CLASS I-RESTRICTED CTL INDUCTION BY SOLUBLE ANTIGENS

IT IS NOW WELL DOCUMENTED THAT CYTOTOXIC T CELL (CTL) RESPONSES PLAY A CRUCIAL ROLE IN THE CONTROL OF VIRAL INFECTION IN VIVO. WHILE A DESIRABLE CHARACTERISTIC OF A VACCINE OR IMMUNOTHERAPEUTIC REAGENT IS THAT IN ADDITION TO ANTIBODY, IT INDUCES A CTL RESPONSE, ATTEMPTS TO ACHIEVE THIS GOAL HAVE BEEN INEFFECTIVE OR UNSAFE. THE INDUCTION OF CLASS I-RESTRICTED CTL RESPONSES IS ALMOST EXCLUSIVELY DICTATED BY A PATHWAY IN WHICH CYTOPLASMIC PROTEINS SYNTHESIZEDWITHIN VIRUS INFECTED CELLS, OR BY SOLUBLE ANTIGENS OSMOTICALLY LOADED INTO THE CYTOPLASM ARE EXPRESSED AT THE SURFACE OF THE CELL IN ASSOCIATION WITH MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) CLASS I MOLECULES. THE USE OF PURE, WELL-DEFINED, ANTIGENS AS IMMUNOTHERAPEUTIC AGENTS FOR THE INDUCTION OF BOTH CELLULAR AND HUMORAL IMMUNE RESPONSES IS DESIRABLE. HOWEVER, IT IS ALMOST IMPOSSIBLE TO INDUCE MHC CLASS I-RESTRICTED CTLS IN RESPONSE TO A SOLUBLE ANTIGEN. THE OBJECTIVE IS TO DETERMINE WHETHER A NOVEL, NON-TOXIC, CHEMICALLY DEFINED, ADJUVANT FORMULATION CAN BE USED TO INDUCE BOTH CLASS I-RESTRICTED CTLS AND HUMORAL RESPONSES AGAINST SOLUBLE PROTEIN ANTIGENS (INCLUDING HIP GP120). WE WILL ALSO EVALUATE WHETHER CTLS ELICITED BY THE ADJUVANT ARE SIMILAR TO THOSE INDUCED BY OTHER ESTABLISHED METHODS INCLUDING THE RECOMBINANT VACCINIA VIRUS TECHNIQUE OR BY SPLEEN CELLS CYTOPLASMICALLY LOADED WITH SOLUBLE ANTIGENS. THIS INVESTIGATION WILL FUNCTION AS A PRELUDE TO THE PHASE II STUDY IN WHICH WE PLAN TO TEST THE FORMULATION IN NON-HUMAN PRIMATES. SUCH A FORMULATION MAY BE USED TO TREAT, BOTH THERAPEUTICALLY AND PROPHYLACTICALLY, VARIOUS VIRAL DISEASES, INCLUDING HIV INFECTION, AND WE ANTICIPATE THE WORK WILL LEAD TO IMPROVED STRATEGIES FOR VACCINE DESIGN.