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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

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Ho, Ya-Chi, Shan, Liang, Hosmane, Nina N., Wang, Jeffrey, Laskey, Sarah B., Rosenbloom, Daniel I.S., Lai, Jun, Blankson, Joel N. +2 more·2013·Cell
DOI 10.1016/j.cell.2013.09.020PMC PMC3896327
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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.

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Crossref · 10.1016/j.cell.2013.09.020

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  • 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)

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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

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