Abstract

This is a continuation of a project which investigates the pathogenesis of human cytomegalovirus (HCMV) infection after bone marrow transplantation (BMT). In the initial 8 years of this project, persistent HCMV infection has been documented and a model of asymptomatic lung infection has been described. The question of how the virus and host interact during periods of persistent infection remains unexplained, and it is possible that structural and non-structural virus-encoded proteins play a role in altering host function and leading to disease. In this regard, this project has cloned and partially expressed the matrix proteins, pp28, pp65, pp71, and pp150, of Towne strain HCMV. In this proposal, the regulation and biologic function of these proteins will be investigated in an effort to further understand the pathogenesis of HCMV-associated disease after BMT. This project will complete the DNA sequencing of pp28 and pp150 from Towne strain HCMV and will characterize the 5'-untranslated structural elements of pp28, pp65, pp71, and pp150 important in transcriptional regulation. In addition, the functional effects of matrix proteins on virus transcription will be studied with emphasis on whether they mediate virion-associated transactivation. The purported kinase activity of pp65 will be characterized using recombinant pp65, and, using deletion mutational analyses, the kinase subdomains and potential phosphorylation sites of the protein will be mapped. To characterize potential effects of matrix proteins on cellular transcription, HCMV-induced fibronectin (FN)-specific mRNA transcription repression will be studied. This model system will be used to determine if HCMV-encoded sequences directly mediate virus-induced transrepression of cellular mRNA. In addition, it is proposed to utilize the repository of wild HCMV isolates, collected to date, in order to determine whether virus sequence domains, found to be important for specific functions in laboratory strains, exist in nature.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Program Projects (P01)
Project #
5P01CA030206-12
Application #
3772241
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
12
Fiscal Year
1993
Total Cost
Indirect Cost

  Institution

Name
City of Hope National Medical Center
Department
Type
DUNS #
City
Duarte
State
CA
Country
United States
Zip Code
91010

  Publications

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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