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Efficient lentiviral transduction of liver requires cell cycling in vivo

Abstract

Human-immunodeficiency-virus (HIV)–based lentiviral vectors are a promising tool for in vivo gene therapy1. Unlike Moloney-murine-leukaemia–based retroviruses (MLV), lentiviruses are believed to stably transduce quiescent (non-cycling) cells in various organs2,3,4,5,6. No previous studies, however, have directly established the cell-cycle status of any transduced cell type at the time of vector administration in vivo. In vitro studies using wild-type HIV or HIV-based vectors have shown that, in some cases, cell-cycle activation is required for infection, even though cellular mitosis is not an absolute requirement for integration7,8,9. Even if the block in reverse transcription is overcome in quiescent T cells, productive infection by HIV cannot be rescued in the absence of cell-cycle activation7,10. The potential use of these vectors for gene therapy prompted our study, which establishes a cell-cycle requirement for efficient transduction of hepatocytes in vivo.

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Figure 1: β-galactosidase expression in mouse liver following lentiviral transduction.
Figure 2: Nuclear lacZ expression in the hepatocytes of mice injected with a lentiviral vector.
Figure 3: Liver toxicity measured by serum alanine aminotransferase (ALT) concentrations.
Figure 4: Co-localization of BrdU and cytoplasmic lacZ labelling in mouse liver.
Figure 5: Genomic Southern-blot analysis.

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Acknowledgements

We thank L. Meuse for handling of the mice. F.P. is a recipient of the Judith Graham Pool Fellowship through the National Hemophilia Foundation. K.O. is a recipient of the Japan Society for the Promotion of Science Fellowship. This work was supported by NIH RO1-HL53682.

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Correspondence to Mark A. Kay.

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Park, F., Ohashi, K., Chiu, W. et al. Efficient lentiviral transduction of liver requires cell cycling in vivo. Nat Genet 24, 49–52 (2000). https://doi.org/10.1038/71673

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