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During the course of simian immunodeficiency virus (SIV) infection, nearly 15% of rhesus macaques (Macaca mulatta) and up to 40% of cynomolgus macaques (Macaca fascicularis) developed SIV-associated non-Hodgkin's lymphomas. Most of these malignant lymphomas harbored lymphocryptoviruses, which are closely related to the human Epstein-Barr virus (EBV; Herpesvirus M. mulatta and Herpesvirus M. fascicularis). To characterize the oncogenic role of simian EBV infection for lymphomagenesis during SIV infection, expression of the EBV-encoded latent membrane protein-1 (LMP-1) was analyzed in malignant lymphomas of SIV-infected rhesus macaques. Nine seropositive rhesus macaques suffering from B-cell lymphomas during the late phase of SIV infection were euthanized. Latency stages of EBV infection within malignant lymphomas and simian EBV-infected lymphoblastoid cell lines (LCL8664, H50) were characterized by analyzing expression of the EBV-encoded nuclear antigens EBNA-1, EBNA-2, and small RNAs EBER1/2. In parallel, the presence of viral LMP-1 transcripts was assessed by reverse transcription-polymerase chain reaction (RT-PCR) and in situ hybridization. Results were compared with findings in AIDS-associated malignant lymphomas in two patients infected with human immunodeficiency virus (HIV)-1. Rhesus macaques developed high-grade B-cell lymphomas of the centroblastic (five of nine), immunoblastic (two of nine), centroblastic-centrocytic (one of nine), and Burkitt-like (one of nine) subtypes within 18-29 months postinfection with SIV(mac)251/32H. The presence of Herpesvirus M. mulatta was detected in eight of nine cases. Transcription of the viral oncogene LMP-1 could be demonstrated within the simian EBV-infected cell lines as well as in four of nine SIV-associated malignant lymphomas. These four cases and both of the HIV-1-related non-Hodgkin's lymphomas expressed the full spectrum of latent EBV gene products (LMP-1, EBER1/2, EBNA-1, EBNA-2) and were thus classified as latency type III stages of EBV infection. Simian EBV infection was demonstrated in 90% of lymphomas in SIV-infected rhesus macaques. Analysis of LMP-1 expression suggests an important role for this viral oncogene in the pathogenesis of both SIV and HIV-1-associated malignant lymphomas.

Background & Aims: Human immunodeficiency virus (HIV) infection leads to severe immunologic and functional disturbances in the intestinal tract in late stages of the disease. Information on mucosal pathology directly after infection is limited. We characterized this early phase in rhesus macaques infected with simian immunodeficiency virus (SIV). Methods: Eight rhesus macaques were infected with SIV. Upper endoscopy was performed at defined times before and after infection. Viral load, percentage of CD4 + T cells, villus height, crypt depth, and Ki-67–positive crypt cells were analyzed in duodenal biopsy specimens. Serum β-carotene and vitamin D levels were assessed. Results: A rapid increase of duodenal SIV core protein (p27) concentration and an almost complete loss of intestinal CD4 + T cells was found within 2 weeks after infection. A decrease of villus height was observed, and the percentage of Ki-67–positive (proliferating) crypt cells increased. Serum concentrations of vitamin D decreased in 6 of 8 animals, and β-carotene concentrations decreased in 3 of 8 animals after infection. Conclusions: Mucosal SIV replication and intestinal CD4 + T cell depletion are early events in SIV-infected rhesus macaques. The structural changes of the mucosa strongly support the concept of HIV/SIV–induced enteropathy. In contrast to late-stage human HIV infection, early small intestinal villous atrophy in SIV infection is associated with crypt hyperplasia. GASTROENTEROLOGY 1999;116:1115-1123