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.

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National Cancer Institute (NCI)
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City of Hope National Medical Center
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Limaye, Ajit P; La Rosa, Corinna; Longmate, Jeff et al. (2016) Plasma IL-10 Levels to Guide Antiviral Prophylaxis Prevention of Late-Onset Cytomegalovirus Disease, in High Risk Solid Kidney and Liver Transplant Recipients. Transplantation 100:210-6
Jonnalagadda, Mahesh; Mardiros, Armen; Urak, Ryan et al. (2015) Chimeric antigen receptors with mutated IgG4 Fc spacer avoid fc receptor binding and improve T cell persistence and antitumor efficacy. Mol Ther 23:757-68
Wang, Xiuli; Wong, ChingLam W; Urak, Ryan et al. (2015) CMVpp65 Vaccine Enhances the Antitumor Efficacy of Adoptively Transferred CD19-Redirected CMV-Specific T Cells. Clin Cancer Res 21:2993-3002
Mardiros, Armen; Forman, Stephen J; Budde, Lihua E (2015) T cells expressing CD123 chimeric antigen receptors for treatment of acute myeloid leukemia. Curr Opin Hematol 22:484-8
Caruso, Hillary G; Hurton, Lenka V; Najjar, Amer et al. (2015) Tuning Sensitivity of CAR to EGFR Density Limits Recognition of Normal Tissue While Maintaining Potent Antitumor Activity. Cancer Res 75:3505-18
Israyelyan, A; Goldstein, L; Tsai, W et al. (2015) Real-time assessment of relapse risk based on the WT1 marker in acute leukemia and myelodysplastic syndrome patients after hematopoietic cell transplantation. Bone Marrow Transplant 50:26-33
Wussow, Felix; Chiuppesi, Flavia; Martinez, Joy et al. (2014) Human cytomegalovirus vaccine based on the envelope gH/gL pentamer complex. PLoS Pathog 10:e1004524
Rushworth, David; Jena, Bipulendu; Olivares, Simon et al. (2014) Universal artificial antigen presenting cells to selectively propagate T cells expressing chimeric antigen receptor independent of specificity. J Immunother 37:204-13
Jena, Bipulendu; Moyes, Judy S; Huls, Helen et al. (2014) Driving CAR-based T-cell therapy to success. Curr Hematol Malig Rep 9:50-6
Singh, Harjeet; Huls, Helen; Kebriaei, Partow et al. (2014) A new approach to gene therapy using Sleeping Beauty to genetically modify clinical-grade T cells to target CD19. Immunol Rev 257:181-90

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