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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.

Funded by the NIH National Center for Advancing Translational Sciences through its Clinical and Translational Science Awards Program, grant number UL1TR002541.