The overall goal of this proposal is to study a novel approach towards vaccine development to a retrovirus in a well-defined animal model system. The system employed will be the AKV-1 (emv-11) endogenous murine leukemia virus and certain mouse strains which constitute a naturally occurring infectious model. Because a key feature of a successful vaccine against a retrovirus is to block infectivity, emphasis will be placed on the generation of neutralizing antibody responses. Rather than employing live attenuated or killed virus preparations as a vaccine, however, monoclonal anti-idiotypic antibodies, particularly of the Ab2B internal image type, directed against the paratope of a neutralizing monoclonal will be used. This approach is favored due to the dangers of employing inactivated or attenuated retrovirus preparations, given their propensity to recombine and mutate and the lethality of retroviruses such as HIV, and due to the presence of inhibitory determinants or molecules such as p15(E) in murine retroviruses. In addition the facility of large scale production of monoclonal anti-idiotypic antibodies offers obvious practical advantages over classical virus vaccines. Although the emphasis will be on the use of anti-idiotypic monoclonals to induce neutralizing antibodies, similar to Ab1, the possibility that T cell responses, especially cytolytic T lymphocytes, may develop will also be examined. Although the degree of sharing of variable region conformations by the B cell and T cell receptor systems is not great due to the MHC restricted nature of the latter, recent evidence suggests that processing of both foreign and self (including immunoglobulin) can be accomplished by many cell types resulting in presentation in the context of self MHC. Thus, it may be that the internal image of the neutralizing epitope of gp70 may be presented with class 1 molecules for potential recognition by CTL. This concept is important because CTL are considered to be effective in eliminating virus infected cells, another key aspect of a successful vaccine.
