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Blood, 15 November 2008, Vol. 112, No. 10, pp. 4227-4234.
Prepublished online as a Blood First Edition Paper on August 29, 2008; DOI 10.1182/blood-2008-04-151498.


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Submitted April 17, 2008
Accepted July 7, 2008

Rhesus macaque rhadinovirus-associated non-Hodgkin's lymphoma: animal model for KSHV associated malignancies

Beata U Orzechowska, Michael F Powers, Jerald Sprague, He Li, Bonnie Yen, Robert P Searles, Michael K Axthelm, and Scott W Wong*

Vaccine and Gene Therapy Institute, Oregon Health & Science University, Beaverton, OR, United States
Oregon National Primate Research Center, Oregon Health & Science University, Beaverton, OR, United States
Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland, OR, United States

* Corresponding author; email: wongs{at}ohsu.edu.

Rhesus macaque rhadinovirus (RRV) is closely related to Kaposi's sarcoma-associated herpesvirus (KSHV) and is associated with the development of B cell hyperplasia and persistent lymphadenopathy resembling multi-centric Castleman's disease (MCD) in rhesus macaques (RM) co-infected with simian immunodeficiency virus (SIV). Here, we investigated whether RM experimentally infected with SIV and RRV can develop other disease manifestations that are observed in HIV and KSHV-infected individuals. As reported earlier, experimental inoculation of SIV-infected RM with RRV results in persistent RRV infection, whereas immunocompetent animals infected with RRV exhibit viremia two weeks post-infection, followed by a period of no virus detection until they are subsequently made immunodeficient by SIV-infection. A subset of animals developed abnormal cellular proliferations characterized as extra-nodal lymphoma and a proliferative mesenchymal lesion. In situ hybridization and immunohistochemistry analysis indicate RRV is present in both malignancies and DNA microarray analysis detected viral interleukin-6 (vIL-6) and viral FLIP transcripts. Subsequent reverse-transcriptase PCR analysis confirmed vIL-6 and vFLIP expression, and that of RRV ORFs 72 and 73, all homologues of the KSHV ORFs shown to be expressed in primary effusion lymphoma. These data support the utility of the RRV/SIV-infected rhesus macaque as an excellent animal model to investigate KSHV-like pathogenesis.


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