Antivirals

Question 1

What is the basic pathogenesis of HIV?

Answer 1

Get a primary infection where you get a burst of virus
This then comes under control of the hosts immune system to some extent and you get a clinical latency with no symptoms
The CD4 count then starts to fall and you see a loss of viral control and start to get symptoms

Question 2

What are the 2 main types of viral infections?

Answer 2

Acute or chronic

Question 3

Name 5 common acute viral infections?

Answer 3

1) Influenza
2) Measles
3) Mumps
4) Hepatitis A

Question 4

What are the 2 types of chronic viral infections?

Answer 4

1) Latent with (or without) recurrences

2) Persistent

Question 5

Give 2 examples of latent chronic viral infections?

Answer 5

1) Herpes simplex

2) Cytomegalovirus

Question 6

Give 3 examples of persistent chronic viral infections?

Answer 6

1) HIV
2) Hepatitis B virus
3) Hepatitis C virus

Question 7

What is meant by the term ‘viruses are obligate intracellular parasites’?

Answer 7

They need to infect host cells to cause disease

Question 8

What is the rough structure of a virus?

Answer 8

1) Nucleic acid (either DNA or RNA)
2) Protein (coat, structural, enzymes - non-structural)
3) +/- lipid envelope

Question 9

Viruses have a structured genome, what 3 kinds of genes can be found within it?

Answer 9

1) Those coding for core structural proteins
2) Those coding for viral enzymes
3) Those coding for envelope structural proteins

Question 10

What is the importance of LTRs (long terminal repeats) in a viral genome?

Answer 10

Enable integration into host genome

Question 11

What are the 8 steps in virus infection and replication?

Answer 11

1) Virus attachment to cell (via receptor)
2) Cell entry
3) Virus uncoating
4) Early proteins produced - viral enzymes
5) Replication
6) Late transcription/translation - viral structural proteins
7) Virus assembly
8) Virus release

Question 12

How can virus replication be used in development of anti-viral therapy?

Answer 12

All viruses encode unique proteins, many of which are vital for virus replication and infectivity
These unique proteins are targets for molecular inhibition

Question 13

What are the 4 types of polymerases and what type of organism is each found in?

Answer 13

1) DNA to DNA: found in eukaryotes and DNA viruses
2) DNA to RNA: found in eukaryotes and DNA viruses
3) RNA to RNA: found in RNA viruses
4) RNA to DNA: found in retroviruses (HIV) and Hepatitis B virus

Question 14

Azidothymidine was originally developed as a drug to treat what?

Answer 14

Anti-cancer drug

Question 15

What is the mode of action of Azidothymidine (AZT)?

Answer 15

Nucleoside reverse transcriptase inhibitor NRTI

It mimics the building blocks used to make DNA and blocks the enzyme

Question 16

What do nucleoside reverse transcriptase inhibitors do?

Answer 16

Inhibit reverse transcriptase

Question 17

What are the 2 types of nucleoside reverse transcriptase inhibitors?

Answer 17

Pyrimidine analogues

Purine analogues

Question 18

Name 2 NRTIs which are pyrimidine analogues?

Answer 18

Zidovudine (thymidine analogues)

Lamivudine (cytosine analogues)

Question 19

Name 2 NRTIs which are purine analogues?

Answer 19

Abacavir and tenofovir

Question 20

Why can NRTIs be useful in therapy for duel infection of HIV and Hepatitis B?

Answer 20

Hepatitis B contains the reverse transcriptase enzyme

Some NRTIs are also active against HBV

Question 21

What are NNRTIs (non-nucleoside reverse transcriptase inhibitors)?

Answer 21

Block reverse transcriptase but don’t look like nucleotides and bind to a different part of the protein

Question 22

Name 2 NNRTIs (non nucleoside reverse transcriptase inhibitors)?

Answer 22

Efavirenz

Nevirapine

Question 23

Why can protease inhibitors be used without causing toxicity?

Answer 23

Although human cells contain proteases, viruses often contain their own unique proteases - PIs inhibit these unique proteases and you don’t get toxicity

Question 24

Why is Ritonavir, a protease inhibitor, particularly useful?

Answer 24

It boosts the levels of other protease inhibitors, allowing the use of less drugs to combat the virus thus reducing side effects

Question 25

Name a protease found in HIV which is targeted by protease inhibitors?

Answer 25

Aspartate protease of HIV

Question 26

Enfuviritide is a newer drug used to treat HIV given by IM injection, it is a fusion inhibitor, what is meant by this and why is it given as an IM injection?

Answer 26

blocks the fusion of the virus with the membrane | Has to be given by IM injection because its only a peptide

Question 27

Raltegravir is a newer drug used to treat HIV, it is an integrase inhibitor, what part of the cell cycle does it affect?

Answer 27

Affects the replication strategy of the virus - cant get its DNA integrated into cell DNA

Question 28

Maroviroc is a new drug to treat HIV which inhibits binding of the virus to CD4 cells how?

Answer 28

Chemokine receptor antagonist | HIV requires CD4 receptor but also co-receptors, Maroviroc blocks one of these co-receptors, the CCR-5 receptor

Question 29

What is HAART (Highly active antiretroviral therapy)?

Answer 29

``` 2NRTIs + NNRTI 2NRTIs + boosted PI Started when CD4 falls Aim to switch off virus replication Taken life long Suppression for more than 10 years However there are starting to be problems with toxicity ```

Question 30

Why are viral mutations common, how can this affect HIV treatment?

Answer 30

Viruses are highly replicative They have a mutational ability to respond when conditions change The error rating in reverse transcriptase suggests every HIV genome will have some sort of mutations, the right mutation can result in resistance to drugs

Question 31

Give the mutation in HIV which would lead to resistance to Lamivudine?

Answer 31

M184V mutation results in resistance to Lamivudine | In the presence of Lamivudine the rare population of strains with this mutation will soon predominate

Question 32

5 years ago HIV infection was cured in one person, how?

Answer 32

A bone marrow transplant from a donor with absent CC5 co-receptor for HIV HIV was suppressed on antivirals Existing CD4 lymphocytes were destroyed by conditioning Stem cells reconstituted with HLA matched by delta 32 homozygous allogeneic donor Antiviral therapy stopped following transplantations Remained HIV negative

Question 33

What are inteferons?

Answer 33

naturally occurring antivirals present in our own cells

Question 34

How has hepatitis C therapy changed in the last 3 years?

Answer 34

Interferons and ribavirin were used which achieved cure rates of 40-90% depending on virus genotype - they were however an IM injection and made people feel generally unwell Last 3 years have seen an increasing number of directly acting antivirals against various virus proteins Now have interferon free regimes with >90% cure rates for all strains

Question 35

Why can interferons be used in anti-viral therapy?

Answer 35

Administering an exogenous source of interferons can boost viral resistance - having a non specific antiviral effect

Question 36

When do antivirals work to treat acute infections?

Answer 36

In general only if given soon after symptoms develop