The principal goal of this proposal is to develop a model for experimental Epstein-Barr virus infection which mimics the persistent, latent EBV infection in humans. Currently available models consist of acute infection of cotton top marmosets, a New World primate, or SCID mice which, if successful, result in the demise of the animal by uncontrolled growth of EBV immortalized B cells. These animal models reproduce the phenomenon of EBV infection and perpetual B cell proliferation occurring in tissue culture, but fail to reproduce the immune response and latency characteristic of human EBV infection. 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 a pathogen free colony of rhesus monkeys at the New England Regional Primate Research Center (NERPRC) which are routinely EBV seronegative. These proposed experiments, aimed at reproducing and characterizing natural EBV infection in these naive rhesus monkeys, benefit considerably from new techniques and insights provided by three decades of EBV research.
The specific aims are as follows: 1. Characterize experimental EBV infection in Old World primates (rhesus monkeys). 2. Evaluate the effect of Simian Immunodeficiency Virus (SIV) and drug induced immunodeficiency on experimental EBV infection in rhesus monkeys. 3. Molecularly characterize the latent genes expressed by H. Papio and rhesus EBV to provide reagents for animal studies and an evolutionary analysis of EBV transforming genes. 4. Develop systems to generate recombinant rhesus EBV for analysis in experimental EBV infection of rhesus monkeys. Successful development of an animal model for persistent, latent EBV infection will have timely and major impact on EBV research by providing a novel approach for analyzing EBV lytic and latent gene function, mechanisms of EBV latency, pathogenesis of EBV infection and associated diseases, and prevention and treatment of EBV-induced diseases.
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