Retargeting Oncolytic Vesicular Stomatitis Virus to Human T-Cell Lymphotropic Virus Type 1-Associated Adult T-Cell Leukemia.
Bottom Line: VSV-gp160G was further noted to be highly attenuated and did not replicate efficiently in or induce significant cell death of primary CD4(+) T cells.Importantly, VSV-gp160G effectively exerted potent oncolytic activity in patient-derived ATL transplanted into NSG mice and facilitated a significant survival benefit.This effect greatly reduced neurotoxic risk associated with VSV infection while still allowing VSV to effectively target ATL cells.
Affiliation: Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida, USA.Show MeSH
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Mentions: Recombinant VSV with endogenous VSV-G has a wide tropism and is able to infect most mammalian cell types (49). In murine models, VSV can exhibit toxicity when administered at high doses due to the onset of neuropathy. To eliminate this potential problem and to create an oncolytic vector that targets only ATL cells, which are CD4+, we generated a VSV vector with the G protein substituted with a hybrid fusion protein containing extracellular and transmembrane domains from HIV1 gp160 and the cytoplasmic region of VSV-G. HIV-1 utilizes its glycoprotein, gp160, to gain entry into T cells through entry association with CD4 (Fig. 1A and B) (48). Due to the lack of human CD4 in the BHK-21-WI cells, VSV-gp160G was first recovered with the inclusion of a support VSV-G plasmid to VSV-G pseudotype the virions and enable infection of BHK-21-WI cells. Then, after successful recovery, VSV-gp160G was grown in HeLa CD4+ cells to amplify the progeny virions sans VSV-G.
Affiliation: Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida, USA.