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Distinct viral reservoirs in individuals with spontaneous control of HIV-1

Author

Listed:
  • Chenyang Jiang

    (Ragon Institute of MGH, MIT and Harvard
    Infectious Disease Division, Brigham and Women’s Hospital)

  • Xiaodong Lian

    (Ragon Institute of MGH, MIT and Harvard
    Infectious Disease Division, Brigham and Women’s Hospital)

  • Ce Gao

    (Ragon Institute of MGH, MIT and Harvard)

  • Xiaoming Sun

    (Ragon Institute of MGH, MIT and Harvard)

  • Kevin B. Einkauf

    (Ragon Institute of MGH, MIT and Harvard
    Infectious Disease Division, Brigham and Women’s Hospital)

  • Joshua M. Chevalier

    (Ragon Institute of MGH, MIT and Harvard
    Infectious Disease Division, Brigham and Women’s Hospital)

  • Samantha M. Y. Chen

    (Ragon Institute of MGH, MIT and Harvard)

  • Stephane Hua

    (Ragon Institute of MGH, MIT and Harvard)

  • Ben Rhee

    (Ragon Institute of MGH, MIT and Harvard
    Infectious Disease Division, Brigham and Women’s Hospital)

  • Kaylee Chang

    (Ragon Institute of MGH, MIT and Harvard)

  • Jane E. Blackmer

    (Ragon Institute of MGH, MIT and Harvard)

  • Matthew Osborn

    (Ragon Institute of MGH, MIT and Harvard)

  • Michael J. Peluso

    (University of California at San Francisco)

  • Rebecca Hoh

    (University of California at San Francisco)

  • Ma Somsouk

    (University of California at San Francisco)

  • Jeffrey Milush

    (University of California at San Francisco)

  • Lynn N. Bertagnolli

    (Johns Hopkins University School of Medicine)

  • Sarah E. Sweet

    (Johns Hopkins University School of Medicine)

  • Joseph A. Varriale

    (Johns Hopkins University School of Medicine)

  • Peter D. Burbelo

    (Dental Clinical Research Core, National Institute of Dental and Craniofacial Research, National Institutes of Health)

  • Tae-Wook Chun

    (National Institute of Allergies and Infectious Diseases)

  • Gregory M. Laird

    (Accelevir Diagnostics)

  • Erik Serrao

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Alan N. Engelman

    (Dana-Farber Cancer Institute
    Harvard Medical School)

  • Mary Carrington

    (Ragon Institute of MGH, MIT and Harvard
    Basic Science Program, Frederick National Laboratory for Cancer Research)

  • Robert F. Siliciano

    (Johns Hopkins University School of Medicine
    Howard Hughes Medical Institute)

  • Janet M. Siliciano

    (Johns Hopkins University School of Medicine
    Howard Hughes Medical Institute)

  • Steven G. Deeks

    (University of California at San Francisco)

  • Bruce D. Walker

    (Ragon Institute of MGH, MIT and Harvard
    Howard Hughes Medical Institute
    Massachusetts Institute of Technology
    Massachusetts Institute of Technology)

  • Mathias Lichterfeld

    (Ragon Institute of MGH, MIT and Harvard
    Infectious Disease Division, Brigham and Women’s Hospital
    Broad Institute of MIT and Harvard)

  • Xu G. Yu

    (Ragon Institute of MGH, MIT and Harvard
    Infectious Disease Division, Brigham and Women’s Hospital)

Abstract

Sustained, drug-free control of HIV-1 replication is naturally achieved in less than 0.5% of infected individuals (here termed ‘elite controllers’), despite the presence of a replication-competent viral reservoir1. Inducing such an ability to spontaneously maintain undetectable plasma viraemia is a major objective of HIV-1 cure research, but the characteristics of proviral reservoirs in elite controllers remain to be determined. Here, using next-generation sequencing of near-full-length single HIV-1 genomes and corresponding chromosomal integration sites, we show that the proviral reservoirs of elite controllers frequently consist of oligoclonal to near-monoclonal clusters of intact proviral sequences. In contrast to individuals treated with long-term antiretroviral therapy, intact proviral sequences from elite controllers were integrated at highly distinct sites in the human genome and were preferentially located in centromeric satellite DNA or in Krüppel-associated box domain-containing zinc finger genes on chromosome 19, both of which are associated with heterochromatin features. Moreover, the integration sites of intact proviral sequences from elite controllers showed an increased distance to transcriptional start sites and accessible chromatin of the host genome and were enriched in repressive chromatin marks. These data suggest that a distinct configuration of the proviral reservoir represents a structural correlate of natural viral control, and that the quality, rather than the quantity, of viral reservoirs can be an important distinguishing feature for a functional cure of HIV-1 infection. Moreover, in one elite controller, we were unable to detect intact proviral sequences despite analysing more than 1.5 billion peripheral blood mononuclear cells, which raises the possibility that a sterilizing cure of HIV-1 infection, which has previously been observed only following allogeneic haematopoietic stem cell transplantation2,3, may be feasible in rare instances.

Suggested Citation

  • Chenyang Jiang & Xiaodong Lian & Ce Gao & Xiaoming Sun & Kevin B. Einkauf & Joshua M. Chevalier & Samantha M. Y. Chen & Stephane Hua & Ben Rhee & Kaylee Chang & Jane E. Blackmer & Matthew Osborn & Mic, 2020. "Distinct viral reservoirs in individuals with spontaneous control of HIV-1," Nature, Nature, vol. 585(7824), pages 261-267, September.
    • Handle: RePEc:nat:nature:v:585:y:2020:i:7824:d:10.1038_s41586-020-2651-8
    DOI: 10.1038/s41586-020-2651-8
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    Cited by:

    1. Eva M. Stevenson & Sandra Terry & Dennis Copertino & Louise Leyre & Ali Danesh & Jared Weiler & Adam R. Ward & Pragya Khadka & Evan McNeil & Kevin Bernard & Itzayana G. Miller & Grant B. Ellsworth & C, 2022. "SARS CoV-2 mRNA vaccination exposes latent HIV to Nef-specific CD8+ T-cells," Nature Communications, Nature, vol. 13(1), pages 1-15, December.
    2. 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.
    3. Xiaolei Wang & Eunice Vincent & Summer Siddiqui & Katherine Turnbull & Hong Lu & Robert Blair & Xueling Wu & Meagan Watkins & Widade Ziani & Jiasheng Shao & Lara A. Doyle-Meyers & Kasi E. Russell-Lodr, 2022. "Early treatment regimens achieve sustained virologic remission in infant macaques infected with SIV at birth," Nature Communications, Nature, vol. 13(1), pages 1-12, December.
    4. Shelby Winans & Hyun Jae Yu & Kenia los Santos & Gary Z. Wang & Vineet N. KewalRamani & Stephen P. Goff, 2022. "A point mutation in HIV-1 integrase redirects proviral integration into centromeric repeats," Nature Communications, Nature, vol. 13(1), pages 1-12, December.

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