Recurrent HSV-1 ocular disease results from reactivation of latent virus in trigeminal ganglia (TG), often following immunosuppression or exposure to a variety of psychological or physical stressors. HSV-specific CD8+ T cells can block HSV-1 reactivation from latency in ex vivo TG cultures in part through production of IFN-γ. Here we establish that either CD8+ T cell depletion or exposure to restraint stress permits HSV-1 to transiently escape from latency in vivo. Restraint stress caused a glucocorticoid-associated reduction of TG-resident HSV-specific CD8+ T cells, and a functional compromise of those cells that survive, at least partly mediated by catecholamines. Together, these effects of stress resulted in an approximate 65% reduction of cells capable of producing IFN-γ, and impairment in the ability of those cells to release lytic granules, in response to reactivating virus. We also establish that restraint stress during the primary infection results in a 54% reduction of virus-specific IL-7Rα+ memory precursor cells in the TG at the peak of expansion. When mice stressed early were stressed again during latency, their T cell response may be further compromised. Our findings demonstrate persistent in vivo regulation of latent HSV-1 by CD8+ T cells, and strongly support the concept that stress induces HSV-1 reactivation from latency at least in part by compromising CD8+ T cell surveillance of latently infected neurons.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-12072007-123821 |
| Date | 07 December 2007 |
| Creators | Freeman, Michael L |
| Contributors | JoAnne Flynn, PhD, Bruce Rabin, MD, PhD, Paul Kinchington, PhD, Robert Hendricks, PhD, Jon Piganelli, PhD |
| 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-12072007-123821/ |
| 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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