This application examines the immune response to human cytomegalovirus (CMV) with a focus on selected epitope characterization of the cellular immune response (CMI) after hematopoietic cell transplantation (HCT). The conventional understanding of CMV-specific CMI is that it mainly targets two CMV proteins--the lower matrix protein, CMVpp65, and the major immediate early protein, CMV-IE1. This CMV-specific CMI is essential in prevention of CMV progression to disease after HCT. For CMV seropositive patients, the incidence of CMV infection is 60-70 percent after HCT. Reactivation of virus is the critical event that guides the antiviral management of this population of HCT patients and control of reactivation by immunologic methods becomes an important goal for improvement in HCT transplantation. The question that is unanswered is what specific immune responses are needed to prevent CMV reactivation and are these the same adaptive responses that are being elicited later in protection from progressive CMV infection and disease? Because of virion encoded alterations in proteasome processing of peptide antigens, it is possible that the immune response to other CMV proteins is modified in order to protect the ability of the virus to reactivate. Using a transgenic HLA-A*0201 mouse model, it is possible to dissect the immune response away from the immune escape mechanisms in order to assess which other CMV proteins could be targeted for CMI. ? The main hypothesis tested here is that immunity to the CMV proteins present early in infection is sufficient to protect from CMV reactivation and disease. With this in mind, important early CMV proteins will be examined for recognition by class I immune processing, including those involved at early stages of replication and those responsible for immune evasion. Therefore, the aims of the study are 1) to reassess the kinetics of the immune response to CMV-pp65 and to CMV-IE1 in all HLA allotypes using pools of overlapping peptides during immune reconstitution after HCT, and 2) using HLA-A*0201 mouse models, to define CD8 epitopes to selected other CMV proteins relevant at early times during immune reconstitution, and to evaluate the immune response to these proteins using CMV wild isolates. ? The importance of this project is that it will define new immune targets of CMV immunity, and these could provide important information for developing new immunotherapeutie strategies for the prevention of CMV reactivation after transplantation. ? ?
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