Cytomegalovirus (CMV) infection is a leading source of morbidity and mortality in immunosupressed patients. Pharmacological treatment is only temporarily effective. The purpose of this grant is to provide an experimental basis for the use of cytokine-producing CMV recombinants for future human CMV vaccines. The efficacy and safety of these recombinants will be determined in murine systems since mouse CMV (MCMV) and various immunosuppressed mouse models are readily available. In this proposal MCMV recombinants expressing genes for interleukin-2, the B lymphocyte activation antigen B7, granulocyte-macrophage stimulating factor, interleukin-12 or interferon-gamma will be constructed and compared for their ability to modify or enhance immune responses to MCMV infection. Their effects on established infection will also be examined. The behavior and tropism of recombinant MCMV containing herpes simplex thymidine kinase to enhance response to antivirals will be examined. The advantages of this approach are that the cytokine is limited to and focused at the site of infection, all viral antigens are produced in this immunogenic context, and a variety of cytokines can be incorporated into the vaccine. Adaptation of the Cre-Lox recombination system to CMVs will be pursued using MCMV and human CMV (HCMV) . This will allow recombinants, particularly of HCMV, to be more easily achieved. They will also make feasible exploration of general questions concerning recombinant construction and stability. These represent novel approaches to the control of CMV infections in immunosuppressed patients.
