Human papovavirus JC (JCV) and simian virus 40 (SV40) genomes share approximately 69% homology; and there is antigenic cross-reactivity between JCV and SV40 tumor or T antigens. In order to determine whether a selective immune response to JCV T antigen could be demonstrated, transgenic mice (SV11+) that express SV40 T antigen in the choroid plexus and are partially tolerant to antigenic determinants on SV40 T antigen were immunized with SV40 or JCV T antigens and their antibody responses were analyzed. The results show that SV11+ mice responded as well as their nontransgenic litter mates to JCV T antigen. Monoclonal antibodies were derived from hybridomas generated from immunized mice which reacted specifically with epitopes in the amino and carboxy terminal halves on JCV T antigen. These studies show that transgenic mice expressing SV40 T antigen are capable of responding to determinants not shared between JCV and SV40 T antigen.