1. Primary resistance against dolutegravir decreases HIV integration
Thibault Mesplède, Kaitlin Anstett, Nathan Osman, Said Hassounah, Jiaming Liang, Yingshan Han, Mark Wainberg
McGill University AIDS Centre
Lady Davis Institute for Medical Research
Jewish General Hospital
Montréal, QC, Canada

2. HIV, drugs, and resistance
Resistance is an evolutionary process
Usual pattern in HIV resistance:
Primary resistance mutations
Secondary resistance mutations
De novo resistance against every ARV drug tested so far (NRTIs, NNRTIs, PIs, FI, CCR5 antagonists)

3. Strand-transfer integrase inhibitors
Raltegravir
Elvitegravir
Dolutegravir
New drugs, new resistance mutations

4. De novo resistance against raltegravir
From Mesplède, Viruses, 2015

5. De novo resistance against elvitegravir
From Mesplède, Viruses, 2015

6. No de novo resistance against dolutegravir in treatment-naïve individuals
From Mesplède, Viruses, 2015

7. R263K prevents the emergence of additional integrase substitutions in vivo
From Cahn et al., Lancet, 2013

8. R263K
R263K is commonly selected in tissue culture selection experiments
R263K decreases viral fitness
No compensatory substitution has been identified (M50I, H51Y, R263K)
From Cahn et al., Lancet, 2013

9. R263K decreases viral integration without compensatory mutations
Early reverse transcripts
Integrated HIV DNA

10. Integrated HIV DNA in HIV pathogenesis
High levels of total and integrated HIV DNA correlate with worst clinical outcomes
Integrated DNA is a marker of viral persistence
From Besson, CID, 2014

11. HIV reservoir and drug resistance: classical model

12. HIV reservoir and drug resistance: R263K

13. Summary
Dolutegravir is the only antiretroviral that is not associated with de novo resistance mutations in treatment-naïve individuals
In treatment-experienced individuals, R263K is the predominant integrase substitution
There is no compensatory substitution for R263K
R263K impairs viral fitness and decreases HIV DNA integration
HIV reservoirs?
Note: variations in integrase can influence HIV pathogenesis (next presentation)

14. Acknowledgments Wainberg Laboratory Collaborators
Mark Wainberg
Peter Quashie
Yingshan Han
Kaitlin Anstett
Nathan Osman
Maureen Oliveira
Daniela Moisi
Said Hassounah
Agnès Dépatureaux
Diane Singhroy
Vincent Cutillas
Sophie Bastarache
Melissa Wares
Jiaming Calvin Liang
Sue Germinario
Veronica Zanichelli
Lady Davis Institute:
Dr. Andrew Mouland
Dr. Anne Gatignol
Dr. Chen Liang
Dr. Valérie Lesage
BC Centre for Excellence in HIV/AIDS:
Dr. Richard Harrigan
Dr. Guinevere Lee
University of British Columbia:
Dr. Ian Tietjen
Western University:
Dr. Stephen Barr
Hôpital Universitaire de Nantes:
Dr. François Raffi
Audrey Rodallec
Posters MOPEA048, TUPEA067, WPEA102 and WEPEA105
Poster TUPEA068: Vavro et al. (GSK)