Mechanism of Antivirals

Question 1

Explain 3 reasons why even though we have vaccines, we need antivirals

Answer 1

• There are poorly effective or no vaccines for some viruses important to human health
• Not everyone can be administered a vaccine even if that vaccine is effective
• Immune response to vaccine administration can take time (and several sequential administrations)

Question 2

What type of infections might we need to use antivirals for?

Answer 2

• acute infections (aka quick killers) like influenza, ebola, MERS and SARS
• viruses that we do not have a vaccine for (like HIV - long term) and chronic infections
• viruses that cause acute inflammatory disease like herpes

Question 3

What is prophylaxis?

Answer 3

Treatment given or action taken to prevent disease

Question 4

When talking about HIV antivirals what is meant by PEP and PrEP?

Answer 4

• Post-exposure prophylaxis and preventing infection: HIV (PEP)
• Pre-exposure prophylaxis: HIV (PrEP)

Question 5

Name some broad different modes of action of antivirals

Answer 5

• Preventing virus absorption into host cell
• Preventing penetration
• Preventing viral nucleic acid replication (nucleoside analogues)
• Preventing maturation of virus
• Preventing virus release

Question 6

Explain why developing antiviral drugs that are non-toxic and effective is so hard

Answer 6

• Viruses use cellular proteins which may have other functions
• Viruses must replicate inside cells - obligate intracellular parasites
• Viruses take over the host cell replicative machinery
• Viruses have high mutation rate - quasispecies
• Anti-virals must be selective in their toxicity
  
  • i.e. exert their action only on infected cells
• Some viruses are able to remain in a latent state e.g. herpes, HPV
• Some viruses are able to integrate their genetic material into host cells
  
  • e.g. HIV

Question 7

What viruses does Aciclovir target?

Answer 7

Herpes virus family including:

• Herpes simplex (HSV)
• Varicella Zoster Virus (VZV)
• Cytomegalovirus (CMV)
• Epstein-Barr virus (EBV)

Question 8

Explain why Aciclovir only works in virus infected cells

Answer 8

This is as it starts as an inactive form and is converted to the active form by 2 viral enzymes

Question 9

The viral enzyme {?} activates Aciclovir

Answer 9

The viral enzyme thymidine kinase (TK) activates Aciclovir

Question 10

Explain what happens to Aciclovir to activate it

Answer 10

It is phosphorylated by a viral enzyme thymidine kinase (TK)

Question 11

Explain how Aciclovir produces its antiviral effect

Answer 11

Aciclovir, when phosphorylated (by a viral enzyme?), looks like a DNA base so the viral DNA pol incorporates the active Aciclovir into the DNA

• Aciclovir is a DNA chain terminator
• Aciclovir has 30x the affinity for HSV DNA polymerase compared to cellular DNA polymerase

Question 12

{?} has {?} the affinity for Aciclovir (ACV) compared with cellular phosphokinases

Answer 12

HSV thymidine kinase (TK) has 100 x the affinity for Aciclovir (ACV) compared with cellular phosphokinases

Question 13

What viruses does Ganciclovir treat?

Answer 13

CMV (cytomegalovirus)

Question 14

What type of virus is CMV (cytomegalovirus)?

Answer 14

Herpes

• Herpes virus 4

Question 15

How does Ganciclovir work?

Answer 15

Is basically the same as Aciclovir but just uses a different enzyme that is specific to CMV (so is converted to an active form by a viral enzyme and then will competitively inhibit viral DNA pol?)

Question 16

Which viral enzyme converts ganciclovir to its active form?

Answer 16

CMV phosphotransferase (UL97 kinase)

Question 17

Name 2 anti-herpes drugs that are not aciclovir or ganciclovir

Answer 17

• Foscarnet
• Cidofovir

Question 18

Name the 2 main mechanisms that viruses can become resistant to aciclovir

Answer 18

As there are 2 enzymes involved in the pathway, if there are mutations to these 2 specific enzymes then aciclovir can not work

Question 19

Why is resitance to antivirals in herpes virus very rare?

Answer 19

As (in immune competent patients) there is a very low viral load

Question 20

If a mutation occuurs in {?} in a herpes virus drugs not needing phsophorylation are still effective

Answer 20

If a mutation occuurs in Thymidine Kinase in a herpes virus drugs not needing phsophorylation are still effective

Question 21

If a mutation in a herpes virus occurs in {?} all drugs are rendered less effective

Answer 21

If a mutation in a herpes virus occurs in viral DNA polymerase all drugs are rendered less effective

Question 22

What virus does HAART target?

Answer 22

HIV

Question 23

What type of genetic material is in HIV?

Answer 23

ss + RNA, 2 strands

Question 24

Is HIV enveloped?

Answer 24

yes

Question 25

What is gp120 on HIV?

Answer 25

The envelope protein, also uses the transmembrane protein gp41 - " a glycoprotein protruding from the outer surface of the HIV virion that has a molecular weight of 120 and must bind to a CD4 receptor on a T cell bearing such receptors before infection of the cell can occur"

Question 26

Explain what Gag (group specific antigen) is

Answer 26

Gag is the major structural protein of HIV and all retroviruses

Question 27

Describe the structure of HIV

Answer 27

Question 28

Name 4 types of anti-HIV drugs

Answer 28

1. Anti-reverse transcriptase inhibitors 2. Protease inhbitors 3. Integrase inhibitors 4. Fusion inhibitors

Question 29

Why is it very common for HIV to produce anti-viral resitant HIV mutants?

Answer 29

Because it produces a large amount of mutations in its replication (reverse transcriptase lacks proof reading capacity?)

Question 30

What is HAART and why do we do it?

Answer 30

Since HIV very often produces antiviral resistant mutants, we use a combination of different types of antiviral HIV drugs (4 types) * this therapy is called HAART = highly active anti retroviral therapy

Question 31

What is the most common type (class) of anti-HIV antiviral and name one

Answer 31

Nucleoside reverse transcriptase inhibitors (NRTI) * AZT

Question 32

Nucleoside reverse transcriptase inhibitors are one type of drug used in the treatment of HIV, explain how these work

Answer 32

They are structurally similar to DNA bases so reverse transcriptase incorporates them but they cause chain termination

Question 33

In the treatment of HIV we can use non-nucleoside reverse transcriptase inhibitors, explain how these work

Answer 33

These do the same thing as nucleoside RT inhibitors but do not look like nucleotides - non competitive inhibition of reverser transcriptase - can be used in combination with NRTIs

Question 34

What is meant by a viral swarm in HIV?

Answer 34

Due to the high mutation rate and high viral load, HIV can cause a large number of multiple different HIV viruses * quasispecies

Question 35

Why does HIV have a high mutation rate?

Answer 35

Reverse transcriptase lacks a proof reading capacity

Question 36

What genetic material is in influenza?

Answer 36

single stranded (ss) RNA

Question 37

What type of virus do we treat with Amantidine?

Answer 37

Influenza

Question 38

How does Amantidine work?

Answer 38

* Inhibit virus uncoating by blocking the influenza encoded M2 protein when inside cells and assembly of haemagglutinin * Now rarely used

Question 39

Zanamivir and Oseltamivir (Tamiflu) are used for treatment of flu, how do they work?

Answer 39

* Inhibits virus release from infected cells via inhibition of neuraminidase * Oseltamivir-oral * Zanamivir- inhaled or IV - less likely for resistance to develop

Question 40

Explain how zanamivir and oseltamivir work

Answer 40

Stop the virus (flu) from leaving the cell as an interaction is needed by neuraminidise with the cell surface - they block this interaction

Question 41

How is hepatitis C (HCV) transmitted?

Answer 41

* Unprotected sex * Blood and body fluid exposure * IV drug use

Question 42

What type of virus (genetic material) is HCV (hepatitis C)?

Answer 42

9.6 Kb RNA virus, enveloped, Flavivridae family

Question 43

Since there is no vaccine for HCV, we rely mostly on the broad acting antiviral {?}

Answer 43

Since there is no vaccine for HCV, we rely mostly on the broad acting antiviral Ribavirin

Question 44

Explain how Ribavirin works

Answer 44

* Is a nucleoside analogue that is orignially inactive and then is activated by phosphorylation * Blocks RNA synthesis (causes chain termination) by inhibiting IMP

Question 45

It is very easy to get mutations that stop the functioning of Ribavirin, and so we now are using {?} to treat {?}

Answer 45

It is very easy to get mutations that stop the functioning of Ribavirin, and so we now are using DAAs (direct acting antivirals) to treat HCV (HepC)

Question 46

Describe what DAAs are and their benefits

Answer 46

* Direct acting antivirals * Relatively new class of medication * Acts to target specitic steps in the HV viral lite cycle * shorten the length of therapy, minimize side effects, target the virus itself, improve sustained virologic response (SVR) rate. * structural and non-structural proteins - replicate and assemble new virions * HCV - first chronic viral infection to be cured without IF or ribavirin.

Question 47

Explain how DAAs work - what 3 things can they inhibit?

Answer 47

Inhibit: * NS3/4 protease (needed for viral protein formation) * NS5A (needed for assembly of virueses) * NS5B polymerase (needed for RNA replication)

Question 48

When talking about HCV, describe the genome and how we name the HCV (hep C) proteins

Answer 48

HCV is ssRNA NS = non-structural protein C = capsid E = envelope

Question 49

What is the function exactly of the viral protease in HCV

Answer 49

I beleive that the whole RNA genome is transcribed into one long protein which is then chopped up by this protease

Question 50

What is post exposure prophylaxis?

Answer 50

The emergency management of exposure-prone incidents such as splashes of contaminated fluids, needle injuries etc.

Question 51

Name some viral infections with no effective therapies

Answer 51

* rabies * dengue * common cold viruses * ebola * HPV * arboviruses * 'Pathogen X'