L8 - HIV (4)

Question 1

What are the 3 classes of drugs licensed for ‘STANDARD’ therapy?

Answer 1

NRTIs
NNRTIs
Protease inhibitors

Question 2

What is HAART?

Answer 2

Highly active AntiRetroviral Therapy (HAART)

triple therapy

2 NRTIs + NNRT or PI

Question 3

What happens if you stop taking HAART?

Answer 3

the virus will come back

Question 4

Where do NRTIs target?

Answer 4

reverse transcription step

Question 5

Where do NNRTIs target?

Answer 5

reverse transcription step

Question 6

Where do PIs targets?

Answer 6

virion maturation after virion release

Question 7

What are NRTIs?

Answer 7

Nucleoside analogue RT inhibitors

inhibit HIV reverse transcriptase

Question 8

examples of NRTIs?

Answer 8

AZT - azidothymidine - analogue of thymidine

ddC- analogue of deoxycytidine

ddI - analogue of adenosine

Question 9

What are problems with NRTIs?

Answer 9

toxicity

resistance

Question 10

What disease was AZT first shown to inhibit?

Answer 10

MLV

Question 11

What are NNRTIs?

Answer 11

Non-nucleoside RT inhibitors

target site - NOT ACTIVE SITE

Question 12

examples of NNRTIs?

Answer 12

Efavirenz
Nevirapine
Etravirine
Delavirdine

ALL VERY DIFF STRUCTURES

Question 13

Where does cleavage occur when HIV matures?

Answer 13

Cleavage of Gag and Gag-pol into individual peptides

Question 14

Examples of PIs?

Answer 14

Saquinavir

Nelfinavir

Question 15

What are pros of HAART?

Answer 15

avoids cross resistance

treatment interruptions to remove selective pressure

reduce viral load & disease progression

Question 16

What are cons of HAART?

Answer 16

Cost

compliance

side effects

drug-drug interaction

post-therapy reversion

Question 17

What is an entry inhibitor for HIV?

Answer 17

Maraviroc

CCR5 antagonist

salvage therapy in patients with R5 virus

Question 18

What is T-20?

Answer 18

peptide based entry inhibitor - ENFUVIRTIDE

blocks conformational changed in fusion of viral-cellular membranes by gp41 fusion domain

Question 19

What is the clinical name for T-20?

Answer 19

Enfuvirtide (ENF)

Fuzeon

Question 20

How does Enfuvirtide work?

Answer 20

prevents membrane fusion by causing a block in the pre-hairpin intermediate

Question 21

What is integrase?

Answer 21

catalyses independent events

resulting in cleavage of host DNA, splicing of provirus into cleavage site

Question 22

What are the 3 domains of Integrase?

Answer 22

HHCC - zinc binding

Core - catalytic

DNA binding domain

Question 23

examples of inhibtors of integrase?

Answer 23

Raltegravir
Elvitegravir
Doltegravir

Question 24

What are problems in developing AIDS vaccine?

Answer 24

HIV genetic variability

Animal models

Clinical trials - Phase I/II and III

moral issues

Question 25

What are phase I/II clinical trials for?

Answer 25

safety & immunology

Question 26

What are phase III clinical trials for?

Answer 26

efficacy

Question 27

What are features of candidate AIDS vaccines?

Answer 27

envelope glycoprotein based rarely induced CD8+ CTL responses - swerve towards antibody response, do not work very well combination vaccine: prime-boost

Question 28

What is the combination vaccine: prime-boost?

Answer 28

prime - recombinant canarypox boost - recombinant gp120

Question 29

What is AIDSVAX?

Answer 29

Bivalent vaccine only stimulated humoral immunity no effect on vaccinated vs. placebo

Question 30

What are some comments on the 'AIDSVAX failure'?

Answer 30

worked better on Black/Asian participants

Question 31

What is RV144 vaccine?

Answer 31

prime - recombinant canarypox expressing gp120 (ALVAC) boost - AIDSVAX recombinant gp120 barely any diff. between vaccinated and placebo

Question 32

How could RV144 be better if virus matched vaccine at certain aa positions?

Answer 32

efficacy improves to 48% or 78%!

Question 33

What are future thoughts for HIV therapy?

Answer 33

bnAbs - broadly neutralising antibodies target conserved region of Env trimer

Question 34

What are challenges for the future thoughts of HIV therapy?

Answer 34

instable Env trimer 50% Env = glycan sequence variation