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HIV Diversity Considerations in the Application of the Intact Proviral DNA Assay (IPDA)

Natalie N. Kinloch, Yanqin Ren, Winiffer D. Conce Alberto, Winnie Dong, Pragya Khadka, Szu Han Huang, Talia M. Mota, Andrew Wilson, Aniqa Shahid, Don Kirkby, Marianne Harris, Colin Kovacs, Erika Benko, Mario A. Ostrowski, Perla M. Del Rio Estrada, Avery Wimpelberg, Christopher Cannon, W. David Hardy, Lynsay MacLaren, Harris Goldstein, Chanson J. Brumme, Guinevere Q. Lee, Rebecca M. Lynch, Zabrina L. Brumme, R. Brad Jones
doi: https://doi.org/10.1101/2020.05.26.115006
Natalie N. Kinloch
1Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada
2British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
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Yanqin Ren
3Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, USA
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Winiffer D. Conce Alberto
3Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, USA
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Winnie Dong
2British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
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Pragya Khadka
3Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, USA
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Szu Han Huang
3Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, USA
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Talia M. Mota
3Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, USA
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Andrew Wilson
4Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington DC, USA
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Aniqa Shahid
1Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada
2British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
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Don Kirkby
2British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
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Marianne Harris
2British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
5Faculty of Medicine, University of British Columbia, Vancouver, Canada
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Colin Kovacs
6Maple Leaf Medical Clinic, Toronto, Canada
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Erika Benko
6Maple Leaf Medical Clinic, Toronto, Canada
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Mario A. Ostrowski
7Department of Medicine, University of Toronto, Toronto, Canada
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Perla M. Del Rio Estrada
8Center for Research in Infectious Diseases, National Institute of Respiratory Diseases, Mexico City, Mexico
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Avery Wimpelberg
9Whitman Walker Health, Washington DC, USA
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Christopher Cannon
9Whitman Walker Health, Washington DC, USA
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W. David Hardy
9Whitman Walker Health, Washington DC, USA
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Lynsay MacLaren
9Whitman Walker Health, Washington DC, USA
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Harris Goldstein
10Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY, USA
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Chanson J. Brumme
2British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
5Faculty of Medicine, University of British Columbia, Vancouver, Canada
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Guinevere Q. Lee
3Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, USA
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Rebecca M. Lynch
4Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington DC, USA
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Zabrina L. Brumme
1Faculty of Health Sciences, Simon Fraser University, Burnaby, Canada
2British Columbia Centre for Excellence in HIV/AIDS, Vancouver, Canada
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  • For correspondence: rbjones@med.cornell.edu
R. Brad Jones
3Infectious Diseases Division, Department of Medicine, Weill Cornell Medical College, New York, USA
4Department of Microbiology, Immunology and Tropical Medicine, George Washington University, Washington DC, USA
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  • For correspondence: rbjones@med.cornell.edu
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The Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a precise and scalable method for intact HIV reservoir quantification1. This duplexed droplet digital PCR (ddPCR) assay simultaneously targets the HIV Packaging Signal (Ψ) and the Rev Responsive Element (RRE) within Envelope (env) to distinguish genomically intact proviruses against a large background of defective ones2. The IPDA requires less time, resources, and biological material than the gold standard for replication-competent HIV reservoir measurement, the Quantitative Viral Outgrowth Assay (QVOA)3, and is being adopted in research and clinical studies4–7. In our cohort of HIV-1 subtype B-infected individuals from North America however, the IPDA yielded a 28% failure rate due to HIV polymorphism. We further demonstrate that within-host HIV diversity can lead the IPDA to underestimate intact HIV reservoir size, which could negatively impact clinical trial results interpretation. While the IPDA represents an important methodological advance, HIV diversity should be addressed before its widespread adoption.

Competing Interest Statement

Dr. R. Brad Jones declares that he has received payment for his previous role on the scientific advisory board of AbbVie Inc. Dr. Lynsay MacLaren declares that she holds the unpaid position of Advanced Practice Practitioner on the HIVMA Board of Directions. Dr. Marrianne Harris received honoraria paid to her institution for services as a consultant, membership on scientific advisory board and/or speaking engagement from Gilead Sciences Canada, Inc., Merck Canada Inc. and ViiV Healthcare

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The copyright holder for this preprint is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under a CC-BY-ND 4.0 International license.
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HIV Diversity Considerations in the Application of the Intact Proviral DNA Assay (IPDA)
Natalie N. Kinloch, Yanqin Ren, Winiffer D. Conce Alberto, Winnie Dong, Pragya Khadka, Szu Han Huang, Talia M. Mota, Andrew Wilson, Aniqa Shahid, Don Kirkby, Marianne Harris, Colin Kovacs, Erika Benko, Mario A. Ostrowski, Perla M. Del Rio Estrada, Avery Wimpelberg, Christopher Cannon, W. David Hardy, Lynsay MacLaren, Harris Goldstein, Chanson J. Brumme, Guinevere Q. Lee, Rebecca M. Lynch, Zabrina L. Brumme, R. Brad Jones
bioRxiv 2020.05.26.115006; doi: https://doi.org/10.1101/2020.05.26.115006
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HIV Diversity Considerations in the Application of the Intact Proviral DNA Assay (IPDA)
Natalie N. Kinloch, Yanqin Ren, Winiffer D. Conce Alberto, Winnie Dong, Pragya Khadka, Szu Han Huang, Talia M. Mota, Andrew Wilson, Aniqa Shahid, Don Kirkby, Marianne Harris, Colin Kovacs, Erika Benko, Mario A. Ostrowski, Perla M. Del Rio Estrada, Avery Wimpelberg, Christopher Cannon, W. David Hardy, Lynsay MacLaren, Harris Goldstein, Chanson J. Brumme, Guinevere Q. Lee, Rebecca M. Lynch, Zabrina L. Brumme, R. Brad Jones
bioRxiv 2020.05.26.115006; doi: https://doi.org/10.1101/2020.05.26.115006

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