Macaque Homologs of EBV and KSHV Show Uniquely Different Associations with Simian AIDS-related Lymphomas

Abstract

Two gammaherpesviruses, Epstein-Barr virus (EBV) (Lymphocryptovirus genus) and Kaposi's sarcoma-associated herpesvirus (KSHV) (Rhadinovirus genus) have been implicated in the etiology of AIDS-associated lymphomas. Homologs of these viruses have been identified in macaques and other non-human primates. In order to assess the association of these viruses with non-human primate disease, archived lymphoma samples were screened for the presence of macaque lymphocryptovirus (LCV) homologs of EBV, and macaque rhadinoviruses belonging to the RV1 lineage of KSHV homologs or the more distant RV2 lineage of Old World primate rhadinoviruses. Viral loads were determined by QPCR and infected cells were identified by immunolabeling for different viral proteins. The lymphomas segregated into three groups. The first group (n = 6) was associated with SIV/SHIV infections, contained high levels of LCV (1–25 genomes/cell) and expressed the B-cell antigens CD20 or BLA.36. A strong EBNA-2 signal was detected in the nuclei of the neoplastic cells in one of the LCV-high lymphomas, indicative of a type III latency stage. None of the lymphomas in this group stained for the LCV viral capsid antigen (VCA) lytic marker. The second group (n = 5) was associated with D-type simian retrovirus-2 (SRV-2) infections, contained high levels of RV2 rhadinovirus (9–790 genomes/cell) and expressed the CD3 T-cell marker. The third group (n = 3) was associated with SIV/SHIV infections, contained high levels of RV2 rhadinovirus (2–260 genomes/cell) and was negative for both CD20 and CD3. In both the CD3-positive and CD3/CD20-negative lymphomas, the neoplastic cells stained strongly for markers of RV2 lytic replication. None of the lymphomas had detectable levels of retroperitoneal fibromatosis herpesvirus (RFHV), the macaque RV1 homolog of KSHV. Our data suggest etiological roles for both lymphocryptoviruses and RV2 rhadinoviruses in the development of simian AIDS-associated lymphomas and indicate that the virus-infected neoplastic lymphoid cells are derived from different lymphocyte lineages and differentiation stages.

Characterization of Spontaneous Malignant Lymphomas in Japanese Macaques (Macaca fuscata)

“…The macaque LCV viral loads in the lymphomas were first examined by the established real-time qPCR assay that can detect LCVs from different macaque species. 4 Unexpectedly, the qPCR assays were negative in case Nos. 1 and 5, although EBER-positive signals were detected by in situ hybridization in both these cases.…”

“…Necropsies were performed at each facility after death (case Nos. [2][3][4][5] 16 but additional analysis was performed in the present study.…”

“…3,4 While the primers and probe of the RV2 qPCR assay matched the genomic sequences of Japanese macaque RV2 rhadinovirus (GenBank accession no. AY528864), 3 no viral DNA was detected in case Nos.…”

“…4,6,14,20,24,26 However, the previously reported cases of lymphoma in Japanese macaques exhibited a T/NK-cell phenotype with EBER-positive signals, 16,29 suggesting the possibility that Japanese macaque LCVs have tropisms for T cells and/or NK cells. Therefore, further investigations are required to characterize the immunophenotypes of lymphomas and to define the cell tropism of LCVs in Japanese macaques.…”

“…4 Interestingly, the RV2 rhadinoviruses were detected in a number of T-cell lymphomas of pig-tailed macaques. 4 Given that the previous cases in Japanese macaques were T/NK-cell lymphomas, there is a possibility that an RV2 rhadinovirus is also associated with lymphoma in Japanese macaques. The present study examined the characteristics of spontaneous lymphomas in Japanese macaques while focusing on the immunophenotypes and presence of macaque LCVs.…”