CoChat
Sign Up
Cited by 1,405HIV Research and TreatmentVirus-based gene therapy researchHIV/AIDS drug development and treatment

Replication-competent noninduced proviruses in the latent reservoir increase barrier to HIV-1 cure

Open access
Ho, Ya-Chi, Shan, Liang, Hosmane, Nina N., Wang, Jeffrey, Laskey, Sarah B., Rosenbloom, Daniel I.S., Lai, Jun, Blankson, Joel N., Siliciano, Janet D., Siliciano, Robert F.·2013·Cell
DOI 10.1016/j.cell.2013.09.020PMC PMC3896327
Open this paper in CoChat — free accountOpen PDF

Abstract

Antiretroviral therapy fails to cure HIV-1 infection because latent proviruses persist in resting CD4(+) T cells. T cell activation reverses latency, but <1% of proviruses are induced to release infectious virus after maximum in vitro activation. The noninduced proviruses are generally considered defective but have not been characterized. Analysis of 213 noninduced proviral clones from treated patients showed 88.3% with identifiable defects but 11.7% with intact genomes and normal long terminal repeat (LTR) function. Using direct sequencing and genome synthesis, we reconstructed full-length intact noninduced proviral clones and demonstrated growth kinetics comparable to reconstructed induced proviruses from the same patients. Noninduced proviruses have unmethylated promoters and are integrated into active transcription units. Thus, it cannot be excluded that they may become activated in vivo. The identification of replication-competent noninduced proviruses indicates that the size of the latent reservoir-and, hence, the barrier to cure-may be up to 60-fold greater than previously estimated.

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 · 10.1016/j.cell.2013.09.020

Cites

4 of 4 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?

  • During therapy, approximately 95% of all detected integrated proviral genomes are defective.

    “during therapy R 95% of all detected integrated proviral genomes are defective. 31,32”

    From Revealing viral and cellular dynamics of HIV-1 at the single-cell level during early treatment periods (2023) · cites this paper as [32]

    The Results section, “Hypermutation and large internal deletions render most non-induced proviruses defective” (page unavailable), reports that 88.3% of non-induced proviruses had obvious defects precluding replication. The Discussion says defective genomes can integrate and be detected by PCR. This supports the general point, but the paper does not establish the claimed approximately 95% figure for all detected integrated proviral genomes during therapy. (LLM, conf=0.88)

    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: 63

  1. Archin, 2009, Expression of latent HIV induced by the potent HDAC inhibitor suberoylanilide hydroxamic acid, AIDS Res. Hum. Retroviruses, 25, 207, 10.1089/aid.2008.0191 · DOI
  2. Archin, 2012, Administration of vorinostat disrupts HIV-1 latency in patients on antiretroviral therapy, Nature, 487, 482, 10.1038/nature11286 · DOI
  3. Bebenek, 1989, Specificity and mechanism of error-prone replication by human immunodeficiency virus-1 reverse transcriptase, J. Biol. Chem., 264, 16948, 10.1016/S0021-9258(19)84799-3 · DOI
  4. Blazkova, 2009, CpG methylation controls reactivation of HIV from latency, PLoS Pathog., 5, e1000554, 10.1371/journal.ppat.1000554 · DOI
  5. Blazkova, 2012, Paucity of HIV DNA methylation in latently infected, resting CD4+ T cells from infected individuals receiving antiretroviral therapy, J. Virol., 86, 5390, 10.1128/JVI.00040-12 · DOI
  6. Böhnlein, 1988, The same inducible nuclear proteins regulates mitogen activation of both the interleukin-2 receptor-alpha gene and type 1 HIV, Cell, 53, 827, 10.1016/0092-8674(88)90099-2 · DOI
  7. Burnett, 2009, Control of stochastic gene expression by host factors at the HIV promoter, PLoS Pathog., 5, e1000260, 10.1371/journal.ppat.1000260 · DOI
  8. Chakraborty, 2010, Pairing computation with experimentation: a powerful coupling for understanding T cell signalling, Nat. Rev. Immunol., 10, 59, 10.1038/nri2688 · DOI
  9. Chávez, 2011, In vivo, in vitro, and in silico analysis of methylation of the HIV-1 provirus, Methods, 53, 47, 10.1016/j.ymeth.2010.05.009 · DOI
  10. Chun, 1997, Presence of an inducible HIV-1 latent reservoir during highly active antiretroviral therapy, Proc. Natl. Acad. Sci. USA, 94, 13193, 10.1073/pnas.94.24.13193 · DOI
  11. Contreras, 2009, Suberoylanilide hydroxamic acid reactivates HIV from latently infected cells, J. Biol. Chem., 284, 6782, 10.1074/jbc.M807898200 · DOI
  12. Coull, 2000, The human factors YY1 and LSF repress the human immunodeficiency virus type 1 long terminal repeat via recruitment of histone deacetylase 1, J. Virol., 74, 6790, 10.1128/JVI.74.15.6790-6799.2000 · DOI
  13. Cujec, 1997, The HIV transactivator TAT binds to the CDK-activating kinase and activates the phosphorylation of the carboxy-terminal domain of RNA polymerase II, Genes Dev., 11, 2645, 10.1101/gad.11.20.2645 · DOI
  14. Davey, 1999, HIV-1 and T cell dynamics after interruption of highly active antiretroviral therapy (HAART) in patients with a history of sustained viral suppression, Proc. Natl. Acad. Sci. USA, 96, 15109, 10.1073/pnas.96.26.15109 · DOI
  15. Deeks, 2012, HIV: Shock and kill, Nature, 487, 439, 10.1038/487439a · DOI
  16. Duh, 1989, Tumor necrosis factor alpha activates human immunodeficiency virus type 1 through induction of nuclear factor binding to the NF-kappa B sites in the long terminal repeat, Proc. Natl. Acad. Sci. USA, 86, 5974, 10.1073/pnas.86.15.5974 · DOI
  17. Durand, 2012, HIV-1 DNA is detected in bone marrow populations containing CD4+ T cells but is not found in purified CD34+ hematopoietic progenitor cells in most patients on antiretroviral therapy, J. Infect. Dis., 205, 1014, 10.1093/infdis/jir884 · DOI
  18. Eriksson, 2013, Comparative analysis of measures of viral reservoirs in HIV-1 eradication studies, PLoS Pathog., 9, e1003174, 10.1371/journal.ppat.1003174 · DOI
  19. Finzi, 1997, Identification of a reservoir for HIV-1 in patients on highly active antiretroviral therapy, Science, 278, 1295, 10.1126/science.278.5341.1295 · DOI · Paper page
  20. Ganesh, 2003, The gene product Murr1 restricts HIV-1 replication in resting CD4+ lymphocytes, Nature, 426, 853, 10.1038/nature02171 · DOI
  21. Han, 2004, Resting CD4+ T cells from human immunodeficiency virus type 1 (HIV-1)-infected individuals carry integrated HIV-1 genomes within actively transcribed host genes, J. Virol., 78, 6122, 10.1128/JVI.78.12.6122-6133.2004 · DOI
  22. Han, 2008, Orientation-dependent regulation of integrated HIV-1 expression by host gene transcriptional readthrough, Cell Host Microbe, 4, 134, 10.1016/j.chom.2008.06.008 · DOI
  23. He, 2002, Counterregulation of chromatin deacetylation and histone deacetylase occupancy at the integrated promoter of human immunodeficiency virus type 1 (HIV-1) by the HIV-1 repressor YY1 and HIV-1 activator Tat, Mol. Cell. Biol., 22, 2965, 10.1128/MCB.22.9.2965-2973.2002 · DOI
  24. Hermankova, 2003, Analysis of human immunodeficiency virus type 1 gene expression in latently infected resting CD4+ T lymphocytes in vivo, J. Virol., 77, 7383, 10.1128/JVI.77.13.7383-7392.2003 · DOI
  25. Herrmann, 1995, Lentivirus Tat proteins specifically associate with a cellular protein kinase, TAK, that hyperphosphorylates the carboxyl-terminal domain of the large subunit of RNA polymerase II: candidate for a Tat cofactor, J. Virol., 69, 1612, 10.1128/jvi.69.3.1612-1620.1995 · DOI
  26. Jones, 1994, Control of RNA initiation and elongation at the HIV-1 promoter, Annu. Rev. Biochem., 63, 717, 10.1146/annurev.bi.63.070194.003441 · DOI
  27. Jordan, 2003, HIV reproducibly establishes a latent infection after acute infection of T cells in vitro, EMBO J., 22, 1868, 10.1093/emboj/cdg188 · DOI · Paper page
  28. Kao, 1987, Anti-termination of transcription within the long terminal repeat of HIV-1 by tat gene product, Nature, 330, 489, 10.1038/330489a0 · DOI
  29. Kauder, 2009, Epigenetic regulation of HIV-1 latency by cytosine methylation, PLoS Pathog., 5, e1000495, 10.1371/journal.ppat.1000495 · DOI
  30. Kinoshita, 1997, The T cell activation factor NF-ATc positively regulates HIV-1 replication and gene expression in T cells, Immunity, 6, 235, 10.1016/S1074-7613(00)80326-X · DOI
  31. Laird, 2013, Rapid quantification of the latent reservoir for HIV-1 using a viral outgrowth assay, PLoS Pathog., 9, e1003398, 10.1371/journal.ppat.1003398 · DOI
  32. Lassen, 2004, The multifactorial nature of HIV-1 latency, Trends Mol. Med., 10, 525, 10.1016/j.molmed.2004.09.006 · DOI
  33. Lehrman, 2005, Depletion of latent HIV-1 infection in vivo: a proof-of-concept study, Lancet, 366, 549, 10.1016/S0140-6736(05)67098-5 · DOI
  34. Lenasi, 2008, Transcriptional interference antagonizes proviral gene expression to promote HIV latency, Cell Host Microbe, 4, 123, 10.1016/j.chom.2008.05.016 · DOI
  35. Li, 2007, Rapid reversion of sequence polymorphisms dominates early human immunodeficiency virus type 1 evolution, J. Virol., 81, 193, 10.1128/JVI.01231-06 · DOI
  36. Malim, 1989, The HIV-1 rev trans-activator acts through a structured target sequence to activate nuclear export of unspliced viral mRNA, Nature, 338, 254, 10.1038/338254a0 · DOI · Paper page
  37. Nabel, 1987, An inducible transcription factor activates expression of human immunodeficiency virus in T cells, Nature, 326, 711, 10.1038/326711a0 · DOI
  38. Patel, 1988, Phenotypic and functional characterization of human T cell clones, J. Immunol., 141, 3726, 10.4049/jimmunol.141.11.3726 · DOI
  39. Richman, 2009, The challenge of finding a cure for HIV infection, Science, 323, 1304, 10.1126/science.1165706 · DOI
  40. Rose, 2000, Detecting hypermutations in viral sequences with an emphasis on G→A hypermutation, Bioinformatics, 16, 400, 10.1093/bioinformatics/16.4.400 · DOI
  41. Sanchez, 1997, Accumulation of defective viral genomes in peripheral blood mononuclear cells of human immunodeficiency virus type 1-infected individuals, J. Virol., 71, 2233, 10.1128/jvi.71.3.2233-2240.1997 · DOI
  42. Schröder, 2002, HIV-1 integration in the human genome favors active genes and local hotspots, Cell, 110, 521, 10.1016/S0092-8674(02)00864-4 · DOI · Paper page
  43. Selby, 1990, Trans-activation by HIV-1 Tat via a heterologous RNA binding protein, Cell, 62, 769, 10.1016/0092-8674(90)90121-T · DOI
  44. Shan, 2011, Influence of host gene transcription level and orientation on HIV-1 latency in a primary-cell model, J. Virol., 85, 5384, 10.1128/JVI.02536-10 · DOI
  45. Shan, 2012, Stimulation of HIV-1-specific cytolytic T lymphocytes facilitates elimination of latent viral reservoir after virus reactivation, Immunity, 36, 491, 10.1016/j.immuni.2012.01.014 · DOI
  46. Siliciano, 2005, Enhanced culture assay for detection and quantitation of latently infected, resting CD4+ T-cells carrying replication-competent virus in HIV-1-infected individuals, Methods Mol. Biol., 304, 3
  47. Simon-Loriere, 2011, Why do RNA viruses recombine?, Nat. Rev. Microbiol., 9, 617, 10.1038/nrmicro2614 · DOI
  48. Singh, 2010, Transcriptional bursting from the HIV-1 promoter is a significant source of stochastic noise in HIV-1 gene expression, Biophys. J., 98, L32, 10.1016/j.bpj.2010.03.001 · DOI
  49. Spivak, 2011, Circulating monocytes are not a major reservoir of HIV-1 in elite suppressors, J. Virol., 85, 10399, 10.1128/JVI.05409-11 · DOI
  50. Strain, 2003, Heterogeneous clearance rates of long-lived lymphocytes infected with HIV: intrinsic stability predicts lifelong persistence, Proc. Natl. Acad. Sci. USA, 100, 4819, 10.1073/pnas.0736332100 · DOI
  51. Tyagi, 2010, Establishment of HIV latency in primary CD4+ cells is due to epigenetic transcriptional silencing and P-TEFb restriction, J. Virol., 84, 6425, 10.1128/JVI.01519-09 · DOI
  52. Van Lint, 1996, Transcriptional activation and chromatin remodeling of the HIV-1 promoter in response to histone acetylation, EMBO J., 15, 1112, 10.1002/j.1460-2075.1996.tb00449.x · DOI
  53. Verdin, 1993, Chromatin disruption in the promoter of human immunodeficiency virus type 1 during transcriptional activation, EMBO J., 12, 3249, 10.1002/j.1460-2075.1993.tb05994.x · DOI
  54. Vicenzi, 1994, An integration-defective U5 deletion mutant of human immunodeficiency virus type 1 reverts by eliminating additional long terminal repeat sequences, J. Virol., 68, 7879, 10.1128/jvi.68.12.7879-7890.1994 · DOI
  55. Weinberger, 2005, Stochastic gene expression in a lentiviral positive-feedback loop: HIV-1 Tat fluctuations drive phenotypic diversity, Cell, 122, 169, 10.1016/j.cell.2005.06.006 · DOI
  56. Weinberger, 2008, Transient-mediated fate determination in a transcriptional circuit of HIV, Nat. Genet., 40, 466, 10.1038/ng.116 · DOI
  57. West, 2001, Activation of human immunodeficiency virus transcription in T cells revisited: NF-kappaB p65 stimulates transcriptional elongation, J. Virol., 75, 8524, 10.1128/JVI.75.18.8524-8537.2001 · DOI
  58. Williams, 2007, Regulation of HIV-1 latency by T-cell activation, Cytokine, 39, 63, 10.1016/j.cyto.2007.05.017 · DOI
  59. Williams, 2006, NF-kappaB p50 promotes HIV latency through HDAC recruitment and repression of transcriptional initiation, EMBO J., 25, 139, 10.1038/sj.emboj.7600900 · DOI
  60. Wong, 1997, Recovery of replication-competent HIV despite prolonged suppression of plasma viremia, Science, 278, 1291, 10.1126/science.278.5341.1291 · DOI · Paper page
  61. Yang, 2009, Isolation of a cellular factor that can reactivate latent HIV-1 without T cell activation, Proc. Natl. Acad. Sci. USA, 106, 6321, 10.1073/pnas.0809536106 · DOI
  62. Yu, 2004, Single-strand specificity of APOBEC3G accounts for minus-strand deamination of the HIV genome, Nat. Struct. Mol. Biol., 11, 435, 10.1038/nsmb758 · DOI
  63. Brown, 2001, Interval Estimation for a Binomial Proportion, Stat. Sci., 16, 101, 10.1214/ss/1009213286 · DOI

Cited by

Sorted by citations

Authors
Ho, Y.-C., Shan, L., Hosmane, N. N., Wang, J., Laskey, S. B., Rosenbloom, D. I. S., Lai, J., Blankson, J. N., Siliciano, J. D., & Siliciano, R. F.
Affiliations
  • Johns Hopkins University (US)
  • Louisiana State University (US)
  • Harvard University (US)
  • Howard Hughes Medical Institute (US)
Corresponding author
Siliciano, Robert F.
ORCID
Venue
Cell
Publisher
Elsevier BV
Published
2013-10
Volume
155
Issue
3
Pages
540-551
ISSN
0092-8674 (ISSN-L)
DOI
10.1016/j.cell.2013.09.020
PMC
PMC3896327
OpenAlex
W2115580899
Cited by
1,405
References
4
Citations by year
2026: 62 · 2025: 90 · 2024: 112 · 2023: 100 · 2022: 88 · 2021: 113 · 2020: 144 · 2019: 130 · 2018: 135 · 2017: 109 · 2016: 116 · 2015: 112 · 2014: 85 · 2013: 8
FWCI
49.14
Type
journal article
Language
en
Open access
Licence
Locations
  • Cell (publishedVersion)
  • PubMed (publishedVersion)
  • Europe PMC (PubMed Central) (acceptedVersion)
  • PubMed Central (acceptedVersion)
Funders
  • Howard Hughes Medical Institute
  • amfAR, The Foundation for AIDS Research
  • Johns Hopkins University
  • National Institutes of Health (AI 096113, AI096109)
  • Center for AIDS Research, University of Washington
  • Center for AIDS Research, Johns Hopkins University
  • National Institute of Allergy and Infectious Diseases (U19AI096109, R01AI043222, AI-096113, AI043222, AI096109, R37AI051178, U19AI096113, P30AI094189)
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, HIV-1 cure, proviral clones, long terminal repeat, CD4+ T cells, antiretroviral therapy failure
MeSH terms
Base Sequence, Lymphocyte Activation, Molecular Sequence Data, Mutation, Phylogeny, Proviruses, CD4-Positive T-Lymphocytes, HIV-1, HIV Infections, HIV Long Terminal Repeat, Sequence Alignment, Virus Latency, DNA Methylation

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