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PNAS 106 (28): 11725-11730

Copyright © 2009 by the National Academy of Sciences.


BIOLOGICAL SCIENCES / MICROBIOLOGY

Toll-like receptor signaling controls reactivation of KSHV from latency

Sean M. Gregorya,b, John A. Westa,b, Patrick J. Dillona,b, Chelsey Hilschera,b, Dirk P. Dittmera,b, and Blossom Damaniaa,b,1

aLineberger Comprehensive Cancer Center and bDepartment of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599

Received for publication March 5, 2009.

Abstract: Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi's sarcoma, primary effusion lymphoma (PEL), and multicentric Castleman's disease. Like other herpesviruses, KSHV establishes life-long latency in the human host with intermittent periods of reactivation. Physiological triggers of herpesviral reactivation are poorly defined. Toll-like receptors (TLRs) recognize pathogens and are vital for the host innate immune response. We screened multiple TLR agonists for their ability to initiate KSHV replication in latently infected PEL. Agonists specific for TLR7/8 reactivated latent KSHV and induced viral lytic gene transcription and replication. Furthermore, vesicular stomatitis virus (VSV), a bonafide physiological activator of TLR7/8, also reactivated KSHV from latency. This demonstrates that secondary pathogen infection of latently infected cells can reactivate KSHV. Human herpesviruses establish life-long latency in the host, and it is plausible that a latently infected cell will encounter multiple pathogens during its lifetime and that these encounters lead to episodic reactivation. Our findings have broad implications for physiological triggers of latent viral infections, such as herpesviral reactivation and persistence in the host.

Key Words: TLR7 • TLR8


Communicated by Clyde A. Hutchison III, The J. Craig Venter Institute, San Diego, CA, May 18, 2009

Author contributions: S.M.G. and B.D. designed research; S.M.G., J.A.W., C.H., and D.P.D. performed research; P.J.D. contributed new reagents/analytic tools; S.M.G., D.P.D., and B.D. analyzed data; and S.M.G., D.P.D., and B.D. wrote the paper.

The authors declare no conflict of interest.

This article contains supporting information online at www.pnas.org/cgi/content/full/0905316106/DCSupplemental.

1To whom correspondence should be addressed. E-mail: damania{at}med.unc.edu


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