BIOLOGY OF CYTOMEGALOVIRUS INFECTION IN BONE MARROW TRANSPLANTATION

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This is a continuation of a project which investigates the pathogenesis of human cytomegalovirus (CMV) infection after bone marrow transplantation (BMT). Although CMV-related mortality has been markedly reduced, CMV pulmonary infection continues to occur in 37% of our allogeneic BMT recipients, and the morbidity associated with prolonged antiviral treatment suggests that the current methods of management are not optimal. This project combines basic research with clinical studies in an attempt to better understand the nature of CMV infection and to improve such treatment. In the past four years, the basic research portion has completed the cloning and structural characterization of several CMV Towne tegument proteins, and viral reagents developed during this time are being applied to vaccine development in projects IV and V of this continuation. A study of the interaction between CMV and the cell surface peptidase, CD13/aminopeptidase N (CD13/APN), will form the basic research portion of this continuation. The clinical studies of the project have been the abase for the CMV antiviral trials within the Program and pioneered the preemptive use of ganciclovir in BMT. In the continuation, we will evaluate a semiquantitative measure of CMV, using a PCR-based assay of CMV DNA in plasma, in comparison with prospective blood and bronchoalveolar lavage cultures for utility in antiviral management of BMT recipients. A major recent accomplishment of this project has been the observation that CD13/APN increases cell susceptibility to CMV infection that soluble CD13/APN can neutralize CMV. In addition, CD13/APN is present on CMV virions, and antibody to CD13/APN efficiently neutralizes virus. The role of CD13/APN in CMV binding and fusion to cells and the interaction of CMV glycoproteins and CD13/APN will be investigated. In addition, the protein domain(s) of CD13/APN necessary for virus inhibition will be determined, and soluble forms of CD13/APN having antiviral potential will be developed. CD13/APN is present inc ells of the gut, kidneys, liver, lung, endothelium, and brain--all regions for which CMV is trophic. In addition, CD13/APN circulates in the plasma and might be involved in some aspect of CMV disease pathogenesis. We hypothesize that CD13/APN plays a previously unrecognized role in the interaction of CMV with the infected host and will utilize the ongoing studies in marrow transplant recipients to evaluate this possibility in clinical studies measuring plasma levels of CD13/APN during CMV infection.