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Characterization of the Cellular and Molecular Factors Mediating Antigen-Independent Noncytolytic CD8+ T Cell Suppression of HIV-1

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 (Unpublished)

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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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Item Type: University of Pittsburgh ETD
Status: Unpublished
CreatorsEmailPitt UsernameORCID
Tumne, Ashwinastst9@pitt.eduASTST9
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairGupta, Phalgunipgupta1@pitt.eduPGUPTA1
Committee MemberDay, Billy Wbday@pitt.eduBDAY
Committee MemberRobbins, Paul Cprobb@pitt.eduPROBB
Committee MemberMontelaro, Ronald Crmont@pitt.eduRMONT
Committee MemberBarratt-Boyes, Simon Msmbb@pitt.eduSMBB
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:, etd-04212006-063351
Date Deposited: 10 Nov 2011 19:40
Last Modified: 15 Nov 2016 13:41


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