Tumne, Ashwin
(2006)
Characterization of the Cellular and Molecular Factors Mediating Antigen-Independent Noncytolytic CD8+ T Cell Suppression of HIV-1.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
CD8+ T cells have a little understood noncytolytic activity that suppresses human immunodeficiency type 1 (HIV-1) replication in an antigen-independent and MHC-unrestricted manner. This activity specifically inhibits transcription of the HIV-1 proviral genome. Little is understood about the molecular nature of the factor(s) mediating this potent antiviral activity of CD8+ T cells. It is known that a factor secreted by CD8+ T cells can suppress the transcription of HIV-1. However, the antiviral mechanism appears most potent with cell-to-cell contact. Previous investigations by several groups into the nature of this secreted factor have been largely based on a presumption that noncytolytic suppression of HIV-1 by CD8+ T cells is exclusively mediated by a soluble protein. Based on several lines of evidence suggesting the specific involvement of cell-contact determinants in eliciting the noncytolytic CD8+ T cell effector function against HIV-1, a novel approach to the problem was utilized based on the hypothesis that a membrane-bound factor is the prime mediator suppressing HIV-1 transcription. In the ensuing investigation, evidence was uncovered demonstrating the existence of a membrane-localized HIV-1 suppressing factor that was secreted as 30-100nm spherical vesicles termed exosomes. Exosomes from a CD8+ T cell line inhibited the replication of R5 and X4 HIV-1 isolates and were shown to specifically suppress of HIV-1 transcription in acute and chronic models of infection. A much greater degree of complexity to the CD8+ T cell secreted antiviral activity was found than a soluble protein alone could account for. The evidence presented in this study suggests that CD8+ T cell suppression of HIV-1 is predominantly mediated by a membrane-bound protein factor that can be cleaved into a soluble isoform with the secreted CD8+ cell antiviral activity being largely exosome-driven. The results presented in this study provide a much more concrete understanding of the mechanisms underlying CD8+ T cells suppression of HIV-1 transcription and outline new approaches to conclusively identifying the molecular factor mediating potent inhibition of the HIV-1 transcritional promoter.
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Details
Item Type: |
University of Pittsburgh ETD
|
Status: |
Unpublished |
Creators/Authors: |
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ETD Committee: |
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Date: |
27 April 2006 |
Date Type: |
Completion |
Defense Date: |
30 November 2005 |
Approval Date: |
27 April 2006 |
Submission Date: |
21 April 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: |
HIV AIDS CD8 T Cells |
Other ID: |
http://etd.library.pitt.edu/ETD/available/etd-04212006-063351/, etd-04212006-063351 |
Date Deposited: |
10 Nov 2011 19:40 |
Last Modified: |
15 Nov 2016 13:41 |
URI: |
http://d-scholarship.pitt.edu/id/eprint/7416 |
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