HIV-1 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:10.1038/s41467-020-20442-3

HIV-1 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 GoldsteinChanson J. Brumme, Guinevere Q. Lee, Rebecca M. Lynch, Zabrina L. Brumme, R. Brad Jones

Pediatrics

Research output: Contribution to journal › Article › peer-review

51 Scopus citations

Abstract

The Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a scalable method for intact HIV-1 reservoir quantification. This droplet digital PCR-based assay simultaneously targets two HIV-1 regions to distinguish genomically intact proviruses against a large background of defective ones, and its application has yielded insights into HIV-1 persistence. Reports of assay failures however, attributed to HIV-1 polymorphism, have recently emerged. Here, we describe a diverse North American cohort of people with HIV-1 subtype B, where the IPDA yielded a failure rate of 28% due to viral polymorphism. We further demonstrate that within-host HIV-1 diversity can lead the IPDA to underestimate intact reservoir size, and provide examples of how this phenomenon could lead to erroneous interpretation of clinical trial data. While the IPDA represents a major methodological advance, HIV-1 diversity should be addressed before its widespread adoption as a principal readout in HIV-1 remission trials.

Original language	English (US)
Article number	165
Journal	Nature communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-020-20442-3
State	Published - Dec 2021

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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10.1038/s41467-020-20442-3

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Kinloch, N. N., Ren, Y., Conce Alberto, W. D., Dong, W., Khadka, P., Huang, S. H., Mota, T. M., Wilson, A., Shahid, A., Kirkby, D., Harris, M., Kovacs, C., Benko, E., Ostrowski, M. A., Del Rio Estrada, P. M., Wimpelberg, A., Cannon, C., Hardy, W. D., MacLaren, L., ... Jones, R. B. (2021). HIV-1 diversity considerations in the application of the Intact Proviral DNA Assay (IPDA). Nature communications, 12(1), Article 165. https://doi.org/10.1038/s41467-020-20442-3

Kinloch, NN, Ren, Y, Conce Alberto, WD, Dong, W, Khadka, P, Huang, SH, Mota, TM, Wilson, A, Shahid, A, Kirkby, D, Harris, M, Kovacs, C, Benko, E, Ostrowski, MA, Del Rio Estrada, PM, Wimpelberg, A, Cannon, C, Hardy, WD, MacLaren, L, Goldstein, H, Brumme, CJ, Lee, GQ, Lynch, RM, Brumme, ZL & Jones, RB 2021, 'HIV-1 diversity considerations in the application of the Intact Proviral DNA Assay (IPDA)', Nature communications, vol. 12, no. 1, 165. https://doi.org/10.1038/s41467-020-20442-3

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abstract = "The Intact Proviral DNA Assay (IPDA) was developed to address the critical need for a scalable method for intact HIV-1 reservoir quantification. This droplet digital PCR-based assay simultaneously targets two HIV-1 regions to distinguish genomically intact proviruses against a large background of defective ones, and its application has yielded insights into HIV-1 persistence. Reports of assay failures however, attributed to HIV-1 polymorphism, have recently emerged. Here, we describe a diverse North American cohort of people with HIV-1 subtype B, where the IPDA yielded a failure rate of 28% due to viral polymorphism. We further demonstrate that within-host HIV-1 diversity can lead the IPDA to underestimate intact reservoir size, and provide examples of how this phenomenon could lead to erroneous interpretation of clinical trial data. While the IPDA represents a major methodological advance, HIV-1 diversity should be addressed before its widespread adoption as a principal readout in HIV-1 remission trials.",

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AU - Brumme, Chanson J.

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AU - Lynch, Rebecca M.

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AU - Jones, R. Brad

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HIV-1 diversity considerations in the application of the Intact Proviral DNA Assay (IPDA)

Abstract

ASJC Scopus subject areas

UN SDGs

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