Retargeting Oncolytic Vesicular Stomatitis Virus (VSV) to Human T-cell lymphotropic Virus 1 (HTLV1) Associated Adult T-cell leukemia (ATL)
OPEN Journal of virology | 18 Sep 2015
D Betancourt, JC Ramos and GN Barber
Adult T cell leukemia/lymphoma (ATL) is an aggressive cancer of CD4/CD25+ T lymphocytes, the etiological agent of which is human T cell lymphotropic virus 1 (HTLV1). ATL is highly refractory to presently existing therapies, making the development of new treatments a high priority. Oncolytic viruses such as Vesicular Stomatitis Virus (VSV) are presently being considered as anti-cancer agents since they readily infect transformed cells compared to normal cells, the former appearing to exhibit defective innate immune responses. Here, we have evaluated the efficacy and safety of a recombinant VSV that has been retargeted to specifically infect and replicate in transformed CD4+ cells. This was achieved by replacing the single VSV glycoprotein (G) with human immunodeficiency virus (HIV1) gp160, to create a hybrid fusion protein, gp160G. The resultant virus, VSV-gp160G, was found to only target cells expressing CD4 and retained robust oncolytic activity against HTLV-1 actuated ATL cells. 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. Accordingly, VSV-gp160G did not elicit any evidence of neurotoxicity even in severely immunocompromised animals such as NOD/Shi-scid, IL-2γ-c null mice (NSG). Importantly, VSV-gp160G effectively exerted potent oncolytic activity in patient-derived ATL transplanted into NSG mice and facilitated a significant survival benefit. Our data indicates that VSV-gp160G exerts potent oncolytic efficacy against CD4+ malignant cells and either alone or in conjunction with established therapies may provide an effective treatment in patients displaying ATL.
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