title: Retargeting Oncolytic Vesicular Stomatitis Virus to Human T-Cell Lymphotropic Virus Type 1-Associated Adult T-Cell Leukemia.
abstract: 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 type 1 (HTLV-1). ATL is highly refractory to current therapies, making the development of new treatments a high priority. Oncolytic viruses such as vesicular stomatitis virus (VSV) are being considered as anticancer 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 type 1 (HIV-1) 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-2Rγ-c-null (NSG) mice. Importantly, VSV-gp160G effectively exerted potent oncolytic activity in patient-derived ATL transplanted into NSG mice and facilitated a significant survival benefit. Our data indicate 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.
  
  
  OBJECTIVE
  Adult T cell leukemia (ATL) is a serious form of cancer with a high mortality rate. HTLV-1 infection is the etiological agent of ATL and, unfortunately, most patients succumb to the disease within a few years. Current treatment options have failed to significantly improve survival rate. In this study, we developed a recombinant strain of vesicular stomatitis virus (VSV) that specifically targets transformed CD4(+) T cells through replacement of the G protein of VSV with a hybrid fusion protein, combining domains from gp160 of HIV-1 and VSV-G. This modification eliminated the normally broad tropism of VSV and restricted infection to primarily the transformed CD4(+) cell population. This effect greatly reduced neurotoxic risk associated with VSV infection while still allowing VSV to effectively target ATL cells.
authors.affiliation: Department of Microbiology and Immunology, University of Miami School of Medicine, Miami, Florida, USA.
authors.forename: Dillon
authors.initials: D
authors.lastname: Betancourt
authors.affiliation: Department of Medicine and Sylvester Comprehensive Cancer Center, University of Miami School of Medicine, Miami, Florida, USA.
authors.forename: Juan Carlos
authors.initials: JC
authors.lastname: Ramos
authors.affiliation: Department of Cell Biology, University of Miami School of Medicine, Miami, Florida, USA gbarber@med.miami.edu.
authors.forename: Glen N
authors.initials: GN
authors.lastname: Barber
mesh_terms: D000818:Animals; D015153:Blotting, Western; D015496:CD4-Positive T-Lymphocytes / Q000378:metabolism*; D017931:DNA Primers / Q000235:genetics; D005434:Flow Cytometry; D019302:HIV Envelope Protein gp160 / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D015459:Leukemia-Lymphoma, Adult T-Cell / Q000534:rehabilitation* / Q000821:virology*; D051379:Mice; D016688:Mice, Inbred NOD; D009500:Neutralization Tests; D050130:Oncolytic Virotherapy / Q000379:methods*; D050504:Oncolytic Viruses / Q000235:genetics / Q000378:metabolism; D011993:Recombinant Fusion Proteins / Q000235:genetics*; D018116:Vesiculovirus / Q000235:genetics* / Q000378:metabolism
chemical_list: D017931:DNA Primers; D019302:HIV Envelope Protein gp160; D011993:Recombinant Fusion Proteins; C514797:gp160 protein, Human immunodeficiency virus 1