1. What if a Drug that Was Developed to Treat HIV Infection Could Actually Help to Cure It?
Mark A Wainberg
McGill University AIDS Centre
Jewish General Hospital
Montreal, Quebec, Canada

2. InI Dissociation from WT IN-DNA Complex at 37°C
DTG
RAL
EVG
1.0
INI
koff (s-1)
t1/2 (h)
DTG
2.7 x 10-6 71
RAL
22 x 10-6
8.8
EVG
71 x 10-6
2.7
0.8
0.6
Relative binding
0.4
0.2
0.0
Key point
DTG dissociated more slowly from the WT-IN-DNA complex at 37oC with a dissociation rate of 2.7x10–6 s–1 and a dissociative half life (t1/2) of 71 hours, significantly longer than t1/2 for RAL (8.8 hours) and EVG (2.7 hours; p<0.0001).
Additional notes
Both RAL and EVG dissociated more quickly than DTG (p<0.0001) with Koff values of 22 x 10-6 s-1 for RAL and 71 x 10-6 s-1 for EVG.
Slow dissociation occurs as the molecular architecture of INI-DNA complex is resistant to substitutions due to stronger co-ordination bonds holding the complex together. This may lead to improvements in efficacy, or reduced probability of resistance emergence.
Reference
Hightower, KE, et al. Antimicrob Agents Chemother 2011; 55(10): 4552–59 10 20 30 40 50 60
Time (h)
DTG dissociated more slowly from a WT IN-DNA complex at 37°C compared with RAL and EVG
DTG dissociation was eight times longer than RAL and 26 times slower than EVG
Koff , dissociation rate; t1/2h, half-life in hours
Adapted from Hightower KE, et al. Antimicrob Agents Chemother 2011;5:4552–9

3. The R263K mutation decreases integrase activity in cell-free assays
Quashie, Mesplède et al., Journal of Virology, 2012

4. The addition of H51Y to R263K further decreases IN strand transfer activityB

5. The combination of H51Y and R263K negatively impacts viral fitness

6. Virus
Weeks 8-15 WT
M184V
H51Y
M184I
R263K
H51Y/R263K
None
G118R
H51Y/G118R

7. Replication Capacity of HIV Containing Various Combinations of INSTI Resistance Mutations
% fitness
E92Q
≈ 75%
Y143
≈ 72%
Q148
N155
R263K
≈ 70%
G140/Q148
≈ 95%
R263K/H51Y
≈ 25%
R263K/E138K
R263K/Q148R
R263K/Y143C
R263K/E92Q

8. Selection of HIV-1 containing R263K with RAL and EVG
Time
(weeks)
Initial Mutation
Acquired Mutations
EVG 30
R263K
M50I, T66I
RAL
--- 38
T97A/T, Y143H/Y, Q148K/Q 41
T97A, Y143R

9. No compensatory mutations in regard to DTG resistance and viral fitness have developed over more than three years in culture.

10. Hypotheses
Viruses resistant to DTG via the R263K pathway should not be transmissible because of low viral fitness
A series of judicious treatment interruptions followed by the use of DTG could conceivably convert viruses that are archived into attenuated forms. This subject should first be addressed in suitable animal models.

11. Acknowledgements Bluma Brenner Hongtao Xu Dimitri Coutsinos
Jerry Zaharatos
Maureen Oliveira
Thibault Mesplède
Peter Quashie

12. Thanks to CIHR and CANFAR