What if a Drug that Was Developed to Treat HIV Infection Could Actually Help to Cure It?

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 0.8 0.6 Relative binding 0.4 0.2 0.0 0 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 Adapted from Hightower KE, et al. Antimicrob Agents Chemother 2011;5:4552–9 Koff , dissociation rate; t1/2h, half-life in hours

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 activity A B

5. The combination of H51Yand R263K negatively impacts viral fitness

7. Replication Capacity of HIV Containing Various Combinations of INSTI Resistance Mutations

8. Selection of HIV-1 containing R263K with RAL and EVG

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