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The Induction and Inhibition of an Antiviral Response by Herpes Simplex Virus 1

Eidson, Kasey Michelle (2006) The Induction and Inhibition of an Antiviral Response by Herpes Simplex Virus 1. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Herpes Simplex Virus-1 (HSV-1) infection has been shown to be very resistant to the effects of the cellular interferon response. However, in the absence of viral gene expression HSV-1 induces the expression of cellular interferon-stimulated genes, possibly through activation of the interferon-regulatory factor 3 (IRF-3) cascade. The induction of IRF-3 by HSV-1 infection has not been well characterized. Using an HSV-1 mutant deficient in the expression of viral genes, we show that HSV-1 can induce the cascade of IRF-3 activation by stimulating the phosphorylation of IRF-3 and the nuclear localization of the protein. We will show that activation of this pathway leads to the expression of interferon-stimulated genes and the production of a protective antiviral response. Further we will show that the expression of one viral gene, ICP0, is essential and sufficient to the inhibition of interferon-stimulated gene expression. An HSV-1 mutant deficient in expression of all immediate-early HSV-1 genes except ICP0 does not induce nuclear accumulation of IRF-3 and does not induce the expression of interferon-stimulated genes. This virus induces the mis-localization of the kinase (TBK-1) responsible for the phosphorylation of IRF-3. Cytoplasmically localized ICP0 expressed in wild-type infection stimulates the translocation of TBK-1 from the cytoplasm to the Golgi apparatus. This ICP0-mediated mis-localization, as well as a portion of that induced by the ICP0 expressing mutant, can be inhibited through the inhibition of the proteasome. Further, IRF-3 nuclear translocation and interferon-stimulated gene expression can be restored during infection with the ICP0-expressing mutant virus in the presence of proteasome inhibitors. This study explores the induction of the interferon regulatory factor-3 cellular antiviral response pathway, and presents a possible mechanism for the virus' resistance to the cellular antiviral response.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Eidson, Kasey Michellekmest20@pitt.eduKMEST20
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairDeLuca, Nealndeluca@pitt.eduNDELUCA
Committee MemberHoma, Fredflhoma@pitt.eduFLHOMA
Committee MemberKinchington, Paulkinch@pitt.eduKINCH
Committee MemberKhan, Saleemkhan@pitt.eduKHAN
Committee MemberSmithgall, Thomastsmithga@pitt.eduTSMITHGA
Date: 30 November 2006
Date Type: Completion
Defense Date: 25 October 2006
Approval Date: 30 November 2006
Submission Date: 14 November 2006
Access Restriction: No restriction; Release the ETD for access worldwide immediately.
Institution: University of Pittsburgh
Schools and Programs: School of Medicine > Molecular Virology and Microbiology
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: d106; d109; HSP90
Other ID: http://etd.library.pitt.edu/ETD/available/etd-11142006-204506/, etd-11142006-204506
Date Deposited: 10 Nov 2011 20:04
Last Modified: 15 Nov 2016 13:51
URI: http://d-scholarship.pitt.edu/id/eprint/9667

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