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Toll-like receptor signaling controls reactivation of KSHV from latency
Sean M. Gregorya,b,
John A. Westa,b,
Patrick J. Dillona,b,
Dirk P. Dittmera,b, and
aLineberger Comprehensive Cancer Center and bDepartment of Microbiology and Immunology, University of North Carolina, Chapel Hill, NC 27599
Received for publication March 5, 2009.
Kaposi's sarcoma-associated herpesvirus (KSHV) is the etiologicalagent 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 intermittentperiods of reactivation. Physiological triggers of herpesviralreactivation are poorly defined. Toll-like receptors (TLRs)recognize pathogens and are vital for the host innate immuneresponse. We screened multiple TLR agonists for their abilityto initiate KSHV replication in latently infected PEL. Agonistsspecific for TLR7/8 reactivated latent KSHV and induced virallytic gene transcription and replication. Furthermore, vesicularstomatitis virus (VSV), a bonafide physiological activator ofTLR7/8, also reactivated KSHV from latency. This demonstratesthat secondary pathogen infection of latently infected cellscan reactivate KSHV. Human herpesviruses establish life-longlatency in the host, and it is plausible that a latently infectedcell will encounter multiple pathogens during its lifetime andthat these encounters lead to episodic reactivation. Our findingshave broad implications for physiological triggers of latentviral infections, such as herpesviral reactivation and persistencein the host.
Key Words: TLR7 TLR8
Communicated by Clyde A. Hutchison III, The J. Craig VenterInstitute, 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. contributednew reagents/analytic tools; S.M.G., D.P.D., and B.D. analyzeddata; and S.M.G., D.P.D., and B.D. wrote the paper.
An Interleukin-6-Related Systemic Inflammatory Syndrome in Patients Co-Infected with Kaposi Sarcoma-Associated Herpesvirus and HIV but without Multicentric Castleman Disease.
T. S. Uldrick, V. Wang, D. O'Mahony, K. Aleman, K. M. Wyvill, V. Marshall, S. M. Steinberg, S. Pittaluga, I. Maric, D. Whitby, et al. (2010)
Clinical Infectious Diseases
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