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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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NEOPLASIA

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

Beata U. Orzechowska1,*, Michael F. Powers1,2,*, Jerald Sprague1, He Li1, Bonnie Yen1, Robert P. Searles1, Michael K. Axthelm1,2, and Scott W. Wong1,2,3

1 Vaccine and Gene Therapy Institute, Oregon Health & Science University, West Campus, Beaverton; 2 Division of Pathobiology and Immunology, Oregon National Primate Research Center, Beaverton; and 3 Department of Molecular Microbiology and Immunology, Oregon Health & Science University, Portland

Rhesus macaque rhadinovirus (RRV) is closely related to Kaposi sarcoma-associated herpesvirus (KSHV) and is associated with the development of B-cell hyperplasia and persistent lymphadenopathy resembling multicentric Castleman disease in rhesus macaques (RMs) coinfected with simian immunodeficiency virus (SIV). Here we investigated whether RMs experimentally infected with SIV and RRV can develop other disease manifestations observed in HIV- and KSHV-infected patients. As reported earlier, inoculation of SIV-infected RMs with RRV results in persistent RRV infection, whereas immunocompetent animals infected with RRV exhibit viremia 2 weeks after 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 extranodal 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 FLICE-like inhibitory protein (vFLIP) transcripts. Reverse-transcriptase polymerase chain reaction analysis confirmed vIL-6 and vFLIP expression, and that of RRV open reading frames 72 and 73, homologs of KSHV open reading frames shown to be expressed in primary effusion lymphoma. These data support the utility of the RRV-/SIV-infected RM as an excellent animal model to investigate KSHV-like pathogenesis.


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