Publication Date

2017-05-05

Availability

Open access

Embargo Period

2017-05-05

Degree Type

Dissertation

Degree Name

Doctor of Philosophy (PHD)

Department

Microbiology and Immunology (Medicine)

Date of Defense

2017-04-28

First Committee Member

Glen N. Barber

Second Committee Member

XiangXi Xu

Third Committee Member

Samita Andreansky

Fourth Committee Member

Enrique A. Mesri

Fifth Committee Member

Jaime Merchan

Sixth Committee Member

Balveen Kaur

Abstract

Oncolytic virotherapy is an exciting field that is currently generating a significant amount of interest. Several viruses have recently been approved for clinical use and there are many more in clinical trials awaiting approval. Vesicular Stomatitis Virus (VSV) has performed remarkably well in many preclinical studies and several strains have entered clinical trials across the world. VSV is a negative strand ssRNA virus in the Rhabdoviridae family and mainly infects livestock which produce sores on the mucus membranes. VSV infection in humans is extremely rare and most often asymptomatic due to its inability to overcome the innate and adaptive immune response of healthy individuals. However, upon infection of many types of cancerous cells VSV displays rapid growth kinetics and significant oncolytic potential due to defects in innate immune and translational control pathways commonly seen in cancer cells. VSV is of significant research interest partly due to its simple genome that is highly malleable. The entire 11kb genome has been cloned into a cDNA plasmid and the insertion and deletion of different genes allows for a highly customizable virus that researchers can take advantage. One such modification in our lab is the replacement of the VSV glycoprotein with a fusion protein created using domains of HIV-1 gp160 and VSV-G. The fusion protein dubbed gp160G was properly incorporated into VSV virions and successfully altered the tropism of the virus. VSV-gp160G was selective for CD4+ cells and induced significant amounts of syncytia and apoptosis during infection of Hela CD4+ and adult T cell leukemia (ATL) cells. When used as a therapeutic in an ATL mouse model, VSV-gp160G improved survival time of tumor bearing mice and significantly reduced the onset of metastasis. The success of VSV-gp160G as a targeted therapy in ATL mouse models warrants further study as the virus could be an important therapeutic option to treat ATL in the clinic.

Keywords

VSV; cancer; oncolytic virotherapy; ATL

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