This research program is investigating questions concerning immune responses with a focus on protective immunity to viral infections. Main projects: A. Antibody variable region repertoire: Antibody responses to protein antigens display considerable diversity. It was thus surprising that the response to the mouse alloantigen Ia.7 displays a dominant cross-reactive idiotype (CRI). The anti-Ia.7 repertoire induced by anti-idiotopes was shown to contain a novel pattern of overlapping but distinct sets of idiotypically-related antibodies. B. Antibody responses to different forms of CD4: Antibody responses of mice to recombinant, soluble CD4 (rCD4) were compared with those to the cell surface form of CD4. The responses were dramatically different, with rCD4 inducing high-titered antibody against sites not detectable on native, cellular CD4. This finding has important implications for vaccine development. Currently, responses to recombinant gp120 versus cell surface expressed HIV envelope are under study. C. Mechanisms of protective immunity to influenza virus infection: Of the immune effectors induced by vaccines or infection, which actually provide protection against infection depends upon an interplay of host and viral vectors. Protective vaccination against influenza has been studied in several types of mice: a) mice of several MHC haplotypes; b) beta2- microglobulin """"""""knock-out"""""""" mice with no expression of MHC class I complexes; and c) normal or beta2micro(-/-) mice depleted of CD4+ T cells in vivo. Protection by vaccinia vectors expressing the HA or NA proteins of influenza virus was shown to be antibody-mediated. Antibody responses were abnormally low in beta2micro(-/-) mice. Ongoing studies examine protective mechanisms under other circumstances thought to involve cell- mediated immunity.