26 - Antiviral Vaccines and Therapies

Question 1

Examples of antiviral targets

Answer 1

Fusion proteins, proteases, and polymerases

Question 2

Effective antiviral drugs also have good pharmacological properties

Answer 2

• Whether the drug has side effects
• Whether it can be taken orally
• How long it persists in the human body
• How the human body breaks down or otherwise modifies the drug

Question 3

Challenges to development of effective antiviral agents

Answer 3

• Viruses replicate intracellularly
• Some viruses establish latent infections (treating active infection does not cure disease)
• Different viruses (especially respiratory viruses) cause similar symptoms, making diagnosis difficult
• Generation of drug resistance

Question 4

HIV RT

Answer 4

Heterodimer composed of 2 subunits (p66 and p51)

Question 5

Nucleoside RT inhibitors (NRTIs) binding site

Answer 5

Bind at the Pol active site

Question 6

Non-nucleoside RT inhibitors (NNRTIs) binding site

Answer 6

Bind in a nearby hydrophobic binding pocket

Question 7

Nucleoside Reverse Transcriptase Inhibitors (NRTIs)

Answer 7

• Competitive inhibitors of viral polymerases (including HIV RT)
• Compete with natural dNTP/NTP substrates for incorporation into the nascent viral nucleic acid, and so act as chain terminators

Question 8

AZT

Answer 8

• Azido (NH3) group on the ribose instead of a hydrogen
• DNA synthesis blocked

Question 9

Resistance to NRTIs

Answer 9

• Emergence of discriminatory mutations
• Allow viral RT to preferentially select naturally occurring deoxynucleotides present in the cell

Question 10

Non nucleoside RT inhibitors

Answer 10

• Bind to p66 subunit at a hydrophobic pocket distant from the active site of the enzyme, causes conformational change that alters active site
• Useful in combination with other drugs
• E.g Nevirapine used to reduce transmission from mother to child during birth

Question 11

How do second gen NNRTIs differ from first gen

Answer 11

In its ability to bind at this site despite the presence of some mutations that limit the efficacy of first-generation agent

Question 12

2 catalytic reactions of proviral integration

Answer 12

• 3’-processing in the host-cell cytoplasm to prepare proviral strands for attachment
• Strand transfer whereby proviral DNA is covalently linked to cellular DNA

Question 13

INSTIs (Integrase Inhibitors)

Answer 13

Competitively inhibit the strand transfer reaction by binding metallic ions in the active site

Question 14

Fusion inhibitors

Answer 14

• First class of antiretroviral medications to target HIV replication cycle extracellularly
• Fusion inhibitors act extracellularly to prevent fusion of HIV to the CD4 molecule

Question 15

Medication ending in ‘mab’

Answer 15

Monoclonal antibody

Question 16

Post attachment inhibitors

Answer 16

Bind to domain2 (D2) of CD4 and prevent normal structural, conformational change required for attachment

Question 17

Resistance to CCR5 antagonist

Answer 17

Occur when R5 tropic HIV 1 develops mutations that facilitate gp120-CCR5 binding despite Maravirox attachment to CCR5

Question 18

Protease inhibitors

Answer 18

Competitive inhibitors that bind directly to HIV-1 protease catalytically active site and prevent cleavage of polypeptides

Question 19

Virologic rebound

Answer 19

Defined as confirmed detectable HIV RNA (greater than 200 copies/mL plasma) after virologic suppression

Question 20

Reemergence of wild type HIV after ceasing antiretroviral therapy

Answer 20

• Discontinuation of the antiretroviral therapy regimen will remove the selective pressure on HIV
• Reversion to wild type virus
• WT virus may have greater replicative fitness than mutant , drug resistant virus
• Growth of WT virus may outpace resistant virus reemergence of a largely WT population

Question 21

Drugs for HSV and VZV

Answer 21

• Oral agents (e.g. Acyclovir)
• Opthalmic
• Topical agents

Question 22

Acyclovir mechanism of action

Answer 22

• Guanosine analog that is active against herpesviruses
• Taken up by herpesvirus-infected cell
• Viral encoded thymidine kinase (TK) phosphorylates to ACV monophosphate
• Cellular enzymes convert to ACV triphosphate
• HSV TK selectively phosphorylates guanosine analogs such as ACV
• Inhibits function of viral DNA polymerase (analogs act as DNA chain terminators)

Question 23

What is acyclovir active against

Answer 23

Active against HSV-I; HSV-2; VZV

Question 24

Gancyclovir

Answer 24

• Acyclic analog of the nucleoside guanosine
• Inhibits viral DNA polymerases more than cellular DNA polymerases

Question 25

Influenza agents

Answer 25

Amantadine

Question 26

Amantadine

Answer 26

Target IVA M2 protein ion channel

Question 27

Function of M2 protein ion channel

Answer 27

• Derived from host cell
• Dissociation of influenza virus RNA from ribonuclear proteins (by acidification of virion interior via M2)

Question 28

Zanamivir and Oseltamivir

Answer 28

• NA inhibitors
• Analogs of sialic acid

Question 29

Passive immunisation

Answer 29

Immune globulins (e.g. HBV immune globulin)

Question 30

Key to global control of viral infections

Answer 30

Vaccination