What if a Drug that Was Developed to Treat HIV Infection Could Actually Help to Cure It?
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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
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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. InI Dissociation from WT IN-DNA Complex at 37°C. DTG RAL EVG. 1.0. 0.8. 0.6. Relative binding. - PowerPoint PPT Presentation
Transcript of What if a Drug that Was Developed to Treat HIV Infection Could Actually Help to Cure It?
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 HospitalMontreal, Quebec, Canada
CONFIDENTIAL – NOT FOR DISSEMINATION
INI DISSOCIATION FROM WT IN-DNA COMPLEX AT 37°C
Adapted from Hightower KE, et al. Antimicrob Agents Chemother 2011;5:4552–9
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
Koff , dissociation rate; t1/2h, half-life in hours
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
DTGRALEVG
1.0
0.8
0.6
0.4
0.2
0.0
Rela
tive
bind
ing
Time (h)
0 10 20 30 40 50 60
The R263K mutation decreases integrase activity in cell-free assays
B
0 5 10 15 20 250
5000
10000
15000
20000ININR263K
[Target DNA] (nM)
RFU
INR263K
0
5000
10000
15000
20000
RFU
C Quashie, Mesplède et al., Journal of Virology, 2012
The addition of H51Y to R263K further decreases IN strand transfer activity
A B
The combination of H51Y and R263K negatively impacts viral fitness
Virus Weeks 8-15
WT M184VH51Y M184IR263K M184IH51Y/R263K NoneG118R NoneH51Y/G118R None
Selection of DTG-Resistant Viruses with 3TC
Replication Capacity of HIV Containing Various Combinations of INSTI Resistance Mutations
Mutation(s) % fitnessE92Q ≈ 75%Y143 ≈ 72%Q148 ≈ 75%N155 ≈ 75%R263K ≈ 70%G140/Q148 ≈ 95%R263K/H51Y ≈ 25%R263K/E138K ≈ 25%R263K/Q148R 0R263K/Y143C 0R263K/E92Q 0
Selection of HIV-1 containing R263K with RAL and EVG
Time(weeks)
Initial Mutation Acquired Mutations
EVG 30 R263K M50I, T66I
RAL 30 R263K ---
RAL 38 --- T97A/T, Y143H/Y, Q148K/Q
RAL 41 --- T97A, Y143R
No compensatory mutations in regard to DTG resistance and viral fitness have developed over more than three years in culture.
Hypotheses1. Viruses resistant to DTG via the R263K
pathway should not be transmissible because of low viral fitness
2. 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.
• Bluma Brenner• Hongtao Xu• Dimitri Coutsinos• Jerry Zaharatos• Maureen Oliveira• Thibault Mesplède• Peter Quashie
Acknowledgements
Thanks to CIHR and CANFAR
