animals

Question 61

How can oncolytic viruses be naturally enhanced? (3)

Answer 61

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

Question 62

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

Answer 62

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

Question 63

What is the problem with NDV as oncolytic virus?

Answer 63

Still infectious to poultry