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Despite combination antiretroviral therapy, high-grade malignantnon-Hodgkin's lymphoma (NHL) is still one of the most frequently acquiredimmunodeficiency syndrome (AIDS)-defining disorders in the end stage ofinfection with human immunodeficiency virus (HIV). NHL can also be observedin rhesus macaques infected with the simian immunodeficiency virus (SIV). Thus, theyrepresent a useful model to study morphological characteristics andoncogenetic mechanisms of NHL in humans. When reviewing the occurrence of lymphoma at the German Primate Center overthe past 25 years within the context of pathogenic SIV infection we noticeda strikingly high incidence (four out of seven animals) of these tumors in rhesusmacaques infected with ex vivo derived SIVmac251/32H/spleen inAIDS-defining end-stage disease. Polymerase chain reaction analysis of this virus stock revealedthe co-presence of rhesus lymphocryptovirus (rhLCV), which represents themonkey homologue to human Epstein–Barr virus (EBV), suggesting an associationbetween co-application of SIV and rhLCV and increased tumorigenesis. In addition, we present two cases of NHL in rhesus macaques infected with aSIVmac239 nef-mutant variant because one exhibited an unusualimmunophenotype and the other an uncommon organ manifestation. Histologicaland immunohistochemical examinations of tumors of the first animal revealedmetastatic diffuse large B-cell lymphomas (DLBCL) affecting the stomach andthe pancreaticoduodenal lymph nodes, of which the one in the stomachpresented the rare dual expression of CD20 and CD3. Necropsy of the secondanimal revealed an obstructive DLBCL around the urinary bladder neck thatled to urine backflow and eventually death due to acute uremia without anyfurther AIDS-like manifestations. In the tumors of both animals, abundantEpstein–Barr nuclear antigen-2 expression was demonstrated, thus verifyingconcurrent rhLCV infection. Flow cytometric analyses revealed a highpercentage of activation as well as proliferation in B cells from peripherallymph nodes in both animals. Moreover, CD4+ T cells were depleted inblood, colon and lymphoid tissue. Concomitantly, CD8+ T cellsshowed an exhausted phenotype. The two case reports and the increasedincidence of NHL following co-application of SIV and rhLCV underline therole of rhLCV in lymphomagenesis

primate biology/primate biology

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