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Cited by 370HIV Research and TreatmentVirus-based gene therapy researchHIV/AIDS drug development and treatment

Identification of genetically intact HIV-1 proviruses in specific CD4 + T cells from effectively treated participants

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Hiener, Bonnie, Horsburgh, Bethany A., Eden, John-Sebastian, Barton, Kirston, Schlub, Timothy E., Lee, Eunok, von Stockenstrom, Susanne, Odevall, Lina +11 more·2017·Cell Reports
DOI 10.1016/j.celrep.2017.09.081PMC PMC5960642
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Abstract

Latent replication-competent HIV-1 persists in individuals on long-term antiretroviral therapy (ART). We developed the Full-Length Individual Proviral Sequencing (FLIPS) assay to determine the distribution of latent replication-competent HIV-1 within memory CD4 + T cell subsets in six individuals on long-term ART. FLIPS is an efficient, high-throughput assay that amplifies and sequences near full-length (∼9 kb) HIV-1 proviral genomes and determines potential replication competency through genetic characterization. FLIPS provides a genome-scale perspective that addresses the limitations of other methods that also genetically characterize the latent reservoir. Using FLIPS, we identified 5% of proviruses as intact and potentially replication competent. Intact proviruses were unequally distributed between T cell subsets, with effector memory cells containing the largest proportion of genetically intact HIV-1 proviruses. We identified multiple identical intact proviruses, suggesting a role for cellular proliferation in the maintenance of the latent HIV-1 reservoir.

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  • The combination of Gag and Env detection covers the functionality of most of the viral genome length, avoiding a 5' or 3' constrained bias.

    “Thereby, the combination covers the functionality of most of the viral genome length, thus avoiding a 5 0 or 3 0 constrained bias”

    From Revealing viral and cellular dynamics of HIV-1 at the single-cell level during early treatment periods (2023) · cites this paper as [37]

    The Results section on FLIPS versus sub-genomic sequencing (page unavailable) examines env and gag-pol regions but reports that sequences appearing intact in those regions were defective when the entire genome was examined. It also says those regions missed defects in the 5′ packaging signal and major splice donor site, contrary to the claim that Gag and Env detection avoids a 5′-constrained bias. (LLM, conf=0.86)

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  • Genetic approaches predicting viral 'intactness' based on the absence of gene alterations miss the fact that, even if long stretches of the Env DNA remain unaltered and appear intact, they may be non-functional due to aberrant or missing protein expression.

    “Genetic approaches, predicting viral ''intactness'' based on the absence of gene alterations (indels, inversions, hypermutations, properties of the packaging signal, or major splice donor site defects 37 ) miss the fact that, even if long stretches of the Env DNA remain unaltered and appear intact, they may be non-functional due to aberrant or missing protein expression. 54”

    From Revealing viral and cellular dynamics of HIV-1 at the single-cell level during early treatment periods (2023) · cites this paper as [37]

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Authors
Hiener, B., Horsburgh, B. A., Eden, J.-S., Barton, K., Schlub, T. E., Lee, E., von Stockenstrom, S., Odevall, L., Milush, J. M., Liegler, T., Sinclair, E., Hoh, R., Boritz, E. A., Douek, D., Fromentin, R., Chomont, N., Deeks, S. G., Hecht, F. M., & Palmer, S.
Affiliations
  • The University of Sydney (AU)
  • Karolinska University Hospital (SE)
  • University of California, San Francisco (US)
  • National Institutes of Health (US)
  • Centre Hospitalier de l’Université de Montréal (CA)
Corresponding author
Hiener, Bonnie
ORCID
Venue
Cell Reports
Publisher
Elsevier BV
Published
2017-10
Volume
21
Issue
3
Pages
813-822
ISSN
2211-1247 (ISSN-L)
DOI
10.1016/j.celrep.2017.09.081
PMC
PMC5960642
OpenAlex
W2766409016
Cited by
370
References
3
Citations by year
2026: 21 · 2025: 30 · 2024: 33 · 2023: 47 · 2022: 47 · 2021: 50 · 2020: 53 · 2019: 52 · 2018: 34 · 2017: 2
FWCI
21.00
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell Reports (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by-nc-nd)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion)
Funders
  • Delaney AIDS Research Enterprise (DARE) to Find a Cure (1U19AI096109, 1UM1AI126611-01)
  • amfAR Research Consortium on HIV Eradication (ARCHE)
  • The Foundation for AIDS Research (amfAR 108074-50-RGRL)
  • Australian Centre for HIV and Hepatitis Virology Research (ACH2) (2015-43)
  • UCSF-GIVI Center for AIDS Research (P30 AI027763)
  • Australian National Health and Medical Research Council (AAP1061681)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
Keywords
HIV-1 latent reservoir, proviral DNA, memory CD4+ T cells, effector memory T cells, antiretroviral therapy, cell proliferation
MeSH terms
Adult, Aged, Base Sequence, Disease Reservoirs, Humans, Male, Middle Aged, Phylogeny, Proviruses, CD4-Positive T-Lymphocytes, HIV-1, HIV Infections, Lymphocyte Subsets, Sequence Analysis, DNA, Lymphocyte Count, Antiretroviral Therapy, Highly Active

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