The long term of this proposal is to conduct basic studies towards vaccine development against retroviruses which appear to cause T cell leukemia and AIDS in man. To this end, this application proposes to develop a vaccine for Akv, a murine leukemia retrovirus, in a mouse model system. The necessary features of the vaccine will be that it induce both a neutralizing antibody response to inhibit the infectivity of free virus and T cell responses, particularly cytolytic T lymphocytes (CTL), to remove infected or transformed cells. Rather than preparing a vaccine using attenuated live virus or killed virus, a vaccine based on peptide antigens and/or monoclonal anti-idiotypic antibodies will be developed. There are three reasons for this approach: 1) live vaccines are inherently dangerous and perhaps even more so in the case of retroviruses due to their great capacity for recombination with other retroviruses, including endogenous ones, 2) certain retrovirus components such as p15(E) are known to be immunosuppressive, and 3) killed viral vaccines are ineffective to inducing CTL reponses. To achieve the development of such a non-viral vaccine, assay systems and the AKR.H-2b:Fv-1b double congenic mouse strain model will first be further defined. This strain is a particularly incisive one as a model for naturally occurring retrovirus infections in that it has already been determined that at about 9-15 weeks of age there is activation and spread of the endogenous Akv leukemia virus, the expression of CTL-defined viral antigens, and conversion from a CTL-responder to a CTL-non-responder phenotype. General strategies for vaccine developmnt and delineation of basic parameters including immunization schedule and use of adjuvants will first be determined by injecting this model strain with Akv exprssing tumor cells. At the same time the peptides of p70 that neutralizing antibodies and antiviral CTL react with will be determined. Using existing or new monoclonal antibodies that bind to the gp70 peptides, internal image anti-idiotypic monoclonals will be developed. Anti-idiotypic monoclonals to the T cell receptor of the predominant CTL clones will also be raised. Once these alternative immunogens have been prepared, they will be employed in the basic vaccination regime defined with cells to raise neutralizing antibodies and CTL that are effective both in vitro and in vivo.
