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Cited by 61HIV Research and TreatmentRNA Interference and Gene DeliveryVirus-based gene therapy research

Promoter Targeting shRNA Suppresses HIV-1 Infection In vivo Through Transcriptional Gene Silencing

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Suzuki, Kazuo, Hattori, Shinichiro, Marks, Katherine, Ahlenstiel, Chantelle, Maeda, Yosuke, Ishida, Takaomi, Millington, Michelle, Boyd, Maureen +4 more·2013·Molecular Therapy - Nucleic Acids
DOI 10.1038/mtna.2013.64PMC PMC3894581
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Abstract

Despite prolonged and intensive application, combined antiretroviral therapy cannot eradicate human immunodeficiency virus (HIV)-1 because it is harbored as a latent infection, surviving for long periods of time. Alternative approaches are required to overcome the limitations of current therapy. We have been developing a short interfering RNA (siRNA) gene silencing approach. Certain siRNAs targeting promoter regions of genes induce transcriptional gene silencing. We previously reported substantial transcriptional gene silencing of HIV-1 replication by an siRNA targeting the HIV-1 promoter in vitro. In this study, we show that this siRNA, expressed as a short hairpin RNA (shRNA) (shPromA-JRFL) delivered by lentiviral transduction of human peripheral blood mononuclear cells (PBMCs), which are then used to reconstitute NOJ mice, is able to inhibit HIV-1 replication in vivo, whereas a three-base mismatched variant (shPromA-M2) does not. In shPromA-JRFL-treated mice, HIV-1 RNA in serum is significantly reduced, and the ratio of CD4(+)/CD8(+) T cells is significantly elevated. Expression levels of the antisense RNA strand inversely correlates with HIV-1 RNA in serum. The silenced HIV-1 can be reactivated by T-cell activation in ex vivo cultures. HIV-1 suppression is not due to offtarget effects of shPromA-JRFL. These data provide "proof-of principle" that an shRNA targeting the HIV-1 promoter is able to suppress HIV-1 replication in vivo.Molecular Therapy-Nucleic Acids (2013) 2, e137; doi:10.1038/mtna.2013.64; published online 3 December 2013.

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  • The first anti-HIV-1, siPromA, targeted the unique and highly conserved NK-κB transcription factor sites in the HIV-1 promoter to induce potent epigenetic silencing.

    “The first anti-HIV-1, siPromA, was first identified in 2005 [309], and targeted the unique and highly conserved NK-κB transcription factor sites in the HIV-1 promoter to induce potent epigenetic silencing [70,310,311,312].”

    From Current State of Therapeutics for HTLV-1 (2024) · cites this paper as [70]

    The Results section on promoter targeting identifies the NF-κB region of the HIV-1 promoter as PromA’s target, and the Introduction and Results describe transcriptional silencing associated with chromatin changes. Our copy does not establish that the targeted sites are unique or highly conserved; it reports a one-base mismatch in the HIV-1JRFL strain. The separate 2005 identification claim is attached to a different citation. (LLM, conf=0.85)

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  • The efficacy of siPromA in the treatment of HIV-1 has been characterised by in vivo humanised mouse models, demonstrating robust protection against infection by lowering the HIV-1 cell-associated RNA levels in siPromA-expressing CD4+ T cells isolated from blood and lymphoid tissue.

    “Recently, the efficacy of siPromA in the treatment of HIV-1 has been characterised by in vivo humanised mouse models, demonstrating robust protection against infection by lowering the HIV-1 cell-associated RNA levels in siPromA-expressing CD4+ T cells isolated from blood and lymphoid tissue [70,314].”

    From Current State of Therapeutics for HTLV-1 (2024) · cites this paper as [70]

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Authors
Suzuki, K., Hattori, S., Marks, K., Ahlenstiel, C., Maeda, Y., Ishida, T., Millington, M., Boyd, M., Symonds, G., Cooper, D. A., Okada, S., & Kelleher, A. D.
Affiliations
  • UNSW Sydney (AU)
  • Kumamoto University (JP)
  • Institute of Medical Science, The University of Tokyo (JP)
Corresponding author
Suzuki, Kazuo
ORCID
Venue
Molecular Therapy - Nucleic Acids
Publisher
Elsevier BV
Published
2013
Volume
2
Pages
e137
ISSN
2162-2531 (ISSN-L)
DOI
10.1038/mtna.2013.64
PMC
PMC3894581
OpenAlex
W1974855063
Cited by
61
References
1
Citations by year
2026: 3 · 2025: 1 · 2024: 6 · 2023: 1 · 2022: 2 · 2021: 6 · 2020: 5 · 2019: 5 · 2018: 7 · 2017: 2 · 2016: 6 · 2015: 11 · 2014: 6
FWCI
3.52
Type
journal article
Language
en
Open access
Licence
Locations
  • Molecular Therapy — Nucleic Acids (publishedVersion, cc-by-nc-nd)
  • Europe PMC (PubMed Central) (publishedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by-nc-nd)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
Japan Society for the Promotion of Science (23590548)
Topics
  • Life Sciences › Immunology and Microbiology › Virology › HIV Research and Treatment
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › RNA Interference and Gene Delivery
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
Keywords
HIV-1, transcriptional silencing, siRNA, HIV-1 latency, HIV-1 replication inhibition, lentiviral gene delivery, peripheral blood mononuclear cells, CD4/CD8 ratio, T cell activation, antisense RNA, off-target effects

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