Simian AIDS-Associated Lymphoma in Rhesus and Cynomolgus Monkeys Recapitulates the Primary Pathobiological Features of AIDS-Associated Non-Hodgkin's Lymphoma

Abstract

Non-Hodgkin's lymphomas occur with increased frequency (3-6%) in HIV-infected individuals. These AIDS-associated lymphomas (AALs) exhibit characteristics that distinguish them from lymphomas in the general population. A proposed model for the pathogenesis of AAL includes the following: (1) Tumorigenesis is multistep; (2) tumors occur in long-term survivors; (3) tumors are of clonal B cell origin; (4) HIV acts early and is an indirect effector; (5) tumor cells are infected with EBV; and (6) specific genetic lesions occur in tumor cells. Many aspects of this process remain to be tested in an animal model system. Since 1984, necropsy examinations have been performed on more than 1000 SIV-infected rhesus and cynomolgus monkeys at the Tulane Regional Primate Research Center. Lymphoid malignancies were detected in a proportion of SIV-infected animals. These SAIDS-associated lymphomas (SALs) have been studied to determine the extent to which their pathological features recapitulate a working model for the pathogenesis of AAL. The results show that lymphomas occur in SIV-infected rhesus macaques at 4% incidence, similar to that of AAL, and that the incidence of SAL in cynomolgus macaques is eightfold higher. Analysis of SAL from both species of macaques demonstrated significant similarity to the hallmark pathobiological features of AAL. These findings indicate that the HIV-infected human and the SIV-infected macaque share a common pathobiology and mechanism of lymphomagenesis.

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

“…2,4,6,14,20,21,24,26,28 Therefore, it is particularly noteworthy that both cases of LCV-positive lymphomas in our study exhibited a T-cell phenotype in Japanese macaques exhibiting cell tropism different from those in cynomolgus and rhesus macaques. In addition, the LCVpositive macaque lymphomas differed substantially with respect to age and cellular morphology.…”

“…While T-cell lymphomas have also been reported in pig-tailed macaques, 3,27 they appear to be much less common than B-cell lymphomas in cynomolgus and rhesus macaques. Although there are many reports on B-cell lymphomas in cynomolgus and rhesus macaques, 4,11,14,[20][21][22][23][24]28 T-cell lymphomas have not been reported in these macaque species, except for 1 case in a rhesus macaque diagnosed with CD8-positive leukemia by flow cytometry. Identifying the cause of lymphoma in each macaque would help in understanding the differences in the tumor phenotype.…”

“…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.…”

Intracranial Lymphomas in Simian Retrovirus-Positive Macaca fascicularis

“…3,5 EBV-like lymphocryptovirus sequences are detected in most lymphomas of rhesus macaques, and less often in lymphomas of cynomolgus macaques. 5 In addition to SIV, simian retrovirus (SRV) type D is immunosuppressive in macaques, causing the simian acquired immunodeficiency syndrome; however, this syndrome is not generally associated with development of lymphomas. 10 We report here two cases of intracranial lymphoma in naturally SRV-infected macaques, in the absence of SIV infection.…”

“…5,6 However, the incidence in experimentally SIV-infected animals ranges from 3.8% to 19% in rhesus 5,6 and from 31% to 38% in cynomolgus monkeys. 3,5 EBV-like lymphocryptovirus sequences are detected in most lymphomas of rhesus macaques, and less often in lymphomas of cynomolgus macaques. 5 In addition to SIV, simian retrovirus (SRV) type D is immunosuppressive in macaques, causing the simian acquired immunodeficiency syndrome; however, this syndrome is not generally associated with development of lymphomas.…”