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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
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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)
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Strand-transfer integrase inhibitors
• Raltegravir
• Elvitegravir
• Dolutegravir
New drugs, new
resistance
mutations
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De novo resistance against raltegravir
From Mesplède, Viruses, 2015
4
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De novo resistance against elvitegravir
From Mesplède, Viruses, 2015
5
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No de novo resistance against
dolutegravir in treatment-naïve
individuals
From Mesplède, Viruses, 2015
6
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R263K prevents the emergence of additional
integrase substitutions in vivo
From Cahn et al., Lancet, 2013
7
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R263K
From Cahn et al., Lancet, 2013
• R263K is commonly
selected in tissue
culture selection
experiments
• R263K decreases
viral fitness
• No compensatory
substitution has been
identified (M50I,
H51Y, R263K)
8
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R263K decreases viral integration
without compensatory mutations
Early reverse transcripts
Integrated HIV DNA
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Integrated HIV DNA in HIV
pathogenesis
From Besson, CID, 2014
• High levels of total
and integrated HIV
DNA correlate with
worst clinical
outcomes
• Integrated DNA is a
marker of viral
persistence
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HIV reservoir and drug resistance:
classical model
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HIV reservoir and drug resistance:
R263K
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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)
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Acknowledgments
Wainberg Laboratory
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
Collaborators
•
Lady Davis Institute:
–
–
–
–
Dr. Andrew Mouland
Dr. Anne Gatignol
Dr. Chen Liang
Dr. Valérie Lesage
•
BC Centre for Excellence in HIV/AIDS:
•
University of British Columbia:
•
Western University:
•
Hôpital Universitaire de Nantes:
– Dr. Richard Harrigan
– Dr. Guinevere Lee
– Dr. Ian Tietjen
– Dr. Stephen Barr
– Dr. François Raffi
– Audrey Rodallec
Posters MOPEA048, TUPEA067, WPEA102 and WEPEA105
Poster TUPEA068: Vavro et al. (GSK)
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