L8 - HIV (4) Flashcards
What are the 3 classes of drugs licensed for ‘STANDARD’ therapy?
NRTIs
NNRTIs
Protease inhibitors
What is HAART?
Highly active AntiRetroviral Therapy (HAART)
triple therapy
2 NRTIs + NNRT or PI
What happens if you stop taking HAART?
the virus will come back
Where do NRTIs target?
reverse transcription step
Where do NNRTIs target?
reverse transcription step
Where do PIs targets?
virion maturation after virion release
What are NRTIs?
Nucleoside analogue RT inhibitors
inhibit HIV reverse transcriptase
examples of NRTIs?
AZT - azidothymidine - analogue of thymidine
ddC- analogue of deoxycytidine
ddI - analogue of adenosine
What are problems with NRTIs?
toxicity
resistance
What disease was AZT first shown to inhibit?
MLV
What are NNRTIs?
Non-nucleoside RT inhibitors
target site - NOT ACTIVE SITE
examples of NNRTIs?
Efavirenz
Nevirapine
Etravirine
Delavirdine
ALL VERY DIFF STRUCTURES
Where does cleavage occur when HIV matures?
Cleavage of Gag and Gag-pol into individual peptides
Examples of PIs?
Saquinavir
Nelfinavir
What are pros of HAART?
avoids cross resistance
treatment interruptions to remove selective pressure
reduce viral load & disease progression
What are cons of HAART?
Cost
compliance
side effects
drug-drug interaction
post-therapy reversion
What is an entry inhibitor for HIV?
Maraviroc
CCR5 antagonist
salvage therapy in patients with R5 virus
What is T-20?
peptide based entry inhibitor - ENFUVIRTIDE
blocks conformational changed in fusion of viral-cellular membranes by gp41 fusion domain
What is the clinical name for T-20?
Enfuvirtide (ENF)
Fuzeon
How does Enfuvirtide work?
prevents membrane fusion by causing a block in the pre-hairpin intermediate
What is integrase?
catalyses independent events
resulting in cleavage of host DNA, splicing of provirus into cleavage site
What are the 3 domains of Integrase?
HHCC - zinc binding
Core - catalytic
DNA binding domain
examples of inhibtors of integrase?
Raltegravir
Elvitegravir
Doltegravir
What are problems in developing AIDS vaccine?
HIV genetic variability
Animal models
Clinical trials - Phase I/II and III
moral issues
What are phase I/II clinical trials for?
safety & immunology
What are phase III clinical trials for?
efficacy
What are features of candidate AIDS vaccines?
envelope glycoprotein based
rarely induced CD8+ CTL responses - swerve towards antibody response, do not work very well
combination vaccine: prime-boost
What is the combination vaccine: prime-boost?
prime - recombinant canarypox
boost - recombinant gp120
What is AIDSVAX?
Bivalent vaccine
only stimulated humoral immunity
no effect on vaccinated vs. placebo
What are some comments on the ‘AIDSVAX failure’?
worked better on Black/Asian participants
What is RV144 vaccine?
prime - recombinant canarypox expressing gp120 (ALVAC)
boost - AIDSVAX recombinant gp120
barely any diff. between vaccinated and placebo
How could RV144 be better if virus matched vaccine at certain aa positions?
efficacy improves to 48% or 78%!
What are future thoughts for HIV therapy?
bnAbs - broadly neutralising antibodies
target conserved region of Env trimer
What are challenges for the future thoughts of HIV therapy?
instable Env trimer
50% Env = glycan
sequence variation
