Decman, Vilma
(2005)
The dual role of gamma interferon during herpes simplex virus type 1 infection.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
In the first project we demonstrate that IFNgamma alone can block HSV-1 reactivation in some latently infected neurons, and we identify points of intervention in the life cycle of the reactivating virus. Cell suspensions of TGs that were latently infected with recombinant HSV-1 expressing EGFP from the promoter for ICP0 or gC were depleted of endogenous CD8+ or CD45+ cells and cultured with or without IFNgamma. IFNgamma treatment reduced: (i) HSV-1 reactivation; and (ii) the number of neurons that express the ICP0 or gC promoter in ex vivo TG cultures. Moreover, those neurons that expressed the ICP0 or gC promoters in the presence of IFNgamma showed a reduced reactivation. Interestingly, we detected transcripts for ICP0, ICP4, and gH in neurons that expressed the ICP0 promoter in the presence of IFNgamma, but were prevented from fully reactivating. Thus, the IFNgamma blockade of HSV-1 reactivation from latency occurs at prior to expression of the ICP0 gene (required for reactivation) as well as at a very late stage in reactivation following expression of at least some structural genes.A second project tested the hypothesis that IFNgamma regulates the observed expansion, contraction, and homeostasis/memory phases of the HSV-1-specific CD8+ T cell response within the latently infected TG. We addressed this hypothesis by observing the effect of in vivo IFNgamma neutralization during the three phases of the response. IFNgamma neutralization significantly reduced the expansion phase through a 50% reduction in proliferation of HSV-1-specific CD8eff cells. IFNgamma neutralization also significantly accelerated the contraction phase through an as yet undefined mechanism. In contrast, IFNgamma neutralization did not affect the homeostasis/memory phase. A novel finding of these studies was that an HSV-1-specific CD8+ memory precursor population (CD8mp, defined by expression of CD127) exhibited a delayed expansion and contraction relative to the overall CD8eff population. We are currently determining if the disruption of the expansion and contraction of CD8mp through IFNgamma neutralization will influence the functional avidity of the CD8mem population that ultimately develops. Since HSV-1-specific CD8mem appear to play an important role in regulating HSV-1 latency, optimizing this population could have important implications for controlling recurrent herpetic disease.
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Details
| Item Type: |
University of Pittsburgh ETD
|
| Status: |
Unpublished |
| Creators/Authors: |
|
| ETD Committee: |
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| Date: |
30 August 2005 |
| Date Type: |
Completion |
| Defense Date: |
18 July 2005 |
| Approval Date: |
30 August 2005 |
| Submission Date: |
15 August 2005 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
abundance; CD8 T cells; gB; gC; HSV-1; ICP0; IFNgamma; latency; memory |
| Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-08152005-114813/, etd-08152005-114813 |
| Date Deposited: |
10 Nov 2011 19:59 |
| Last Modified: |
15 Nov 2016 13:49 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/9100 |
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