1 / 27

Novel HIV Suppressive Approaches with Integrase Inhibitors

Novel HIV Suppressive Approaches with Integrase Inhibitors. Mark A Wainberg McGill University AIDS Centre Montreal, Canada. 1. URF 4.2%. A 12%. AE 3.1%. AG 6.7%. G 5%. B 10%. D 3.6%. Global distribution of HIV-1 subtypes. 2 million. 1.3 million. 4.8 million.

hadar
Download Presentation

Novel HIV Suppressive Approaches with Integrase Inhibitors

An Image/Link below is provided (as is) to download presentation Download Policy: Content on the Website is provided to you AS IS for your information and personal use and may not be sold / licensed / shared on other websites without getting consent from its author. Content is provided to you AS IS for your information and personal use only. Download presentation by click this link. While downloading, if for some reason you are not able to download a presentation, the publisher may have deleted the file from their server. During download, if you can't get a presentation, the file might be deleted by the publisher.

E N D

Presentation Transcript

  1. Novel HIV Suppressive Approaches with Integrase Inhibitors Mark A Wainberg McGill University AIDS Centre Montreal, Canada 1

  2. URF 4.2% A 12% AE 3.1% AG 6.7% G 5% B 10% D3.6% Global distribution of HIV-1 subtypes 2 million 1.3 million 4.8 million

  3. Rapid Selection of K65R Resistance in Subtype C Isolates

  4. 6

  5. Previous work in our lab showed that MK-2048, a Merck INSTI, selected G118R followed by E138K. The latter augmented levels of resistance against MK-2048 and also restored replicative fitness. 7

  6. Major resistance pathways against INSTIs(clinical and tissue culture data) Quashie et al., Curr. Opin. Infect. Diseases, in press

  7. Secondary INSTI-resistance mutations often restore HIV replication capacity Mbisa et al., Infect. and drug resistance, 2011--Canducci et al., JAC, 2010--Reigadas et al., Plos One, 2010--Delelis et al., AAC, 2009

  8. Dolutegravir activity on RAL-resistant clinical isolates (n=39)(median IC50 for wild-type=1.07 nM) Underwood et al., JAIDS, 2012

  9. Resistance to INSTIs in clinical trials in treatment-naïve patients RALTEGRAVIR Cooper et al., NEJM, 2008 Sichtig et al, JAC, 2009 Canducci et al, AIDS, 2009 Hatano et al, JAIDS, 2010 ELVITEGRAVIR Sax et al, Lancet, 2012 DeJesus et al, Lancet, 2012 DOLUTEGRAVIR vanLunzen et al., Lancet Infect. Dis., 2012

  10. Selection results with DTG Quashie, et al, Journal of Virology 2012

  11. Selection results with DTG Quashie, et al, Journal of Virology 2012

  12. Selection results with DTG Quashie, et al, Journal of Virology 2012

  13. Subtype-specific mutations selected in vitro with dolutegravir Quashie, Mesplède et al., Journal of Virology, 2012

  14. The R263K mutation confers low-level resistance to dolutegravir in cell culture *Methodological differences (EC50 for wild-type ≈1-6nM) Quashie, Mesplède et al., Journal of Virology, 2012

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

  16. The R263K mutation decreases dolutegravir residency time in an integrase-vDNA complex

  17. The addition of H51Y to R263K further decreases IN strand transfer activity A B

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

  19. Effects of G118R and H51Y on in vitro strand transfer activity

  20. Effects of H51Y, G118R and R263K mutations on susceptibility to dolutegravir in cell culture *Methodological differences (EC50 for wild-type ≈1-6nM)

  21. Dolutegravir resistance associates with a decrease in viral replication capacity

  22. Conclusions • Resistance mutations selected in vitro with dolutegravir are: R263K or G118R plus H51Y • R263K and G118R confer low-level resistance against dolutegravir, e.g. 2.5-6 fold • The addition of H51Y to either R263K or G118R increases resistance against DTG but also further decreases viral fitness • These findings help to explain why resistance against dolutegravir in INSTI-naïve patients has not been observed

  23. No compensatory mutations in regard to DTG resistance and viral fitness have developed over more than one year in culture. Might there be other implications for a drug that selects for an unfit virus and can animal models be of use?

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

  25. MERCI

More Related