Treatment of viral disease Flashcards
(21 cards)
What are the three types of antiviral treatment?
Utilise the body’s own – very broad – anti-viral response: the interferon system. Drugs with a specific antiviral property. Treatment that alleviates symptoms but do not inhibit virus replication – important because many symptoms of viral infection is body’s immune system turning in on itself. So drugs enable body to still tackle the disease by itself.
How does body interferon response work?
If a virus comes into cell, it recognises that its foreign and cell switched on interferon response. Interferon produced and released. Warns neighbouring cells – so those cells ramp up expression of interferon stimulator genes which give some protection to the cells. But has bad side-effects e.g. inflammation and feeling more sick.
Why is it hard to produce selective anti-viral drugs?
- Viruses are obligate intracellular parasites.
So, viruses do the same things that your cells do e.g. viruses use your ribosomes for their translation, so if we target our ribosomes, we will harm ourselves too.
BUT EASIER to invent than anti-cancer drugs. - They can develop drug resistance.
It’s important that anti-viral drugs are selective because we don’t want too much damage to the host i.e. more risk than benefit.
What do antiviral drugs usually target?
Target viral enzymes. Often act as SUBSTRATE ANALOGUES – blocks active site. Enzymes are easier to target. Enzymes are important in viruses for their functions including replication.
OR target replication. Drugs are NUCLEOSIDE ANALOGUES. Work like cancer drugs by blocking replication by giving nucleosides that don’t work – but must be careful that this doesn’t block replication in human cells.
What is the mechanism of nucleoside analogue in antiviral therapy?
Nucleoside analogues work as chain TERMINATORS in DNA replication. They lack the 3’ -OH which receives the next nucleoside and forms a phosphodiester bond.
What examples are there of nucleoside analogue drugs? (x2)
Acyclovir.
Zidovudine AZT.
What is the mechanism by which acyclovir works? What are the two layers of specificity?
Because it’s given as a pro-drug – an unphosphorylated, inactive form, meaning it cannot yet be used as a substrate in DNA replication.
Nucleosides can only be added in replication if they are tri-phosphorylated. The specificity of acyclovir comes from an enzyme only made by a cell infected by the herpes virus that puts the first phosphate onto the acyclovir, forming acyclo-guanosine monophosphate. This is because the virus encodes THYMIDINE KINASE. After, the normal cell kinases phosphorylate acyclovir to acyclo-guanosine tri-phosphate.
SO, acyclovir activated inside virus infected cells only. NOTE that acyclovir is not a CURE, but instead, greatly suppresses the overall viral load. The host’s immune system can then work to eradicate the infection completely!!!
Also, acyclovir tri-phosphate has higher affinity to viral DNA polymerases, so there’s an extra layer of specificity for the drug there.
Once activated, it is added to the growing DNA chain in herpes virus genome where it TERMINATES the reaction because it lacks the 3’ OH by which the next nucleoside would be attached (note that in relation to its structure, its sugar is NOT CYCLIC).
What is the history of Zidovudine AZT?
Nucleoside analogue used against HIV, but resistance quickly emerged.
How did Zidovudine work, in relation to its structure?
It was a chain terminator (nucleoside analogue). Rather than a 3’ OH, there was a N3 group.
What is now used for HIV treatment? Disadvantages? (x2)
Uses three or four different drugs in combination known as HAART (highly active antiretroviral therapy) which prevents virus from being able to generate resistance mutants.
BUT: does lead to difficult treatment regimens (drug administration plans) and is associated with significant side effects.
Other than acyclovir and AZT, what other classes of anti-viral drugs are there, and what have they been able to successfully treat? (x4)
Protease inhibitors (HCV (Hepatitis C) and HIV) Ion channel blockers (influenza) Neuraminidase inhibitors (influenza). Interferon is currently used in combination with ribavirin to treat HCV.
What drugs target influenza? (x3)
I don’t think this needs to be emphasised too much.
Amantadine – now resistant.
Oseltamivir (neuraminidase inhibitor).
Zanamivir (neuraminidase inhibitor).
What is the difference between large and small viruses regarding their potential to be treated for anti-viral therapy?
Small viruses have less nucleic acid material and hence encode fewer virus-specific genes, and the larger viruses have more nucleic acid and hence encode many more virus-specific proteins. Thus, the bigger the virus, the more proteins that differ from the host and the more potential targets for drug intervention and hence therapy against infection by that virus.
How are anti-viral drugs most often administered? Why?
In combination with other anti-viral drugs.
To reduce chance of anti-drug resistance. Drugs are used in combination because it is very unlikely that ONE viral genome will become resistant to SEVERAL anti-viral drugs.
For example, if some viruses acquire mutation that makes them resistant to a drug that targets a transcriptase enzyme, a second drug targeting a different mechanism in its replication cycle can kill those viruses instead, and entire virus population can be eliminated.
What makes viruses suited for evolution? (x3)
High mutation rate.
Large progeny numbers (lots of offspring).
Short replication time.
How does antiviral drug resistance work? How does it proliferate in the population?
Drug applied.
Viral evolution in response to selective pressure = fast. Resistant viruses emerge and predominate in that host.
Relative fitness of the drug-resistant virus vs wild type virus in vivo can influence whether the drug resistant viruses proliferate. [Explanation below if you cannot understand why this is.]
If drug taken away, will the drug resistant virus or the wild-type virus in vivo be fitter?
If the virus transmits to another patient who isn’t being treated with the drug, then you would often revert to wild type population, as the drug-resistant type will be outcompeted. If there is no fitness cost, or if there is a fitness advantage with being drug resistant and you pass on your drug-resistant virus to another individual, then that patient cannot be treated with the anti-viral drug because the virus population will NOT revert to wild-type.
What is antigenic drift in viruses?
Antibodies can act as a selection pressure!
FOR EXAMPLE: When antibodies are produced in response to influenza, a selection pressure is imposed on the virus.
Viruses exist as a quasispecies in patients (remember!). So, a mutation could mean that the antigen on the virus changes shape, antibody doesn’t bind anymore, and patient is no longer immune. This mutated-virus survives and is transmitted to another person.
This is what happens in human populations and is the reason why every year, people can be infected again with influenza. CALLED ANTIGENIC DRIFT.
How can reassortment lead to antigenic drift? What is the global risk of the disease at this point?
Where two viruses from different organisms come together, both genes are mixed, and totally new virus emerges. Occurs in animals that are readily infected by both viruses e.g. bird and human viruses can both infect pigs.
Results in pandemic.
What is the different between prophylactic and therapeutic approaches to viral disease?
PROPHYLAXIS: vaccines, used before infection.
THERAPEUTIC: anti-viral drugs, administered when person is infected.
What stages in life cycle of a virus could be used for anti-viral therapy? (x4 + x2 potentials in future)
- Blocking viral entry into the cell.
- Interfering with transcription of the viral genome (nucleoside analogues, or target enzymes unique to virus that our cell does not have e.g. reverse transcriptase in HIV – DNA from RNA)
- Stopping integration of viral genome into host DNA through TARGETING ENZYMES OF VIRUSES.
- Blocking exit of virus from cell by budding.
- We can now identify many host cell genes that viruses need for their replication – the hope is that we can target some of them because our genome has some redundancy (gene redundancy: multiple genes in the genome of an organism that perform the same function; targeting one of these genes will therefore have little effect on the phenotype).
- There is hope that broadly acting antivirals may be discovered. New breakthroughs include small molecules that freeze the lipids on enveloped viruses but seem not to affect the plasma membranes of our own host cells.
What is CCR5 in respect to the potential future of anti-viral therapy?
CCR5 protein is used by HIV to enter cells. A group of exposed, uninfected individuals with 32bp deletion in CCR5 remained resistant to HIV.
We can now identify many host cell genes that viruses need for their replication – the hope is that we can target some of them because our genome has some redundancy (gene redundancy: multiple genes in the genome of an organism that perform the same function; targeting one of these genes will therefore have little effect on the phenotype).
