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.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-04212006-063351 |
| Date | 27 April 2006 |
| Creators | Tumne, Ashwin |
| Contributors | Ronald C. Montelaro, Ph.D., Billy W. Day, Ph.D., Simon M. Barratt-Boyes, Ph.D., Paul C. Robbins, Ph.D., Phalguni Gupta, Ph.D. |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-04212006-063351/ |
| Rights | unrestricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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