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. ? ?

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI058148-04
Application #
7248037
Study Section
Special Emphasis Panel (ZRG1-SSS-F (03))
Program Officer
Beisel, Christopher E
Project Start
2004-07-01
Project End
2008-06-30
Budget Start
2007-07-01
Budget End
2008-06-30
Support Year
4
Fiscal Year
2007
Total Cost
$407,717
Indirect Cost
Name
City of Hope/Beckman Research Institute
Department
Type
DUNS #
027176833
City
Duarte
State
CA
Country
United States
Zip Code
91010
Gallez-Hawkins, Ghislaine M; Li, Xiuli; Franck, Anne E et al. (2012) KIR2DS2 and KIR2DS4 promoter hypomethylation patterns in patients undergoing hematopoietic cell transplantation (HCT). Hum Immunol 73:1109-15
Guerrero, Abraham; Riddell, Stanley R; Storek, Jan et al. (2012) Cytomegalovirus viral load and virus-specific immune reconstitution after peripheral blood stem cell versus bone marrow transplantation. Biol Blood Marrow Transplant 18:66-75
Gallez-Hawkins, Ghislaine M; Franck, Anne E; Li, Xiuli et al. (2011) Expression of activating KIR2DS2 and KIR2DS4 genes after hematopoietic cell transplantation: relevance to cytomegalovirus infection. Biol Blood Marrow Transplant 17:1662-72
Behrendt, Carolyn E; Nakamura, Ryotaro; Zaia, John (2010) Institution affects association between CMV seronegative graft and leukemic relapse after pediatric HCT. Biol Blood Marrow Transplant 16:133-5
Behrendt, Carolyn E; Rosenthal, Joseph; Bolotin, Ellen et al. (2009) Donor and recipient CMV serostatus and outcome of pediatric allogeneic HSCT for acute leukemia in the era of CMV-preemptive therapy. Biol Blood Marrow Transplant 15:54-60
Zaia, John A; Li, Xiuli; Franck, Anne E et al. (2009) Biologic and immunologic effects of knockout of human cytomegalovirus pp65 nuclear localization signal. Clin Vaccine Immunol 16:935-43
Zaia, John A; Sun, Joel Y; Gallez-Hawkins, Ghislaine M et al. (2009) The effect of single and combined activating killer immunoglobulin-like receptor genotypes on cytomegalovirus infection and immunity after hematopoietic cell transplantation. Biol Blood Marrow Transplant 15:315-25
Zhou, Wendi; Longmate, Jeff; Lacey, Simon F et al. (2009) Impact of donor CMV status on viral infection and reconstitution of multifunction CMV-specific T cells in CMV-positive transplant recipients. Blood 113:6465-76
Gallez-Hawkins, Ghislaine M; Thao, Lia; Palmer, Joycelynne et al. (2009) Increased programmed death-1 molecule expression in cytomegalovirus disease and acute graft-versus-host disease after allogeneic hematopoietic cell transplantation. Biol Blood Marrow Transplant 15:872-80
Wang, Z; Zhou, W; Srivastava, T et al. (2008) A fusion protein of HCMV IE1 exon4 and IE2 exon5 stimulates potent cellular immunity in an MVA vaccine vector. Virology 377:379-90

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