Expression of the simian Epstein-Barr virus-encoded latent membrane protein-1 in malignant lymphomas of SIV-infected rhesus macaques.
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.
Blaschke
S
S
Department of Nephrology and Rheumatology, University of Göttingen, Göttingen, Germany. sblasch@gwdg.de
Hannig
H
H
Buske
C
C
Kaup
F J
FJ
Hunsmann
G
G
Bodemer
W
W
D000818:Animals; D001402:B-Lymphocytes / Q000821:virology; D002461:Cell Line, Transformed; D018076:DNA, Complementary; D004195:Disease Models, Animal; D020031:Epstein-Barr Virus Infections / Q000821:virology*; D015658:HIV Infections / Q000150:complications*; D004854:Herpesvirus 4, Human / Q000378:metabolism*; D006801:Humans; D017403:In Situ Hybridization; D016483:Lymphoma, AIDS-Related / Q000821:virology*; D008252:Macaca fascicularis; D008253:Macaca mulatta; D020133:Reverse Transcriptase Polymerase Chain Reaction; D016097:Simian Acquired Immunodeficiency Syndrome / Q000150:complications*; D015302:Simian Immunodeficiency Virus; D014407:Tumor Cells, Cultured; D014763:Viral Matrix Proteins / Q000235:genetics / Q000378:metabolism*
D018076:DNA, Complementary; C037662:EBV-associated membrane antigen, Epstein-Barr virus; D014763:Viral Matrix Proteins