CoChat
Sign Up
Cited by 77HIV Research and TreatmentHIV/AIDS drug development and treatmentVirus-based gene therapy research

Relationship between intact HIV-1 proviruses in circulating CD4 + T cells and rebound viruses emerging during treatment interruption

Open access
Lu, Ching-Lan, Pai, Joy A., Nogueira, Lilian, Mendoza, Pilar, Gruell, Henning, Oliveira, Thiago Y., Barton, John, Lorenzi, Julio C. C. +6 more·2018·Proceedings of the National Academy of Sciences
DOI 10.1073/pnas.1813512115PMC PMC6275529
Open this paper in CoChat — free accountOpen PDF

Abstract

Combination antiretroviral therapy controls but does not cure HIV-1 infection because a small fraction of cells harbor latent viruses that can produce rebound viremia when therapy is interrupted. The circulating latent virus reservoir has been documented by a variety of methods, most prominently by viral outgrowth assays (VOAs) in which CD4 + T cells are activated to produce virus in vitro, or more recently by amplifying proviral near full-length (NFL) sequences from DNA. Analysis of samples obtained in clinical studies in which individuals underwent analytical treatment interruption (ATI), showed little if any overlap between circulating latent viruses obtained from outgrowth cultures and rebound viruses from plasma. To determine whether intact proviruses amplified from DNA are more closely related to rebound viruses than those obtained from VOAs, we assayed 12 individuals who underwent ATI after infusion of a combination of two monoclonal anti–HIV-1 antibodies. A total of 435 intact proviruses obtained by NFL sequencing were compared with 650 latent viruses from VOAs and 246 plasma rebound viruses. Although, intact NFL and outgrowth culture sequences showed similar levels of stability and diversity with 39% overlap, the size of the reservoir estimated from NFL sequencing was larger than and did not correlate with VOAs. Finally, intact proviruses documented by NFL sequencing showed no sequence overlap with rebound viruses; however, they appear to contribute to recombinant viruses found in plasma during rebound.

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Integrity signals

Registry

Crossref · 10.1073/pnas.1813512115

Cites

2 of 2 references verified0 citation errors · 0 not checkable

Statistics

Claims the paper makes

The claims and statistics of this paper haven’t been checked yet.

Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.

A few free checks a day · papers already verified open instantly · results are public

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Env expression alone is more affected by genetic defects than the gag region, and assay formats exclusively based on free Gag protein as a reservoir marker only insufficiently assess the presence of infectious particles.

    “Moreover, Env expression alone is more affected by genetic defects than the gag region, 36,53 and assay formats exclusively based on free Gag protein as a reservoir marker only insufficiently assess the presence of infectious particles.”

    From Revealing viral and cellular dynamics of HIV-1 at the single-cell level during early treatment periods (2023) · cites this paper as [53]

    The Results report that defective proviruses frequently have env deletions and that full-length env proviruses were 21 times less frequent than gag-positive proviruses. This supports a difference in genetic integrity, but the paper measured proviral DNA, not Env expression. The citation follows the first clause; the later claim about free Gag protein is not attributed to this source. (LLM, conf=0.82)

    Experimental — accuracy not yet measured

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

The self-check needs the paper’s full text.

Cites

Flagged first, then by citations

Research works printed but not linked: 27

  1. [1]Doitsh G 2014 Cell death by pyroptosis drives CD4 T-cell depletion in HIV-1 infection Nature 505 509 514 24356306 PMC4047036
  2. [2]Sengupta S Siliciano RF 2018 Targeting the latent reservoir for HIV-1 Immunity 48 872 895 29768175 PMC6196732
  3. [3]Margolis DM Archin NM 2017 Proviral latency, persistent human immunodeficiency virus infection, and the development of latency reversing agents J Infect Dis 215 Suppl 3 S111 S118 28520964 PMC5410986
  4. [4]Finzi D 1997 Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy Science 278 1295 1300 9360927
  5. [5]Lorenzi JC 2016 Paired quantitative and qualitative assessment of the replication-competent HIV-1 reservoir and comparison with integrated proviral DNA Proc Natl Acad Sci USA 113 E7908 E7916 27872306 PMC5150408
  6. [6]Hosmane NN 2017 Proliferation of latently infected CD4+ T cells carrying replication-competent HIV-1: Potential role in latent reservoir dynamics J Exp Med 214 959 972 28341641 PMC5379987
  7. [7]Bui JK 2017 Ex vivo activation of CD4+ T-cells from donors on suppressive ART can lead to sustained production of infectious HIV-1 from a subset of infected cells PLoS Pathog 13 e1006230 28225830 PMC5338860
  8. [8]Eriksson S 2013 Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies PLoS Pathog 9 e1003174 23459007 PMC3573107
  9. [10]Crooks AM 2015 Precise quantitation of the latent HIV-1 reservoir: Implications for eradication strategies J Infect Dis 212 1361 1365 25877550 PMC4601910
  10. [11]Ho YC 2013 Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure Cell 155 540 551 24243014 PMC3896327
  11. [12]Josefsson L 2013 The HIV-1 reservoir in eight patients on long-term suppressive antiretroviral therapy is stable with few genetic changes over time Proc Natl Acad Sci USA 110 E4987 E4996 24277811 PMC3870728
  12. [13]Metcalf Pate KA Blankson JN 2017 The mouse viral outgrowth assay: Avatars for the detection of HIV-1 reservoirs Retrovirology 14 52 29157283 PMC5697021
  13. [14]Charlins P 2017 A humanized mouse-based HIV-1 viral outgrowth assay with higher sensitivity than in vitro qVOA in detecting latently infected cells from individuals on ART with undetectable viral loads Virology 507 135 139 28432928 PMC5901664
  14. [15]Hiener B 2017 Identification of genetically intact HIV-1 proviruses in specific CD4+ T cells from effectively treated participants Cell Rep 21 813 822 29045846 PMC5960642
  15. [16]Cohen YZ 2018 Relationship between latent and rebound viruses in a clinical trial of anti-HIV-1 antibody 3BNC117 J Exp Med 215 2311 2324 30072495 PMC6122972
  16. [17]Mendoza P 2018 Combination therapy with anti-HIV-1 antibodies maintains viral suppression Nature 561 479 484 30258136 PMC6166473
  17. [18]Scheid JF 2011 Sequence and structural convergence of broad and potent HIV antibodies that mimic CD4 binding Science 333 1633 1637 21764753 PMC3351836
  18. [19]Mouquet H 2012 Complex-type N-glycan recognition by potent broadly neutralizing HIV antibodies Proc Natl Acad Sci USA 109 E3268 E3277 23115339 PMC3511153
  19. [20]Li B 2007 Rapid reversion of sequence polymorphisms dominates early human immunodeficiency virus type 1 evolution J Virol 81 193 201 17065207 PMC1797245
  20. [22]Wang Z 2018 Expanded cellular clones carrying replication-competent HIV-1 persist, wax, and wane Proc Natl Acad Sci USA 115 E2575 E2584 29483265 PMC5856552
  21. [23]Siliciano JD Siliciano RF 2017 Assays to measure latency, reservoirs, and reactivation Curr Top Microbiol Immunol 417 23 41 29071475
  22. [24]Pollack RA 2017 Defective HIV-1 proviruses are expressed and can be recognized by cytotoxic T lymphocytes, which shape the proviral landscape Cell Host Microbe 21 494 506.e4 28407485 PMC5433942
  23. [25]Salantes DB 2018 HIV-1 latent reservoir size and diversity are stable following brief treatment interruption J Clin Invest 128 3102 3115 29911997 PMC6026010
  24. [26]Winckelmann A 2018 Genetic characterization of the HIV-1 reservoir after Vacc-4x and romidepsin therapy in HIV-1-infected individuals AIDS 32 1793 1802 29762162 PMC6072375
  25. [27]Robertson DL Sharp PM McCutchan FE Hahn BH 1995 Recombination in HIV-1 Nature 374 124 126 7877682
  26. [28]Burke DS 1997 Recombination in HIV: An important viral evolutionary strategy Emerg Infect Dis 3 253 259 9284369 PMC2627633
  27. [29]Chun TW 2008 Persistence of HIV in gut-associated lymphoid tissue despite long-term antiretroviral therapy J Infect Dis 197 714 720 18260759

Cited by

Sorted by citations

Authors
Lu, C.-L., Pai, J. A., Nogueira, L., Mendoza, P., Gruell, H., Oliveira, T. Y., Barton, J., Lorenzi, J. C. C., Cohen, Y. Z., Cohn, L. B., Klein, F., Caskey, M., Nussenzweig, M. C., & Jankovic, M.
Affiliations
  • Rockefeller University (US)
  • German Center for Infection Research (DE)
  • University of California, Riverside (US)
  • University of Cologne (DE)
  • Howard Hughes Medical Institute (US)
  • Laboratory of Molecular Immunology, The Rockefeller University, New York, NY 10065;
Corresponding author
Nussenzweig, Michel C.
ORCID
Venue
Proceedings of the National Academy of Sciences
Publisher
National Academy of Sciences
Published
2018-11-12
Volume
115
Issue
48
Pages
E11341-E11348
ISSN
  • 0027-8424 (ISSN-L)
  • 1091-6490
DOI
10.1073/pnas.1813512115
PMC
PMC6275529
OpenAlex
W2901737815
Cited by
77
References
2
Citations by year
2026: 6 · 2025: 9 · 2024: 7 · 2023: 6 · 2022: 8 · 2021: 13 · 2020: 16 · 2019: 12
FWCI
5.37
Type
journal article
Language
en
Open access
Licence
Locations
  • Proceedings of the National Academy of Sciences (publishedVersion, cc-by)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Kölner Universitäts PublikationsServer (Universität zu Köln) (publishedVersion)
  • eScholarship (California Digital Library) (submittedVersion)
  • eScholarship (California Digital Library) (submittedVersion, cc-by)
Funders
  • National Institutes of Health (UL1TR001866)
  • National Institute of Allergy and Infectious Diseases (UM1AI126620, R01AI129795, UM1AI100663, T32AI070084, P30AI124414)
  • National Center for Advancing Translational Sciences
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Health Sciences › Medicine › Infectious Diseases › HIV/AIDS drug development and treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Keywords
HIV-1 latent reservoir, proviral DNA, CD4+ T cells, treatment interruption, viral outgrowth assay, viral recombination, HIV cure
MeSH terms
Broadly Neutralizing Antibodies, Humans, Phylogeny, Proviruses, Virus Replication, HIV Antibodies, CD4-Positive T-Lymphocytes, HIV-1, HIV Infections, Virus Latency, Anti-HIV Agents, Antibodies, Neutralizing, Antibodies, Monoclonal, Humanized

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

Are you an author, or do you see a problem with this page? Request a review