A successful HIV-1 vaccine will likely have to induce strong CD4 and CD8 T cell immunity. For example, there is evidence that CD4+ T cells are required for the function of virus-specific CD8+ T cells in many experimental models of immunity, and that CD8+ T cells provide resistance against SIV and HIV-1. Likewise, EBV-associated lymphoproliferative disorders develop in AIDS, suggesting a need for CD4+ T cells in resistance in EBV as well. Dendritic cells [DCs) are specialized antigen presenting cells for initial combined CD4+ and CD8+ T cell immunity. Therefore our hypothesis is that the targeting of HIV-1 and EBV antigens to mature, immunostimulatory DCs will lead to strong virus-specific immunity. In the two years of this grant, we have learned to deliver HIV-1 and EBV antigens to DCs with different viral vectors, and we find that these DCs then stimulate strong T cell responses. In other grants, we have injected antigen-bearing DCs to healthy volunteers and elicited rapid and broad T cell immunity in situ. We will now pursue the data along 3 lines: 1] To optimize the use of DCs infected with a non- perturbing, envelope-pseudotyped HIV-1--to elicit strong immunity in culture. This approach will then be used to detect and quantify CD4 and CD8 immune status in important cohorts, 3e.g., exposed uninfected individuals, long term non-progressors, and patients receiving highly active anti-retroviral therapy; 2] To vaccinate, in collaboration with the Walter Reed Army Research Institute vaccine group, volunteers with autologous DCs charged with recombinant avipox. The immunity will then be compared to separate cohorts vaccinated with recombinant avipox directly; an approach that to date has not induced strong or reliable immunity. 3] To use DCs to elicit immunity to Epstein Barr Virus, especially CD4+ T cells specific to EBNA-1. We have identified strong CD4+ T cell responses to the critical EBNA-1 protein and now will use DCs to understand the processing of EBNA-1 and the biological functions of the reactive T cells.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
2R01AI040874-04
Application #
6076545
Study Section
Special Emphasis Panel (ZRG1-VACC (03))
Program Officer
Bradac, James A
Project Start
1997-02-01
Project End
2004-03-31
Budget Start
2000-04-15
Budget End
2001-03-31
Support Year
4
Fiscal Year
2000
Total Cost
$332,093
Indirect Cost
Name
Rockefeller University
Department
Microbiology/Immun/Virology
Type
Other Domestic Higher Education
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Nchinda, Godwin; Amadu, David; Trumpfheller, Christine et al. (2010) Dendritic cell targeted HIV gag protein vaccine provides help to a DNA vaccine including mobilization of protective CD8+ T cells. Proc Natl Acad Sci U S A 107:4281-6
Romani, Nikolaus; Thurnher, Martin; Idoyaga, Juliana et al. (2010) Targeting of antigens to skin dendritic cells: possibilities to enhance vaccine efficacy. Immunol Cell Biol 88:424-30
Bozzacco, Leonia; Trumpfheller, Christine; Huang, Yaoxing et al. (2010) HIV gag protein is efficiently cross-presented when targeted with an antibody towards the DEC-205 receptor in Flt3 ligand-mobilized murine DC. Eur J Immunol 40:36-46
Cheong, Cheolho; Choi, Jae-Hoon; Vitale, Laura et al. (2010) Improved cellular and humoral immune responses in vivo following targeting of HIV Gag to dendritic cells within human anti-human DEC205 monoclonal antibody. Blood 116:3828-38
Cheong, Cheolho; Matos, Ines; Choi, Jae-Hoon et al. (2010) Microbial stimulation fully differentiates monocytes to DC-SIGN/CD209(+) dendritic cells for immune T cell areas. Cell 143:416-29
Flacher, Vincent; Tripp, Christoph H; Stoitzner, Patrizia et al. (2010) Epidermal Langerhans cells rapidly capture and present antigens from C-type lectin-targeting antibodies deposited in the dermis. J Invest Dermatol 130:755-62
Longhi, M Paula; Trumpfheller, Christine; Idoyaga, Juliana et al. (2009) Dendritic cells require a systemic type I interferon response to mature and induce CD4+ Th1 immunity with poly IC as adjuvant. J Exp Med 206:1589-602
Iwai, Yoshiko; Hemmi, Hiroaki; Mizenina, Olga et al. (2008) An IFN-gamma-IL-18 signaling loop accelerates memory CD8+ T cell proliferation. PLoS One 3:e2404
Trumpfheller, Christine; Caskey, Marina; Nchinda, Godwin et al. (2008) The microbial mimic poly IC induces durable and protective CD4+ T cell immunity together with a dendritic cell targeted vaccine. Proc Natl Acad Sci U S A 105:2574-9
Idoyaga, Juliana; Cheong, Cheolho; Suda, Koji et al. (2008) Cutting edge: langerin/CD207 receptor on dendritic cells mediates efficient antigen presentation on MHC I and II products in vivo. J Immunol 180:3647-50

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