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Longitudinal HIV sequencing reveals reservoir expression leading to decay which is obscured by clonal expansion

Author

Listed:
  • Marilia Rita Pinzone

    (University of Pennsylvania)

  • D. Jake VanBelzen

    (University of Pennsylvania
    Northwestern University)

  • Sam Weissman

    (University of Pennsylvania)

  • Maria Paola Bertuccio

    (University of Pennsylvania)

  • LaMont Cannon

    (University of Pennsylvania)

  • Emmanuele Venanzi-Rullo

    (University of Pennsylvania
    University of Messina)

  • Stephen Migueles

    (National Institutes of Health)

  • R. Brad Jones

    (Weill Cornell Medical College)

  • Talia Mota

    (Weill Cornell Medical College)

  • Sarah B. Joseph

    (University of North Carolina at Chapel Hill)

  • Kevin Groen

    (University of Amsterdam)

  • Alexander O. Pasternak

    (University of Amsterdam)

  • Wei-Ting Hwang

    (University of Pennsylvania)

  • Brad Sherman

    (Leidos Biomedical Research Inc., supporting the Division of Clinical Research, NIAID)

  • Anastasios Vourekas

    (University of Pennsylvania)

  • Giuseppe Nunnari

    (University of Messina)

  • Una O’Doherty

    (University of Pennsylvania)

Abstract

After initiating antiretroviral therapy (ART), a rapid decline in HIV viral load is followed by a long period of undetectable viremia. Viral outgrowth assay suggests the reservoir continues to decline slowly. Here, we use full-length sequencing to longitudinally study the proviral landscape of four subjects on ART to investigate the selective pressures influencing the dynamics of the treatment-resistant HIV reservoir. We find intact and defective proviruses that contain genetic elements favoring efficient protein expression decrease over time. Moreover, proviruses that lack these genetic elements, yet contain strong donor splice sequences, increase relatively to other defective proviruses, especially among clones. Our work suggests that HIV expression occurs to a significant extent during ART and results in HIV clearance, but this is obscured by the expansion of proviral clones. Paradoxically, clonal expansion may also be enhanced by HIV expression that leads to splicing between HIV donor splice sites and downstream human exons.

Suggested Citation

  • Marilia Rita Pinzone & D. Jake VanBelzen & Sam Weissman & Maria Paola Bertuccio & LaMont Cannon & Emmanuele Venanzi-Rullo & Stephen Migueles & R. Brad Jones & Talia Mota & Sarah B. Joseph & Kevin Groe, 2019. "Longitudinal HIV sequencing reveals reservoir expression leading to decay which is obscured by clonal expansion," Nature Communications, Nature, vol. 10(1), pages 1-12, December.
    • Handle: RePEc:nat:natcom:v:10:y:2019:i:1:d:10.1038_s41467-019-08431-7
    DOI: 10.1038/s41467-019-08431-7
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    Cited by:

    1. Caroline Dufour & Corentin Richard & Marion Pardons & Marta Massanella & Antoine Ackaoui & Ben Murrell & Bertrand Routy & Réjean Thomas & Jean-Pierre Routy & Rémi Fromentin & Nicolas Chomont, 2023. "Phenotypic characterization of single CD4+ T cells harboring genetically intact and inducible HIV genomes," Nature Communications, Nature, vol. 14(1), pages 1-15, December.
    2. Marion Pardons & Basiel Cole & Laurens Lambrechts & Willem van Snippenberg & Sofie Rutsaert & Ytse Noppe & Nele De Langhe & Annemieke Dhondt & Jerel Vega & Filmon Eyassu & Erik Nijs & Ellen Van Gulck , 2023. "Potent latency reversal by Tat RNA-containing nanoparticle enables multi-omic analysis of the HIV-1 reservoir," Nature Communications, Nature, vol. 14(1), pages 1-18, December.

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