Abstract

application): The overall goal of the application is to examine the feasibility of reconstitution of HCMV immunity in HIV-infected patients by adoptive transfer of autologous in vitro expanded CD8+ HCMV-specific cytotoxic T lymphocytes (CTL) and CD4+ HCMV-specific Th clones which will be genetically modified to resist infection with HIV. The adoptive transfer of HCMV-specific CD8+ and CD4+ T-cell clones has already been used successfully by the applicants to restore protective levels of immunity in immunodeficient bone marrow transplant recipients. Besides adoptive transfer of HCMV-specific T cells, an important part of the proposed studies will be to determine whether prospective immunologic and virologic monitoring of AIDS patients can be used to identify individuals who are at high risk for HCMV disease.
The specific aims of the proposed studies are: (1) to determine whether concurrent immunologic and virologic monitoring can identify patients with AIDS at high risk for development of HCMV disease; (2) to evaluate the safety, in vivo persistence and antiviral activity of adoptively transferred CD8+ HCMV-specific CTL clones in HIV-infected patients; and (3) to evaluate the safety, in vivo persistence and immunomodulatory function of adoptively transferred CD4+ HCMV-specific Th clones genetically modified to resist HIV infection.

  Funding Agency

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI041754-03
Application #
2887547
Study Section
Special Emphasis Panel (ZAI1-VSG-A (M1))
Program Officer
Laughon, Barbara E
Project Start
1997-09-01
Project End
2002-05-31
Budget Start
1999-06-01
Budget End
2000-05-31
Support Year
3
Fiscal Year
1999
Total Cost
Indirect Cost

  Institution

Name
Fred Hutchinson Cancer Research Center
Department
Type
DUNS #
075524595
City
Seattle
State
WA
Country
United States
Zip Code
98109

  Publications

Boeckh, Michael; Huang, MeeiLi; Ferrenberg, James et al. (2004) Optimization of quantitative detection of cytomegalovirus DNA in plasma by real-time PCR. J Clin Microbiol 42:1142-8
Manley, Thomas J; Luy, Lisa; Jones, Thomas et al. (2004) Immune evasion proteins of human cytomegalovirus do not prevent a diverse CD8+ cytotoxic T-cell response in natural infection. Blood 104:1075-82
Boeckh, Michael; Nichols, W Garrett (2004) The impact of cytomegalovirus serostatus of donor and recipient before hematopoietic stem cell transplantation in the era of antiviral prophylaxis and preemptive therapy. Blood 103:2003-8
Topp, Max S; Riddell, Stanley R; Akatsuka, Yoshiki et al. (2003) Restoration of CD28 expression in CD28- CD8+ memory effector T cells reconstitutes antigen-induced IL-2 production. J Exp Med 198:947-55
Boeckh, Michael; Nichols, W Garrett (2003) Immunosuppressive effects of beta-herpesviruses. Herpes 10:12-6
Mutimer, Helen P; Akatsuka, Yoshiki; Manley, Thomas et al. (2002) Association between immune recovery uveitis and a diverse intraocular cytomegalovirus-specific cytotoxic T cell response. J Infect Dis 186:701-5
Groh, V; Rhinehart, R; Randolph-Habecker, J et al. (2001) Costimulation of CD8alphabeta T cells by NKG2D via engagement by MIC induced on virus-infected cells. Nat Immunol 2:255-60
Nichols, W G; Boeckh, M (2000) Recent advances in the therapy and prevention of CMV infections. J Clin Virol 16:25-40
Riddell, S R; Greenberg, P D (2000) T-cell therapy of cytomegalovirus and human immunodeficiency virus infection. J Antimicrob Chemother 45 Suppl T3:35-43
Berger, C; Xuereb, S; Johnson, D C et al. (2000) Expression of herpes simplex virus ICP47 and human cytomegalovirus US11 prevents recognition of transgene products by CD8(+) cytotoxic T lymphocytes. J Virol 74:4465-73

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