Antivirals Flashcards
What is the basic pathogenesis of HIV?
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
What are the 2 main types of viral infections?
Acute or chronic
Name 5 common acute viral infections?
1) Influenza
2) Measles
3) Mumps
4) Hepatitis A
What are the 2 types of chronic viral infections?
1) Latent with (or without) recurrences
2) Persistent
Give 2 examples of latent chronic viral infections?
1) Herpes simplex
2) Cytomegalovirus
Give 3 examples of persistent chronic viral infections?
1) HIV
2) Hepatitis B virus
3) Hepatitis C virus
What is meant by the term ‘viruses are obligate intracellular parasites’?
They need to infect host cells to cause disease
What is the rough structure of a virus?
1) Nucleic acid (either DNA or RNA)
2) Protein (coat, structural, enzymes - non-structural)
3) +/- lipid envelope
Viruses have a structured genome, what 3 kinds of genes can be found within it?
1) Those coding for core structural proteins
2) Those coding for viral enzymes
3) Those coding for envelope structural proteins
What is the importance of LTRs (long terminal repeats) in a viral genome?
Enable integration into host genome
What are the 8 steps in virus infection and replication?
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
How can virus replication be used in development of anti-viral therapy?
All viruses encode unique proteins, many of which are vital for virus replication and infectivity
These unique proteins are targets for molecular inhibition
What are the 4 types of polymerases and what type of organism is each found in?
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
Azidothymidine was originally developed as a drug to treat what?
Anti-cancer drug
What is the mode of action of Azidothymidine (AZT)?
Nucleoside reverse transcriptase inhibitor NRTI
It mimics the building blocks used to make DNA and blocks the enzyme
What do nucleoside reverse transcriptase inhibitors do?
Inhibit reverse transcriptase
What are the 2 types of nucleoside reverse transcriptase inhibitors?
Pyrimidine analogues
Purine analogues
Name 2 NRTIs which are pyrimidine analogues?
Zidovudine (thymidine analogues)
Lamivudine (cytosine analogues)
Name 2 NRTIs which are purine analogues?
Abacavir and tenofovir
Why can NRTIs be useful in therapy for duel infection of HIV and Hepatitis B?
Hepatitis B contains the reverse transcriptase enzyme
Some NRTIs are also active against HBV
What are NNRTIs (non-nucleoside reverse transcriptase inhibitors)?
Block reverse transcriptase but don’t look like nucleotides and bind to a different part of the protein
Name 2 NNRTIs (non nucleoside reverse transcriptase inhibitors)?
Efavirenz
Nevirapine
Why can protease inhibitors be used without causing toxicity?
Although human cells contain proteases, viruses often contain their own unique proteases - PIs inhibit these unique proteases and you don’t get toxicity
Why is Ritonavir, a protease inhibitor, particularly useful?
It boosts the levels of other protease inhibitors, allowing the use of less drugs to combat the virus thus reducing side effects
Name a protease found in HIV which is targeted by protease inhibitors?
Aspartate protease of HIV
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?
blocks the fusion of the virus with the membrane
Has to be given by IM injection because its only a peptide
Raltegravir is a newer drug used to treat HIV, it is an integrase inhibitor, what part of the cell cycle does it affect?
Affects the replication strategy of the virus - cant get its DNA integrated into cell DNA
Maroviroc is a new drug to treat HIV which inhibits binding of the virus to CD4 cells how?
Chemokine receptor antagonist
HIV requires CD4 receptor but also co-receptors, Maroviroc blocks one of these co-receptors, the CCR-5 receptor
What is HAART (Highly active antiretroviral therapy)?
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
Why are viral mutations common, how can this affect HIV treatment?
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
Give the mutation in HIV which would lead to resistance to Lamivudine?
M184V mutation results in resistance to Lamivudine
In the presence of Lamivudine the rare population of strains with this mutation will soon predominate
5 years ago HIV infection was cured in one person, how?
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
What are inteferons?
naturally occurring antivirals present in our own cells
How has hepatitis C therapy changed in the last 3 years?
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
Why can interferons be used in anti-viral therapy?
Administering an exogenous source of interferons can boost viral resistance - having a non specific antiviral effect
When do antivirals work to treat acute infections?
In general only if given soon after symptoms develop
