A novel therapeutic molecule against HTLV-1 infection targeting provirus
Abstract
Human T-cell leukemia virus type 1 (HTLV-1), which causes adult T-cell leukemia (ATL) in humans, establishes a life-long latent infection. Current therapies are not very effective against HTLV-1-associated disorders. A novel therapeutic approach may help to combat HTLV-1 infection. A molecular therapy that targets the proviral genome is favorable because the therapeutic effect occurs specifically in HTLV-1-infected cells, regardless of whether they express viral genes. In this proof-of-concept study, we developed a therapeutic molecule based on zinc finger nuclease (ZFN) to achieve this goal. We designed a ZFN that specifically recognized conserved region of HTLV-1 long terminal repeat (LTR) and introduced it into various HTLV-1-positive human T-cell lines, including HTLV-1-transformed and ATL-derived cell lines. The ZFN disrupted the promoter function of HTLV-1 LTR and specifically killed HTLV-1-infected cells. We also showed a potential approach of this therapeutic molecule to remove the proviral genome from HTLV-1-infected cells, something that has not been possible before. The therapeutic effect of ZFN was confirmed in an in vivo model of ATL. This strategy may form the basis of a therapy that can eradicate HTLV-1 infection. Similar approaches can be used to target other malignancy-associated viruses.
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ZFNs targeted the HTLV-1 LTR regions and demonstrated potent disruption of the HTLV-1 LTR promoter, anti-tumour effects in vivo, and apoptosis of HTLV-1-infected cells triggered by DSBs in the LTR.
“These studies demonstrated potent disruption of the HTLV-1 LTR promoter and subsequent proviral gene expression, anti-tumour effects in vivo, and, most importantly, apoptosis of HTLV-1-infected cells triggered by DSBs in the LTR.”
From Current State of Therapeutics for HTLV-1 (2024) · cites this paper as [293]
ZFN technology has been used to successfully target proviral DNA in HBV, HSV-2 and HTLV-1 infection.
“ZFN technology has also been used to successfully target proviral DNA in HBV [49], HSV-2 [50] and HTLV-1 [51] infection.”
From Newer Gene Editing Technologies toward HIV Gene Therapy (2013) · cites this paper as [51]
These proof-of-concept studies suggest that it is also possible to target HIV proviral DNA.
“These proof-of-concept studies suggest that it is also possible to target HIV proviral DNA.”
From Newer Gene Editing Technologies toward HIV Gene Therapy (2013) · cites this paper as [51]
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“Argonaute 1 (Ago1) protein ushers the promoter–complementary siRNA to enter the nucleus and forms the RNA-induced transcriptional silencing (RITS) complex, which induces heritable, epigenetic modifications that repress transcription, thereby silencing gene expression [303] (Figure 5).”
Background
- Authors
- Tanaka, A., Takeda, S., Kariya, R., Matsuda, K., Urano, E., Okada, S., & Komano, J.
- Affiliations
- Research Institute for Microbial Diseases, The University of Osaka (JP)
- National Institute of Infectious Diseases (JP)
- Kumamoto University (JP)
- Corresponding author
- Komano, J
- Venue
- Leukemia
- Published
- 2013-02-15
- Volume
- 27
- Issue
- 8
- Pages
- 1621-1627
- ISSN
- 0887-6924 (ISSN-L)
- 1476-5551
- OpenAlex
- W2056486686
- Cited by
- 46
- References
- 22
- Citations by year
- 2026: 1 · 2025: 5 · 2024: 2 · 2023: 3 · 2022: 6 · 2021: 1 · 2020: 4 · 2019: 2 · 2018: 3 · 2017: 2 · 2016: 3 · 2015: 6 · 2014: 6 · 2013: 2
- FWCI
- 3.13
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Leukemia (publishedVersion)
- PubMed (publishedVersion)
- Funders
- Japan Health Sciences Foundation
- Topics
- Life Sciences › Immunology and Microbiology › Immunology › T-cell and Retrovirus Studies
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Virus-based gene therapy research
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › CRISPR and Genetic Engineering
- Keywords
- HTLV-1, adult T-cell leukemia/lymphoma, zinc finger nucleases, long terminal repeat, viral latency, gene therapy
- MeSH terms
- Animals, Base Sequence, Binding Sites, Cell Line, Cell Transformation, Neoplastic, Endonucleases, Genetic Vectors, Humans, Molecular Sequence Data, Protein Binding, Proviruses, Transduction, Genetic, Human T-lymphotropic virus 1, Leukemia-Lymphoma, Adult T-Cell, HTLV-I Infections, Gene Expression, Mutagenesis, Site-Directed, Zinc Fingers, Genes, Reporter, Terminal Repeat Sequences, Gene Order, Tumor Burden, Mice, Molecular Targeted Therapy
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