0528 - Antiviral Agents

Question 1

What are the basic properties of a virus?

Answer 1

Small (18-300nm)
Obligate intracellular pathogens
DNA or RNA
Require host machinery for replication
May also have essential or accessory viral proteins/enzymes
Packaged in a capsid shell
May have outer envelope (makes it more fragile).

Question 2

How can viruses be classified? What factors can be considered?

Answer 2

Size and shape on electron microscopy
Type of Genome (DNA vs RNA, Ds vs Ss, +ve or -ve sense RNA)
Enveloped vs non-enveloped (non-enveloped more resilient in environment)
Clinical syndrome caused by the virus.

Question 3

How are DNA viruses classified?

Answer 3

Enveloped or nonenveloped
Enveloped all dsDNA - so then by family
Non-enveloped - dsDNA or ssDNA, then by family.

Question 4

Which viruses are targets for antiviral therapy?

Answer 4

DNA - Enveloped, DsDNA viruses - Herpes and Hepadna.

RNA - +ve Sense, Enveloped - Retro (HIV) and Flavi (Hep C)

Question 5

What are the basic steps of viral replication?

Answer 5

Recognise specific target cell
Attach via specific mechanisms
Penetrate cell.
Uncoat from capsid to release genetic material and accessory proteins
Macromolecular synthesis - initial synthesis of proteins required fro genome replication, actual genome replication, and translation of structural protein
Post-translational modification
Assembly of virus
Release of virus by lysis (non-enveloped) or budding (enveloped)

Question 6

What are the important innate and adaptive immune responses to viruses?

Answer 6

Innate - interferon, NK cells, macrophages (inactivate opsonised particles, produce interferon, and APC)
Adaptive - T cells (prevent re-activation by latent viruses); Antibodies (neutralise extracellular virus, protect against re-infection or post-vaccine infection)

Question 7

Outline obstacles to the development and use of antiviral agents

Answer 7

Difficulties getting drug to the virus (intracellular)
Targeting host-cell machinery can damage host cells
Viral resistance due to high genomic mutation (esp. RNA), and treatment selecting mutations
Viral infections are generally self-limiting.
Difficult to grow, test sensitivities, dangerous to handle, and drugs thus expensive to develop
Vaccines are often more effective than treatment.

Question 8

Outline general indications for antiviral indications.

Answer 8

Acute illnesses with high mortality/morbidity (trying, but doesn’t happen much yet)
Chronic infections with long-term complications. (currently used)
Immunocompromised hosts a risk of severe disease (latent viruses - CMV, HSV; or RSV)
Acute or reactivation of common infections (Flu, HSV, VZV)
Reduce transmission (pandemic influenza)

Question 9

What are the Specific indications for HIV treatment?

Answer 9

Pregnancy
HIV-associated nephropathy
Co-infection with HBV
HIV related infection or malignancy

Question 10

What are the general indications for HIV treatment?

Answer 10

Based on CD4 count - below 350 is strong recommendation to treat, 350-500 moderate recommendation. Not everyone needs treatment from the beginning.

Question 11

What are the indications for antiviral therapy in influenza?

Answer 11

Severe influenza or influenza in high-risk groups (must give early)
Uncomplicated influenza (reduce symptoms by 24 hours)
Prophylaxis following exposure in instances such as pandemics.

Question 12

What are the indications for antiviral therapy in herpes viruses?

Answer 12

Immunosuppressed - Particularly those with poor T-cell immunity (HIV, steroid treatment, transplantation), to prevent reactivation of latent virus.
Severe or complicated herpes simplex
Severe or recurring genital herpes
Severe chickenpox, and shingles
Keratitis

Question 13

What is the MoA for Herpes antivirals?

Answer 13

Provide a false substrate for nucleos(t)ides, and inhibit DNA polymerase.
Acyclovir, Valaciclovir, Famciclovir - Nucleoside analogues that inhibit DNA polymerase.
Competes with natural substrate to inhibit DNA polymerase and terminate the growing viral DNA chain.

Question 14

What is the MoA for influenza antivirals?

Answer 14

Neuraminidase inhibitors - zanamivir/oseltamivir - Siacilic acid analogue that prevents the release of the virus by inhibiting neuraminidase.
Amantadine/rimantadine - Block M2 ion channels, preventing uncoating of the virus. (not used much)

Question 15

What is the MoA for HIV antivirals?

Answer 15

Nucleos(t)ide reverse transcriptase inhibitors - terminate DNA chain - Main drugs
Non-nucleoside reverse transcriptase inhibitors - block reverse transcriptase enzyme
Protease inhibitors - Prevent HIV protease undertaking post-transcriptional modification of long polypeptide into individual proteins.
Integrase inhibitors - Prevent integration of HIV DNA into genome.

Question 16

How does HIV therapy differ from other viruses?

Answer 16

Target multiple parts of viral life cycle with combined drugs - more potent and reduce resistance.
Clear parameters to monitor response to treatment and decide when to treat.
Molecular markers of resistance can be used to guide the therapy.
Always replace a failing drug regimen with 2 or more drugs from different classes.

Question 17

What are the goals of HIV treatment?

Answer 17

Reduce morbidity and prolong survival
Improve quality of life
Restore and preserve immune functions
Suppress viral load
Prevent vertical and horizontal transmission.

Question 18

Distinguish passive from active vaccination

Answer 18

Passive - administered or maternal antibodies. Short lived (no memory, 1/2 life) but good for post-exposure treatment.
Active - stimulate a natural immune response by providing live attenuated or noninfectious (subunit, bovine-hybrid, inactivated) antigens.
Can’t use live-attenuated in immunosuppressed people.

Question 19

List some vaccine-preventable viral infections.

Answer 19

Measles, Mumps, Rubella
Varicella-zoster
Rotavirus
Hep A, B
Papilloma Virus
Rotavirus
Polio