IMMUNE MODIFICATION OF CYTOMEGALOVIRUS INFECTION IN BONE MARROW

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Despite recent progress in prophylaxis and treatment, CMV continues to be a major obstacle to success in allogeneic bone marrow transplantation (BMT). Studies have shown that the outcome of CMV infection in this setting is improved by both early reconstitution of recipient immunity to CMV and reduction of CMV replication. Furthermore, previous studies in both humans and animals have demonstrated that several facets of donor immunity to CMV can be transferred to BMT recipients and that such transfer improves outcome. This proposal will explore the ability to modify donor immunity to CMV by several immunization strategies. We will further test whether immunization immunity an be transferred to BMT recipients and alter the outcome of CMV infection. We hypothesize that immunity to CMV infection can be altered by immunization with either DNA of specific viral genes or with H2-compatible cellular vectors expressing specific gene products. This immunity will be manifested by humoral and cell mediated responses and by alterations in the course of infection. We further hypothesize that this immunization induced alteration in immunity to CMV can be transferred from a bone marrow donor tot he recipient of an allogeneic transplant. There are three specific aims of this project; Specific Aim 1: To develop optimal expression vectors for obtaining maximal expression of HCMV (pp65, pp150, pp28, pp71) and MCMV (gB and gH) proteins in vitro and in vivo. once, an optimal vector is developed, we will insert the herpes simplex-1 thymidine kinase (HSV 1-tk) gene into the expression vector to provide a suicidal constituent. We will also develop new murine gene vectors for study. Specific Aim 2: We will evaluate the expression plasmids containing specific CMV genes (HCMV pp65, pp150, pp28, pp71; MCMV gB, and gH) for their ability to alter host immunity in vivo, using DNA immunization and using H2-compatible cell vectors expression specific viral gene products. Specific Aim 3: Using an established murine model of allogeneic bone marrow transplantation, we will determine the efficacy of transferring immunization-induced immunity from a donor to the transplant recipient. These studies will determine the feasibility of altering donor immunity to CMV using immunization with either DNA of specific viral genes or with H2- compatible cellular vectors expressing specific gene products and the subsequent transfer of immunization induced immunity to recipients of allogenic marrow recipients.