Functional Genomic Studies of Vaccinia Virus Provide Fundamental Insights into Virus-Host Interactions

Title: Functional Genomic Studies of Vaccinia Virus Provide Fundamental Insights into Virus-Host Interactions
Authors: Keller, Brian Andrew
Date: 2017
Embargo: 2018-09-13
Abstract: The oncolytic virus field is in the midst of strong and sustained growth. The clinical utility of this class of therapeutics has been bolstered in recent years by the rise of immune checkpoint inhibition, which has the potential to work synergistically with oncolytic viruses to increase the scope of patients who respond favourably to therapy. This growth has been further driven by clear industry support with several pharmaceutical companies acquiring or developing oncolytic virus products following the 2015 FDA approval of Talimogene laherparepvec and the generally-accepted potential of immunotherapeutic approaches to cancer treatment. Vaccinia virus is a double-stranded DNA virus with an extensive history of vaccine use in humans and a desirable safety profile. It is a large virus with a complex lifecycle, and its history of use as a vaccine has resulted in the generation of dozens of unique strains. Although it has been studied extensively, much remains unknown about many vaccinia virus gene function(s) and the virus’ interactions with cellular hosts. Vaccinia virus-based oncolytic viruses have been developed, however clinical outcomes thus far have been unsatisfactory. A more complete understanding of vaccinia virus gene functions must therefore precede the effective design of a next-generation vaccinia virus-based oncolytic candidate. With this downstream goal, we sought to (1) understand the unique oncolytic virus-relevant phenotypic properties of five clinical candidate vaccinia virus strains, and (2) generate and characterize a library of single-gene mutants of the Copenhagen strain of vaccinia virus. These studies resulted in the selection of vaccinia virus-Copenhagen as the wild-type strain of choice that will be utilized for future oncolytic virus development. Furthermore, the generation and initial characterization of an 89-member clonal library of vaccinia-Copenhagen single-gene mutants will be an important tool as we seek to generate a next-generation oncolytic virus candidate. Completed characterization studies challenge the role that viral thymidine kinase should play in oncolytic virus design, demonstrate novel functions of the vaccinia virus gene A47L, and provide an understanding of the role of the vaccinia virus gene F15L. These studies also raise the concept of the personalized selection of oncolytic virotherapeutics. This virus library has the potential to increase the fundamental understanding of vaccinia virus biology in this field as well as in the study of vaccine development and pathogen-host interactions.
CollectionThèses, 2011 - // Theses, 2011 -