Journal
PLOS ONE
Volume 12, Issue 5, Pages -Publisher
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0177935
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Funding
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek - Chemische Wetenschappen (NWO-CW)
- Zorg Onderzoek Nederland - Medische Wetenschappen (ZonMw)
- Nederlandse Organisatie voor Wetenschappelijk Onderzoek-Chemische Wetenschappen (NWO-CW)
- Zorg Onderzoek Nederland-Medische Wetenschappen (ZonMw)
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Allogeneic transplantation of blood stem cells from a CCR5-Delta 32 homozygous donor to an HIV-infected individual, the Berlin patient, led to a cure. Since then there has been a search for approaches that mimic this intervention in a gene therapy setting. RNA interference (RNAi) has evolved as a powerful tool to regulate gene expression in a sequence-specific manner and can be used to inactivate the CCR5 mRNA. Short hairpin RNA (shRNA) mole-cules can impair CCR5 expression, but these molecules may cause unintended side effects and they will not be processed in cells that lack Dicer, such as monocytes. Dicer-independent RNAi pathways have opened opportunities for new AgoshRNA designs that rely exclusively on Ago2 for maturation. Furthermore, AgoshRNA processing yields a single active guide RNA, thus reducing off-target effects. In this study, we tested different AgoshRNA designs against CCR5. We selected AgoshRNAs that potently downregulated CCR5 expression on human T cells and peripheral blood mononuclear cells (PBMC) and that had no apparent adverse effect on T cell development as assessed in a competitive cell growth assay. CCR5 knockdown significantly protected T cells from CCR5 tropic HIV-1 infection.
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