Advances in cellular and molecular immunology have provided new opportunities for defining the mechanisms operative in the control of persistent virus infections, for developing immune-based therapies for progressive infection in immunocompromised hosts, and for the rational design and testing of vaccines to prevent or modulate infection. Cytomegalovirus (CMV) is an important cause of prenatal infection and infection in immunocompromised hosts. CD8+ class I MHC-restricted cytotoxic T cells are thought to have a decisive role in controlling CMV infection and deficiencies permit progressive infection. However, CMV is endowed with genes that function to interfere with class I antigen presentation and eliciting T cell responses of the desired specificity and magnitude pose a significant challenge for CMV vaccine development. Recent studies using a strain of CMV that is deleted in the genes that interfere with class I presentation and can display all potentially relevant epitopes from the viral proteome, demonstrate that the CD8+ T cell response to CMV In immunocompetent CMV individuals is more complex than previously appreciated. The results suggest there are additional immunodominant CMV antigens that may be essential to consider in the development of cell therapy or vaccination for CMV. The proposed experiments are designed to identify novel CMV antigens recognized by CD8+ CTL, elucidate their role in controlling CMV infection in normal CMV+ individuals, and determine if adoptive transfer of CMV-specific T cell clones can restore protective immunity in haploidentical stem cell transplant recipients.
The specific aims are: 1. To identify cytomegalovirus genes encoding novel antigens recognized by CD8+ CMV-specific cytotoxic T cells. 2. To determine the frequency and function of CD8+ T cells specific for individual CMV antigens in healthy CMV+ individuals with protective immunity. 3. To determine if adoptively transferring CMV-specific T cell clones to recipients of T cell depleted haploidentical stem cell transplant (SCT) is safe, restores CMV-specific immunity, and mediates antiviral activity.
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