All ETDs from UAB

Advisory Committee Chair

James M Markert

Advisory Committee Members

Peter R Smith

Mark N Prichard

Gregory Y Gillespie

Document Type

Thesis

Date of Award

2012

Degree Name by School

Master of Science in Biomedical Science (MSBMS) School of Engineering

Abstract

Glioblastoma Multiforme is a primary malignancy of the central nervous system and is fatal for patients despite surgical resection and radiotherapy. Oncolytic Herpes Simplex Virus (oHSV) vectors deleted of the γ134.5 neurovirulence gene are potential therapies for treating glioblastoma tumors. Although replication in permissive cells is considered the primary mechanism of oHSV mediated tumor clearance, there is evidence that the immune system is part of the tumor clearance mechanism during treatment with oncolytic viruses. Specifically, natural killer (NK) cells may be important for tumor clearance during oHSV therapy. NK cell activation relies partially on the stimulation of activating or inhibitory receptors and their respective ligands encountered on the surfaces of stressed cells. One of the most important and well studied receptor/ligand pairs is the natural killer cell activating receptor Natural Killer Group 2 member D (NKG2D) and the ligand MHC-class-I-polypeptide-related chain A (MICA). Members of the herpes family of viruses have evolved mechanisms of down-modulating MICA surface expression to prevent NK cell activation. This phenomenon is observed with HSV type-1 infection of epithelial tumor lines, yet the mechanism of action is currently unknown. In this work, we tested the hypothesis that HSV infection down-modulates MICA on glioma cells, a phenomenon which could negatively impact the NK cell mediated anti-tumor activity of oHSV. Specificity of MICA down-modulation was studied by analyzing another surface membrane protein, transferrin receptor. The contribution of Virion Host Shut-off (VHS) protein to MICA mRNA degradation as a possible mechanism to surface protein down-modulation was studied by utilization of a VHS deleted virus. These studies demonstrate that MICA is down-modulated from the surface and interior of glioma cells during HSV infection and that down-modulation is specific to MICA compared to levels of transferrin receptor, which in contrast were increased. Comparison of mRNA and protein levels during wild type and VHS deleted recombinant infection suggests that VHS contributes to MICA mRNA degradation but not to protein down-modulation. Continued studies to identify the mechanism of MICA surface down-modulation and will allow for design of oHSV vectors able to optimize anti-tumor immune responses and prolong patient survival.

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Engineering Commons

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