HIV- treatment Flashcards
HIV can be treated but not cured. What are the three classes of drugs licensed for standard therapy?
What % reduction in viraemia is seen in the last therapy?
Nucleoside analogue reverse transcriptase inhibitors (NRTI) e.g AZT, ddI, ddC
Non-nucleoside reverse transcriptase inhibitors (NNRTI) e.g nevirapine and protein inhibitors e.g saquinavir
Highly Active AntiRetroviral Therapy (HAART)
-triple therapy, usually two NRTIs and NNRTI or PI
99% reduction in viraemia
Which parts of the HIV life cycle do the therapies target?
NRTIs and NNRTIs target just before reverse transcription and PIs target at virion release before maturation of the virus
HAART therefore uses combinations of these to stop the virus
HIV-1 reverse transcription structure is well known. Explain what you know about it.
Dimer formed from P66 and P51
RNAse H is present in p66 which is important in transcription- p66 is the catalytically active one
Has a thumb and finger shape
How do NRTIs work?
Deoxythymidine is a normal building block of DNA. Triphosphorylation of naturally found deoxythymidine makes AZT and this prevents elongation of the protein. This is the NRTI, it basically tricks reverse transcriptase into incorporating one of these instead of a normal one.
AZT has a high affinity for reverse transcriptase as this does not pick up the mistake as much as the cellular polymerase
What are the problems that can occur due to NRTIs?
Toxicity as these AZTs can be incorporated into normal cells and cause cell death
Resistance can occur due to mutations in reverse transcriptase
What was AZT first synthesised as in 1964?
What previously mentioned virus was it shown to inhibit?
Why was it used in combination therapies and not on its own?
As an anti-tumour agent (this was before discovery of HIV)
MLV inhibition
AZT was used in combination therapy as on its own, the virus mutated and became resistant
What other examples are there of NRTIs?
ddI- modified Adenosine
ddC- modified Deoxycytidine
Which other therapy targets the virus by inhibiting reverse transcriptase?
What are three examples?
NNRTIs- these all bind to the active site of reverse transcriptase
Efavirenz, Nevirapine and Entravirine
Protein inhibitors act before maturation. Maturation is what makes the virus infectious- before that, it cannot produce more viruses. Embedded into the membrane of the virus is the Gag proteins and the Gag-Pol proteins due to the fatty acid which sticks them onto the membrane. Protease is part of the Pol reading frame. What does it do?
Cleaves all the proteins and itself from the precursors so the matrix antigen stays in the membrane whilst all the others condense in to make the capsid with the virus RNA and the required enzymes for reverse transcription
Where do the protein inhibitors act upon and are they cell specific?
They act to block the protease and are specific to HIV poteases so do not affect other cells
What are the pros of HAART therapy?
Can manipulate treatment to avoid resistance- mutations to make virus resistant to certain medications are known, so if there are signs of the mutation, the patient is swapped to another drug
Treatment interruptions- patients taken off all treatment so no selective advantage of the resistant viruses as the selective pressure is removed; the fitness cost of the resistant ones means they don’t survive
Highly effective at reducing viral load and disease progression
What are the cons of HAART therapy?
Cost
Compliance: effects on lifestyles- used to have to take it at certain times of the day
Side effects
Drug-drug interactions
Post-therapy reversion- virus comes back, not curable
Some patients do not respond to any of the mentioned treatments so undergo Salvage therapy. What is Maraviroc (made by Pfizer)?
An antiviral that targets entry inhibition- prevents the virus interacting with its coreceptor, CCR5 (does not affect CCR5 signalling)
This is obviously for patients in the early phase rather than late as CxCR4 receptor is used later on
What is T-20?
A peptide based entry inhibitor that blocks conformational change involved in fusion of viral and cellular membranes by gp41 fusion domain
Tested in 16 patients- no toxicity whilst reducing viral load by 100-fold
Other studies found this was very effective in combination with other drugs
What name is now given to T-20 now it has been licensed for salvage therapy?
How is it taken?
Is it cheap?
Can resistance develop?
Enfurvirtide (ENF)
Two daily injections
Expensive as only small quantities are available
Resistance can develop resistance
Are there any more peptide fusion inhibitors in development?
TRI1144
What is the Enfuvirtide mechanism of action?
The virus binds to the CD4 cell surface and undergoes a conformational change so that its gp41 molecule will stick into the membrane of the host cell (called a pre-hairpin intermediate). Then the membranes are pulled together and this involves a coil. The enfurvitide binds into that coil to prevent the fusion of membranes
Another target is the Integrase which is good as it is unique to the virus cycle. What does this enzyme do?
What treatment is available for this?
Helps integration of viral genome into host genome
Raltegravir (by Merck) targets the integrase
So what treatments can we use to target the following stages in the virus life cycle:
Before fusion Fusion Before reverse transcription Integration into the host cell's chromosome Maturation
Before fusion: Maraviroc Fusion: Enfurvirtide Reverse transcription: NRTI/NNRTI Integration: Raltegravir Maturation: PI
What future therapy for HIV was researched in Leeds?
HIV-1 Nef protein structure is well known and using a rational drug design in silico approach, it is possible to identify small molecules that bind into the pocket of it so this was done for Nef cavity (this is involved in CD4 down modulation)
Did the research done at Leeds with Nef and CD4 down modulation work?
Three compounds were found to reduce the levels of CD4 down modulation but unfortunately had no effect on viral replication
What are the problems in developing in AIDS vaccine?
Nature of protective immunity- should it be humoral or cellular? Antibody response? What sort of immunity is needed?
HIV genetic variability - Envelope genes-10 genetic subtypes- many geographical places so some vaccines won’t work in other places so which one should be used?
Animal models- not allowed to work on Chimps
Clinical trials- vaccines may cause side effects/toxic etc
Moral/ethical issues
There have been over 60 phase 1 trials of 30 candidate vaccines so far. What part of the virus was concentrated on and why?
Envelope glycoproteins as it is on the outside of virus particle/ most immunogenic
The trials have been safe but why have they not been developed further?
No CD8 cytotoxic T-cell reponse
Why did AIDVAX fail?
No statistical significance between vaccinated people and non-vaccinated
RV144 vaccine was a prime-boost one. What were the results from this study?
Slight difference but ongoing study- not that effective
