ArticleGenetic vaccines and therapy2009
Characterization of a potent non-cytotoxic shRNA directed to the HIV-1 co-receptor CCR5.
Article in Genetic vaccines and therapy, 2009. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed.
- Anti-HIV-1 HSPC-based gene therapy with safety kill switch to defend against and attack HIV-1 infection.Molecular therapy. Methods & clinical development · 2025Article
- In vivo selection of anti-HIV-1 gene-modified human hematopoietic stem/progenitor cells to enhance engraftment and HIV-1 inhibition.Molecular therapy : the journal of the American Society of Gene Therapy · 2024Article
- Potent dual block to HIV-1 infection using lentiviral vectors expressing fusion inhibitor peptide mC46- and Vif-resistant APOBEC3G.Molecular therapy. Nucleic acids · 2023Article
- Review
- Genetic Strategies for HIV Treatment and Prevention.Molecular therapy. Nucleic acids · 2018Review
- Article
- Modern biotechnology-based therapeutic approaches against HIV infection.Biomedical reports · 2017Article
- The Role of Natural Antibodies to CC Chemokine Receptor 5 in HIV Infection.Frontiers in immunology · 2017Review
- Article
- Development of Lentiviral Vectors Simultaneously Expressing Multiple siRNAs Against CCR5, vif and tat/rev Genes for an HIV-1 Gene Therapy Approach.Molecular therapy. Nucleic acids · 2016Article
- Ectopic expression of anti-HIV-1 shRNAs protects CD8(+) T cells modified with CD4ζ CAR from HIV-1 infection and alleviates impairment of cell proliferation.Biochemical and biophysical research communications · 2015Article
- Review
- Bone Marrow Gene Therapy for HIV/AIDS.Viruses · 2015Review
- RNAi-Mediated CCR5 Knockdown Provides HIV-1 Resistance to Memory T Cells in Humanized BLT Mice.Molecular therapy. Nucleic acids · 2015Article
- RNA interference approaches for treatment of HIV-1 infection.Genome medicine · 2015Article
- Modulation of Gene Expression by Polymer Nanocapsule Delivery of DNA Cassettes Encoding Small RNAs.PloS one · 2015Article
- Pol III Promoters to Express Small RNAs: Delineation of Transcription Initiation.Molecular therapy. Nucleic acids · 2014Article
- Dynamics of HSPC repopulation in nonhuman primates revealed by a decade-long clonal-tracking study.Cell stem cell · 2014Article
- Preclinical safety and efficacy of an anti-HIV-1 lentiviral vector containing a short hairpin RNA to CCR5 and the C46 fusion inhibitor.Molecular therapy. Methods & clinical development · 2014Article
- Article
Corrections and comments
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Authors and funding
10 authors.
Funding
Abstract
backgroundThe use of shRNAs to downregulate the expression of specific genes is now relatively routine in experimentation but still hypothetical for clinical application. A potential therapeutic approach for HIV-1 disease is shRNA mediated downregulation of the HIV-1 co-receptor, CCR5. It is increasingly recognized that siRNAs and shRNAs can have unintended consequences such as cytotoxicities in cells, particularly when used for long term therapeutic purposes. For the clinical use of shRNAs, it is crucial to identify a shRNA that can potently inhibit CCR5 expression without inducing unintended cytotoxicities.
resultsPrevious shRNAs to CCR5 identified using conventional commercial algorithms showed cytotoxicity when expressed using the highly active U6 pol III promoter in primary human peripheral blood derived mononuclear cells. Expression using the lower activity H1 promoter significantly reduced toxicity, but all shRNAs also reduced RNAi activity. In an effort to identify shRNAs that were both potent and non-cytotoxic, we created a shRNA library representing all potential CCR5 20 to 22-nucleotide shRNA sequences expressed using an H1 promoter and screened this library for downregulation of CCR5. We identified one potent CCR5 shRNA that was also non-cytotoxic when expressed at a low level with the H1 promoter. We characterized this shRNA in regards to its function and structure. This shRNA was unique that the use of commercial and published algorithms to predict effective siRNA sequences did not result in identification of the same shRNA. We found that this shRNA could induce sequence specific reduction of CCR5 at post transcriptional level, consistent with the RNA interference mechanism. Importantly, this shRNA showed no obvious cytotoxicity and was effective at downregulating CCR5 in primary human peripheral blood derived mononuclear cells.
conclusionWe report on the characterization of a rare shRNA with atypical structural features having potent RNAi activity specific to CCR5. These results have implications for the application of RNAi technology for therapeutic purposes.
Identifiers
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.