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
What are nucleoside analogues?
Compounds analogous to nucleosides, which have their hydroxy-group swapped for another type of group
What do nucleoside analogues need to become active? Why?
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
How do nucleoside analogues interfere with viral replication? (2 mechanisms)
- They act as chain terminators -> no complete copy of the genetic material
- They interfere with the confirmation of the DNA, causing hypermutations -> produces non-replication competent virus
What is special about the activation of acyclovir?
It is activated by a thymidine kinase that is produces by herpesvirus -> only active when herpes virus is present
How can nucleoside analogues be specific for viruses?
They can be made in such a way that they only get used by viral polymerases -> only built into viral genome
How can non-selective nucleoside analogues be used?
Cancer therapy -> targets fast dividing cells
Which three groups of replication inhibitors can be used against viruses?
- Classic antivirals
- Repurposed drugs
- Neutralizing antibodies
How do neutralizing antibodies prevent viral replication?
Prevent virus from binding to its receptor -> prohibits entry into host cells
Which two different immunmodulatory strategies can be applied against a (viral) infection?
- Suppression to prevent a cytokine storm
- Enhancement of immune response
What mainly determines the duration of virus infectivity?
The titre of neutralizing antibodies -> a low titre means little to no neutralization of virus -> high viral load -> (often) high infectivity
Which patients benefit from antibody therapy in the treatment of COVID-19?
Immune suppressed individuals -> don’t generate a natural antibody response
Which three stages can be identified in the disease course of COVID-19?
- Early infection
- Pulmonary phase
- Hyperinflammatory phase
What are the characteristics of the early infection stage of COVID-19? (3)
- High viral replication
- Asymptomatic or mild/moderate symptoms
- High viral replication -> neutralizing antibodies are effective at this stage
What are the characteristics of the pulmonary phase of COVID-19? (2)
- Low(er) viral replication
- Pneumonia, dyspnoea, opacities on X-thorax and CT
What are the characteristics of the hyperinflammatory phase of COVID-19? (3)
- Cytokine storm -> strong inflammatory response, causing high mortality
- ARDS, sepsis, pneumonia
- Immunosuppressants reduce cytokine storm -> reduce mortality
Why is it hard to modify faulty genes by inserting replacement genes into human cells?
Human cells have evolved to prevent foreign genetic material from entering the cell, because this is usually a viral genome
How can we circumvent stategies the cell uses to prevent entry of foreign genetic material?
Using viruses that evade these strategies
Why are lentiviruses a good vector for viral gene therapy?
They integrate their genome into host cells -> all daugther cells will carry the fixed gene
What is an important characteristic of genetic defects that is required for effective gene therapy?
The mutation has to be recessive -> dominant mutations would still overpower the replacement gene
What is an important danger of treating SCID-patients with gene therapy?
Development of leukaemia due to viral integration in places in the genome that induce cell division
How can leukaemia in SCID-patients treated with viral gene therapy be prevented?
Vector improvement -> make sure the vector does not land in promotor regions to prevent turning on undesirable genes
Why is Parvovirus AAV9 a good option to treat SMA?
It solely targets cells in the spinal chord
What is the disadvantage of using parvoviruses as a vector for gene therapy? What is the solution to this?
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
What are the two types of viral gene therapy?
- Chromosomal gene therapy
- Extrachromosomal gene therapy
What is an example, disadvantage and advantage of chromosomal gene therapy?
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
What is an example, advantage and disadvantage of extrachromosomal gene therapy?
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
What is the goal of immunization using vaccines?
Formation of immunological memory, allowing for a faster & stronger response
What is the difference between active & passive immunization?
Active immunization generates immunological memory, passive immunization doesn’t
What are the natural & artificial ways of active immunzation?
Natural: natural infection
Artificial: vaccination
What are the natural & artificial ways of passive immunization?
Natural: maternal antibodies
Artificial: monoclonal antibodies
Who don’t benefit from vaccination?
Can only be used in immunocompetent patients -> immunocompromised don’t benefit since they don’t generate immunological memory
What are the benefits of passive immunization? (2)
- Can be used in immunocompromised patients
- Works very fast
What are examples of passive immunization? (3)
- Maternal antibodies
- IVIG
- Monoclonal antibodies
Which types of IVIG are available? (3)
- Homologous pooled human antibody
- Homologous human hyperimmmune globulins
- Heterologous hyperimmune serum
What is homologous pooled human antibody? When is it used?
Pooled antibodies from a lot of different donors
Used in congenital immunoglobulin deficiencies to replace antibodies
What are homologous hyperimmune globulins? When is it used?
Pooled IgG from selected donors with high levels of antibodies of interest
Used as post-exposure prophylaxis against various diseases
What is heterologous hyperimmune serum? When is it used?
Antibodies produced in animals
Used as post-exposure prophylaxis against diseases for which there is no human antibody available
What is the disadvantage of monoclonal antibodies when treating viral infections?
Monoclonals recognize specific epitopes and are therefore susceptible to resistance due to viral mutations
When does the highest burden of morbidity/mortality from infectious diseases occur?
<5 years of life
What is a problem when vaccinating very young children?
Presence of maternal antibodies prevents effective memory formation
What are two important features of the immature immune system of infants?
- Less bone marrow to (rapidly) generate immune cells
- Incompletely mature marginal zone B-cells to protect from sepsis
How can maternal antibodies be used to protect children from infectious diseases?
Vaccinating mothers leads to transfer of antibodies against certain pathogens to the child
Who, in addition to children, can especially benefit from vaccinations? (2)
- Immunocompromised individuals
- Elderly
What is the main weakness of the immune system of elderly?
Reduced number of functioning T-cells. T-cells that are still present are often in hyperinflammatory state.
Against which diseases can elderly be vaccinated? (4)
- Seasonal influenza viruses
- Pneumococcal disease
- Herpes zoster
- SARS-CoV-2
Why is vaccination preferred over natural infection to immunize a population? (3)
- Easier to consistenly immunize the population
- Side effects often milder than disease
- Vaccines provide a more consistent immune response compared to natural disease
Why do people in their 30s usually get a boost of immunity to varicella zoster virus?
They encounter a lot of infected children
When are people at risk of varicella zoster?
When they get older and immunity to VZV starts to drop
Decreasing [antibodies/T-cells] are the biggest cause of decreasing immunity to VZV
T-cells
What should a VZV-vaccine for elderly target in order to effectively increase immunity?
Cellular immunity, as this drops (the most) when people age
What is an oncolytic virus?
Virus that specifically target cancers cells, while leaving other cells unharmed
How do oncolytic viruses target cancer cells? (2)
- Characteristic cell surface receptors/promotors
- Differences in gene expression
What are the mechanisms by which oncolytic viruses can exert anti-tumour effects? (4)
- Direct oncolysis
- Non-specific immune stimulation
- Attraction of cytotoxic T-cells
- Forming a vector for therapeutic genes
How can oncolytic viruses induce non-specific immune stimulation?
Lysis of tumour cells provokes immune cells against other tumour cells due to spillage of intracellular tumour antigens
What is NDV? What is its natural host?
Newcastle Disease Virus
Natural host = poultry
Is NDV naturally specific to cancer cells?
No, oncolytic specificity needs to be built in through exploitation of defective antiviral immunity of cancer cells
Cell lines don’t offer a reliable model for cancers. Which model system provides a more reliable model?
Organoids
Why are nude mice not a good model to study the efficacy of oncolytic viruses?
Because they don’t have an immune system and thus can’t be used to study the interaction between the oncolytic virus & immune system
What are the general characteristics of oncolytic viruses? (4)
- Tumour selective infection
- Antitumour effect
- Safe for patients and surrounding
- Artificial enhancement of efficacy and safety
What are important characteristics of safe oncolytic viruses? (2)
- Selective towards tumour cells
- Don’t cause serious disease in humans or animals
How can oncolytic viruses be naturally enhanced? (3)
- Attenuation -> higher safety
- Increasing virulence -> higher effectivity
- Arming the virus -> higher effectivity & safety
What are characteristics of NDV that make it suitable as oncolytic virus? (4)
- Animal virus -> safe for patients
- Efficacy proven in clinical trials
- Genetic manipulation possible
- Increase in virulence = increase in effectivity
What is the problem with NDV as oncolytic virus?
Still infectious to poultry
