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  • A gene transfer construct composed of a self-inactivating (SIN) lentiviral vector (LV) expressing a short hairpin RNA (shRNA) that targets the human C-C chemokine receptor type 5 (CCR5) mRNA (sh5) and expressing the HIV entry inhibitor C46, with potential anti-human immunodeficiency virus (HIV) type 1 (HIV-1) activity. Upon transduction of the anti-HIV-1 LVsh5/C46 Cal-1 in specified blood cell populations, such as peripheral blood mononuclear cells (PBMCs), hematopoietic stem/progenitor cells (HSPCs) and CD4+ T-lymphocytes, the cells express shCCR5 and C46. shCCR5 targets and binds to CCR5 mRNA, which inhibits the expression of CCR5 and prevents binding of the virus to the cellular CCR5 co-receptor. The cell surface expression of the cell membrane-anchored C46 peptide blocks HIV-1 fusion to the cellular membrane. The removal of CCR5 from and the production of C46 in the bone marrow and white blood cells, make the transduced cells resistant to and protect them from HIV-1 entry, infection and replication. HIV-resistant HSPCs could provide long-term protection against latent HIV infection and against HIV-associated cancers. C46 is a membrane-anchored 46-amino acid sequence found in HIV-1 gp41. CCR5 is a HIV-1 co-receptor that mediates HIV attachment and cell entry.
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