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Impact of misclassified defective proviruses on HIV reservoir measurements

Author

Listed:
  • Daniel B. Reeves

    (Fred Hutchinson Cancer Center)

  • Christian Gaebler

    (The Rockefeller University
    Charité -Universitätsmedizin)

  • Thiago Y. Oliveira

    (The Rockefeller University)

  • Michael J. Peluso

    (Infectious Diseases, and Global Medicine, Department of Medicine, UCSF)

  • Joshua T. Schiffer

    (Fred Hutchinson Cancer Center
    University of Washington)

  • Lillian B. Cohn

    (Fred Hutchinson Cancer Center)

  • Steven G. Deeks

    (Infectious Diseases, and Global Medicine, Department of Medicine, UCSF)

  • Michel C. Nussenzweig

    (The Rockefeller University
    The Rockefeller University)

Abstract

Most proviruses persisting in people living with HIV (PWH) on antiretroviral therapy (ART) are defective. However, rarer intact proviruses almost always reinitiate viral rebound if ART stops. Therefore, assessing therapies to prevent viral rebound hinges on specifically quantifying intact proviruses. We evaluated the same samples from 10 male PWH on ART using the two-probe intact proviral DNA assay (IPDA) and near full length (nfl) Q4PCR. Both assays admitted similar ratios of intact to total HIV DNA, but IPDA found ~40-fold more intact proviruses. Neither assay suggested defective proviruses decay over 10 years. However, the mean intact half-lives were different: 108 months for IPDA and 65 months for Q4PCR. To reconcile this difference, we modeled additional longitudinal IPDA data and showed that decelerating intact decay could arise from very long-lived intact proviruses and/or misclassified defective proviruses: slowly decaying defective proviruses that are intact in IPDA probe locations (estimated up to 5%, in agreement with sequence library based predictions). The model also demonstrates how misclassification can lead to underestimated efficacy of therapies that exclusively reduce intact proviruses. We conclude that sensitive multi-probe assays combined with specific nfl-verified assays would be optimal to document absolute and changing levels of intact HIV proviruses.

Suggested Citation

  • Daniel B. Reeves & Christian Gaebler & Thiago Y. Oliveira & Michael J. Peluso & Joshua T. Schiffer & Lillian B. Cohn & Steven G. Deeks & Michel C. Nussenzweig, 2023. "Impact of misclassified defective proviruses on HIV reservoir measurements," Nature Communications, Nature, vol. 14(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:14:y:2023:i:1:d:10.1038_s41467-023-39837-z
    DOI: 10.1038/s41467-023-39837-z
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