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: VSV-gp160G's ability to induce apoptosis in HeLa CD4+ cells was confirmed using flow cytometry with annexin V-PI staining. HeLa or HeLa CD4+ cells were infected with either VSV-XN2 or VSV-gp160G at an MOI of 0.1, and representative gating results at 24 hpi are shown (Fig. 2A). Cells and supernatant were collected 6, 12, 24, and 48 hpi to establish the kinetics of VSV-mediated apoptosis for each cell line at an MOI of 0.1. VSV-XN2 exerted oncolytic activity against both HeLa and HeLa CD4+ cells and induced robust cell death within 24 to 48 h of infection. In contrast, VSV-gp160G induced significant apoptosis only in HeLa CD4+ cells with the HeLa cells being completely resistant. Despite its attenuated growth kinetics, VSV-gp160G was able to induce comparable levels of apoptosis in HeLa CD4+ cells (Fig. 2B). To confirm that VSV-gp160G is dependent upon cellular CD4 and viral gp120 interaction, infections were performed in the presence of neutralizing antibodies against either hCD4 or HIV-gp120. VSV-XN2's ability to induce apoptosis was not affected in the presence of either antibody, whereas the ability of VSV-gp160G to induce syncytia or apoptosis was severely attenuated in the presence of the neutralizing antibodies (Fig. 2C and D). Thus, VSV-gp160G specifically infects and kills transformed CD4+ cells in vitro via gp160G.
Affiliation: Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida, USA.