Abstract
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.
Highlights
Lymphomas are linked to human immunodeficiency virus (HIV) infection in that they are known to occur in association with acquired immunodeficiency syndrome (AIDS) and are classified as an AIDS-defining disease
A total of 163 simian immunodeficiency virus (SIV)-infected rhesus macaques were included to calculate the incidence of lymphoma development in SIVinfected rhesus macaques at the German Primate Puerto Rico (Center) over the past two and a half decades
We correlated the incidence of SIV-associated lymphoma that occurred during the last 25 years at the German Primate Center with the different virus stocks used for infection
Summary
Lymphomas are linked to human immunodeficiency virus (HIV) infection in that they are known to occur in association with acquired immunodeficiency syndrome (AIDS) and are classified as an AIDS-defining disease. Lymphoid neoplasms can be divided into Hodgkin’s and nonHodgkin’s lymphomas (NHL). Most of the AIDS-associated lymphomas are high-grade malignant NHL of B-cell origin, and co-infection with Epstein–Barr virus (EBV) is assumed to play an important role in oncogenesis (HamiltonDutoit et al, 1993). Virus reactivation is associated with the development of tumors. The most common NHL type according to this classification is the diffuse large B-cell lymphoma (DLBCL), accounting for 31 % of all NHLs (Armitage and Weisenburger, 1998)
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