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

• Published in: Blood 2008-11, Vol.112 (10), p.4227-4234
• Main Authors: Orzechowska, Beata U., Powers, Michael F., Sprague, Jerald, Li, He, Yen, Bonnie, Searles, Robert P., Axthelm, Michael K., Wong, Scott W.
• Format: Article
• Language: English
• Subjects: Animals; Biological and medical sciences; Castleman Disease - metabolism; Castleman Disease - virology; Disease Models, Animal; Gene Expression Regulation, Leukemic; Gene Expression Regulation, Viral; Hematologic and hematopoietic diseases; Herpesviridae Infections - metabolism; Herpesviridae Infections - virology; Herpesvirus 8, Human - metabolism; HIV; HIV Infections - metabolism; HIV Infections - virology; Humans; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Lymphoma, Non-Hodgkin - metabolism; Lymphoma, Non-Hodgkin - virology; Macaca mulatta; Medical sciences; Neoplasia; Rhadinovirus - metabolism; Simian Acquired Immunodeficiency Syndrome - metabolism; Simian Acquired Immunodeficiency Syndrome - virology; Simian Immunodeficiency Virus; Tumor Virus Infections - metabolism; Tumor Virus Infections - virology; Viral Proteins - biosynthesis
• ISSN: 0006-4971; 1528-0020
• DOI: 10.1182/blood-2008-04-151498

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.