NDLI: Modulation of lentiviral vector tropism in cerebellar Purkinje cells in vivo by a lysosomal cysteine protease cathepsin K

Content Provider	Springer Nature Link
Author	Goenawan, Hanna Hirai, Hirokazu
Copyright Year	2012
Abstract	We previously reported that vesicular stomatitis virus-derived glycoprotein (VSV-G)-pseudotyped lentiviral vectors harvested 2 days post-transfection preferred to infect Purkinje cells (PCs), whereas those harvested after a longer cultivation period exhibited Bergmann glia-preferential transduction. However, the mechanisms by which lentiviral tropism was altered remained unsolved. Here, we investigated whether proteases released from the cells during viral production affect lentiviral tropism. Enhanced green fluorescence protein-expressing lentiviral vectors were produced using human embryonic kidney (HEK) 293FT or 293 T cells and injected into the mouse cerebellum to examine tropism in PCs. We found that the addition of a protease inhibitor—in particular, the cathepsin K (CatK) inhibitor—into the culture medium significantly increased lentiviral tropism in PCs. Moreover, the concentration of CatK in the culture medium drastically increased upon prolonged cultivation, concomitant with the expression levels of CatK in HEK 293 T cells. An increase in CatK activity by the addition of recombinant CatK enzyme to PC-preferential viral solution, which was obtained 2 days post-transfection, shifted the viral tropism toward Bergmann glia. In contrast, a decrease in CatK activity in the Bergmann glia-preferential viral solution, which was obtained 6 days post-transfection by the addition of CatK inhibitor or by the removal of a CatK-containing fraction, restored the PC preference of viruses. These results suggest that the CatK released from deteriorated HEK 293 T cells plays a key role in reducing lentiviral tropism in PCs, presumably by affecting a receptor molecule for lentiviral VSV-G, resulting in the preferential transduction of Bergmann glia.
Starting Page	521
Ending Page	531
Page Count	11
File Format	PDF
ISSN	13550284
Journal	Journal of NeuroVirology
Volume Number	18
Issue Number	6
e-ISSN	15382443
Language	English
Publisher	Springer US
Publisher Date	2012-10-16
Publisher Place	Boston
Access Restriction	One Nation One Subscription (ONOS)
Subject Keyword	Lentiviral vector Purkinje cell Protease Cathepsin K HEK 293 Neurology Neurosciences Virology Immunology Infectious Diseases
Content Type	Text
Resource Type	Article
Subject	Neurology Virology Neurology (clinical) Cellular and Molecular Neuroscience

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