Simian immunodeficiency virus (SIV) infection of macaques provides the best non-human primate model for studying AIDS. We will utilize the SIV/macaque model to determine whether Epstein Barr virus (EBV) can be used as a vector to generate strong immune responses to SIV in vivo. It has been difficult to devise an effective vaccine for human immunodeficiency virus (HIV). Live attenuated SIV has protected rhesus macaques from subsequent challenge with pathogenic strains of SIV. However, questions concerning the safety of this live vaccine still remain. Since HIV and EBV share many similar characteristics, we propose to use EBV as a live virus vector for generating SIV-specific responses. We will use both EBV-transformed B Lymphocyte cell lines (BLCL) stably transfected with SIV genes and mini-EBV vectors expressing SIV genes to immunize rhesus monkeys. In many respects, EBV and the HIV share several important characteristics. Both of these viruses cause a massive T-cell proliferative response upon infection. This is especially evident in the CD8+ subset of T cells, and there is some evidence to suggest that both of these viruses induce an antigen-specific response within the first month after infection. There is also evidence that CD8+ cytotoxic T lymphocytes (CTL) provide some kind of protection against infection with both of these viruses. Individuals that have been previously infected with EBV will occasionally exhibit EBV-induced tumors if they are immunosuppressed. Withdrawal of the immunosuppression normally results in disappearance of the tumors. EBV and HIV are also persistent lymphotropic viruses. That is, after the initial round of replicative activity, both of these viruses assume a quiescent state within the immune system. These similarities between EBV and HIV make the use of EBV as a vector to deliver HIV genes an excellent candidate for inducing strong immune responses. The fact that EBV infected-B cells home to the lymph nodes suggests that EBV would be an excellent live virus vector for HIV. In this proposal, we will develop EBV based vectors to use as AIDS virus vaccines using the rhesus monkey as an animal model to test these vaccines.
In Specific Aim I we will test the hypothesis that transfection of EBV-transformed autologous BLCL with vectors expressing SIV genes can be used to generate a strong AIDS-virus specific immune response in MHC defined animals.
In Specific Aim II, we will test the hypothesis that a mini-EBV vector expressing SIV genes can be used to generate an AIDS-virus specific immune response in MHC-defined animals.
| Vogel, T U; Allen, T M; Altman, J D et al. (2001) Functional impairment of simian immunodeficiency virus-specific CD8+ T cells during the chronic phase of infection. J Virol 75:2458-61 |
