The principal goal of this proposal is to apply our expertise with Epstein-Barr virus to relevant areas of AIDS related research. We will study the interactions between EBV and SIV infection using a novel animal model for experimental Epstein-Barr virus infection. In addition, we will develop recombinant EBV vectors to facilitate HIV gene transfer in vitro and provide these for use by other labs studying immune responses to HIV. Old World primates are naturally infected with a gamma herpesvirus closely related to human EBV. These simian viruses are colinear and share considerable nucleotide homology with the human counterpart. More importantly, the biologic behavior of these viruses mimics human EBV infection, i) simian EBV infect and immortalize B lymphocytes in vitro, ii) serologic evidence of EBV infection is very common, iii) transmission requires intimate contact, iv) the virus persists asymptomatically in the animal for life, and v) EBV-positive malignancies can arise in immunosuppressed animals. We have identified that rhesus monkeys in a pathogen free colony at the New England Regional Primate Research Center (NERPRC) are routinely EBV seronegative, and our preliminary experiments indicate that they should provide a novel experimental model for natural EBV infection. These animals provide the unique opportunity to study the interactions between two pathogenic viruses, i.e. SIV and EBV, in an experimental model in vivo.
The specific aims are as follows: 1. Characterize the natural course of experimental EBV infection. 2. Determine the effect of SIV-induced immunodeficiency on experimental EBV infection in rhesus monkeys. 3. Characterize the phenotype of EBV- induced malignancies arising in she setting of SW-induced immunodeficiency. 4. Evaluate whether cytokine profiles or EBV-specific tests can identify SIV-infected animals at risk for development of EBV- induced lymphomas. 5. Evaluate potential therapeutic modalities against EBV-induced lymphomas. 6. Develop recombinant EBV vectors for HP/gene transfer in vitro. These experiments will apply novel EBV systems to relevant areas of AIDS- related research. New advance in recombinant EBV technology and gene transfer will be useful for in vitro evaluation of HIV- and vaccine- induced immune responses. A novel model for experimental EBV infection in rhesus monkeys also provides a unique opportunity to study the natural interactions between EBV and SIV with direct relevance to the increasing clinical problem of EBV-induced lymphomas in AIDS patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA065319-03
Application #
2458143
Study Section
AIDS and Related Research Study Section 3 (ARRC)
Project Start
1995-09-30
Project End
1999-07-31
Budget Start
1997-08-01
Budget End
1998-07-31
Support Year
3
Fiscal Year
1997
Total Cost
Indirect Cost
Name
Brigham and Women's Hospital
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02115
Rivailler, Pierre; Carville, Angela; Kaur, Amitinder et al. (2004) Experimental rhesus lymphocryptovirus infection in immunosuppressed macaques: an animal model for Epstein-Barr virus pathogenesis in the immunosuppressed host. Blood 104:1482-9
Cho, Y; Ramer, J; Rivailler, P et al. (2001) An Epstein-Barr-related herpesvirus from marmoset lymphomas. Proc Natl Acad Sci U S A 98:1224-9
Jiang, H; Cho, Y G; Wang, F (2000) Structural, functional, and genetic comparisons of Epstein-Barr virus nuclear antigen 3A, 3B, and 3C homologues encoded by the rhesus lymphocryptovirus. J Virol 74:5921-32
Rao, P; Jiang, H; Wang, F (2000) Cloning of the rhesus lymphocryptovirus viral capsid antigen and Epstein-Barr virus-encoded small RNA homologues and use in diagnosis of acute and persistent infections. J Clin Microbiol 38:3219-25
Cho, Y G; Gordadze, A V; Ling, P D et al. (1999) Evolution of two types of rhesus lymphocryptovirus similar to type 1 and type 2 Epstein-Barr virus. J Virol 73:9206-12
Rivailler, P; Quink, C; Wang, F (1999) Strong selective pressure for evolution of an Epstein-Barr virus LMP2B homologue in the rhesus lymphocryptovirus. J Virol 73:8867-72
Blake, N W; Moghaddam, A; Rao, P et al. (1999) Inhibition of antigen presentation by the glycine/alanine repeat domain is not conserved in simian homologues of Epstein-Barr virus nuclear antigen 1. J Virol 73:7381-9
Ruf, I K; Moghaddam, A; Wang, F et al. (1999) Mechanisms that regulate Epstein-Barr virus EBNA-1 gene transcription during restricted latency are conserved among lymphocryptoviruses of Old World primates. J Virol 73:1980-9
Wang, F; Seldin, D C; Annis, B et al. (1998) Immune modulation of human B lymphocytes by gene transfer with recombinant Epstein-Barr virus amplicons. J Virol Methods 72:81-93
Moghaddam, A; Koch, J; Annis, B et al. (1998) Infection of human B lymphocytes with lymphocryptoviruses related to Epstein-Barr virus. J Virol 72:3205-12

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