Articles | Volume 3, issue 2
Primate Biol., 3, 65–75, 2016

Special issue: 3R issues and immunosuppression in non-human primates

Primate Biol., 3, 65–75, 2016

Research article 20 Dec 2016

Research article | 20 Dec 2016

Lymphocryptovirus-dependent occurrence of lymphoma in SIV-infected rhesus macaques with particular consideration to two uncommon cases of non-Hodgkin's lymphoma

Antonina Klippert1,*, Martina Bleyer2,*, Ulrike Sauermann1, Berit Neumann1, Artur Kaul3, Maria Daskalaki1, Nicole Stolte-Leeb1, Frank Kirchhoff4, and Christiane Stahl-Hennig1 Antonina Klippert et al.
  • 1Unit of Infection Models, German Primate Center, Goettingen, Germany
  • 2Pathology Unit, German Primate Center, Goettingen, Germany
  • 3Unit of Infection Biology, German Primate Center, Goettingen, Germany
  • 4Institute of Molecular Virology, Ulm University Medical Center, Ulm, Germany
  • *These authors contributed equally to this work.

Abstract. Despite combination antiretroviral therapy, high-grade malignant non-Hodgkin's lymphoma (NHL) is still one of the most frequently acquired immunodeficiency syndrome (AIDS)-defining disorders in the end stage of infection with human immunodeficiency virus (HIV). NHL can also be observed in rhesus macaques infected with the simian immunodeficiency virus (SIV). Thus, they represent a useful model to study morphological characteristics and oncogenetic mechanisms of NHL in humans.

When reviewing the occurrence of lymphoma at the German Primate Center over the past 25 years within the context of pathogenic SIV infection we noticed a strikingly high incidence (four out of seven animals) of these tumors in rhesus macaques infected with ex vivo derived SIVmac251/32H/spleen in AIDS-defining end-stage disease. Polymerase chain reaction analysis of this virus stock revealed the co-presence of rhesus lymphocryptovirus (rhLCV), which represents the monkey homologue to human Epstein–Barr virus (EBV), suggesting an association between co-application of SIV and rhLCV and increased tumorigenesis.

In addition, we present two cases of NHL in rhesus macaques infected with a SIVmac239 nef-mutant variant because one exhibited an unusual immunophenotype and the other an uncommon organ manifestation. Histological and immunohistochemical examinations of tumors of the first animal revealed metastatic diffuse large B-cell lymphomas (DLBCL) affecting the stomach and the pancreaticoduodenal lymph nodes, of which the one in the stomach presented the rare dual expression of CD20 and CD3. Necropsy of the second animal revealed an obstructive DLBCL around the urinary bladder neck that led to urine backflow and eventually death due to acute uremia without any further AIDS-like manifestations. In the tumors of both animals, abundant Epstein–Barr nuclear antigen-2 expression was demonstrated, thus verifying concurrent rhLCV infection. Flow cytometric analyses revealed a high percentage of activation as well as proliferation in B cells from peripheral lymph nodes in both animals. Moreover, CD4+ T cells were depleted in blood, colon and lymphoid tissue. Concomitantly, CD8+ T cells showed an exhausted phenotype. The two case reports and the increased incidence of NHL following co-application of SIV and rhLCV underline the role of rhLCV in lymphomagenesis.

Short summary
Despite effective antiviral therapy, HIV infection frequently leads to blood cell tumors known as lymphoma in the final disease stage. We have observed the same tumors in monkeys infected with simian immunodeficiency virus. Tumor development coincided with and was fostered by co-infection with the tumorigenic simian homolog to human Epstein–Barr virus. Two cases of lymphoma are presented, one exhibiting an unusual cell surface marker composition and the other obstructing the urogenital tract.