The Mechanism of Action of Anti-Viral Drugs

Question 1

what are viruses

Answer 1

obligate intracellular parasites

Question 2

what are the current classifications

Answer 2

– Type and structure of the nucleic acid virion and the strategy used in its replication
– Symmetry of the capsid (icosahedral v helical)
– Presence or absence of a lipid membrane (envelope)

Question 3

what’re the stages in a viral life cycle

Answer 3

1. Attachment
2. Penetration - by endocytosis
3. Disassembly
4. Transcription
5. Translation
6. Replication
7. Assembly
8. Release

Question 4

what are the three broad group of treatments

Answer 4

– Virucides – directly inactivate viruses

– Antivirals – inhibit replication at the cellular level

– Immunomodulators

Question 5

Targets for antiviral drugs

Answer 5

• Entry inhibition – virus binding to host cells
• Viral uncoating/disassembly e.g. amantadine/rimantadine
• Viral replication
• Viral polymerases e.g. HIV reverse transcriptase, HBV
• Viralproteasese.g.HIV,HCV
• Integrase
• Viral release inhibitors (neuraminidase)

Question 6

Retroviruses

Answer 6

• Positive sense single stranded RNA virus
• Contains reverse transcriptase (RT) - an RNA-dependent DNA
polymerase, which makes a DNA copy of the viral RNA
• This DNA copy is integrated into the genome of the host cell
and it is then termed a provirus
• The provirus DNA is transcribed into both new genomic RNA and mRNA for translation into viral proteins using host cell machinery
• Some RNA retroviruses can transform normal cells into malignant cells

Question 7

examples of retroviruses

Answer 7

HIV, human T cell leukaemia virus

Question 8

the binding of HIV

Answer 8

Binds to CD4 and either CCR5 or CXCR4

Question 9

what mediates HIV entry

Answer 9

Entry of HIV into a new cell is mediated by the Env glycoprotein spike (a trimer of gp120 and gp41)
Entry requires the receptor CD4 plus one of two co-receptors, CCR5 or CXCR4

Question 10

HAART

Answer 10

• Combination therapy–classically 2NRTIs and additional drug from another class
• Prevention of morbidity and mortality associated with chronic HIV infection, at low cost of drug toxicity
• Reduction in sexual and vertical transmission of HIV
• Restore and preserve immunological function

Question 11

RNA viruses

Answer 11

• RNA viruses are classified according to the sense (polarity) of their RNA

Question 12

what are the two types of RNA virus

Answer 12

– Positive-sense viral RNA - similar to mRNA and can be immediately translated by the host cell
– Negative-sense viral RNA - complementary to mRNA and must be converted to positive-sense by an RNA dependent RNA polymerase before translation

Question 13

what are the three types of RNA genome

Answer 13

dsRNA, +ssRNA, -ssRNA

Question 14

where does virus replication occur

Answer 14

• Typically virus replication occurs in the host cell cytoplasm not
the nucleus

Question 15

examples of RNA viruses

Answer 15

influenza, hepatitis C virus

Question 16

Hepatitis C virus

Answer 16

• Flaviviridae family
– positive sense, single stranded RNA virus
– primarily transmitted through parenteral route, sexual transmission also recognised
– causes acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma

• Mainstay of therapy for many years was pegIFNα and ribavirin – now IFN-free combinations are first line

Question 17

Influenza

Answer 17

• Orthomyxoviridae
– 3 distinct types: A, B and C
– enveloped, negative sense, single-stranded RNA virus
– Viral NA – catalyses removal of terminal sialic acids from glycoprotein. Allows mobility and elution of viral progeny

Question 18

DNA viruses

Answer 18

1. Entry of the viral DNA into the host cell nucleus
2. Mostly use cellular enzymes for transcription and replication of their genomes
3. Early and late mRNA transcripts are synthesized; early = regulatory proteins and proteins for DNA replication, late = structural proteins

Question 19

examples of DNA viruses

Answer 19

herpes simplex virus, human papilloma virus, hepatitis B virus

Question 20

Hepatitis B virus

Answer 20

• Hepadnavirus
– enveloped, partially dsDNA virus, genome maintained in circular confirmation
– causes acute and chronic hepatitis, cirrhosis and hepatocellular carcinoma
– replication occurs via RNA intermediate (template for HBV polymerase)

Question 21

Treatment of chronic HBV -• Immunomodulatory - pegylated IFNα

Answer 21

– Recombinant version of human IFN
– Variable response
– Finite treatment – 48 weeks
– AE = flu like illness, myalgia, depression, autoimmunity