Access Type

Open Access Dissertation

Date of Award

January 2017

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Immunology and Microbiology

First Advisor

Philip E. Pellett

Abstract

Human cytomegalovirus (HCMV) is a ubiquitous viral pathogen. In individuals with fully functioning and mature immune systems, HCMV is associated with mild symptoms prior to establishing latency. In individuals with naïve or compromised immune systems, HCMV is capable of causing severe organ damage. HCMV is the leading infectious cause of congenital birth defects and a major non-genetic cause of hearing loss. Unfortunately, antiviral treatment options lack diversity due to limited knowledge of virion replication. If HCMV replication were better understood, new antiviral treatments could be developed.

In this work, we describe the development and implementation of new tools to study HCMV replication with a focus on envelopment and egress. We generated a novel HCMV bacterial artificial chromosome (BAC) expression system for characterizing the effects of exogenous proteins in the context of HCMV replication. While demonstrating the new BAC, TB40/E/Cre, we are also able to draw conclusions relating HCMV genome size to replication efficiency. In addition, we characterize the transcriptional profile of cellular proteins during HCMV infection. We found that HCMV causes significant alteration in host mRNA expression and targets a number of transcripts related to vesicle-mediated trafficking. By tracing the effects of HCMV on cellular trafficking, we propose a model of virion envelopment and egress.

Through this work, we now have the capability to test our predictions and determine the route of viral maturation and exocytosis in host cells. By constructing a map of HCMV replication, we provide critical control points for use in developing novel antiviral therapies.

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