We will take a new approach to harness dendritic cell (DC) biology to improve vaccine design for SIV and HIV. We will pursue recent advances in mice involving antigen uptake, processing and maturation by DCs in situ. Vaccines will be targeted to monkey and human DCs by engineering antigens into antibodies to uptake receptors that are selectively expressed by DCs in lymphoid organs, e.g., DEC-205. Antibody targeting to DEC-205 enhances antigen presentation in mice 100-1000 fold to both CD4 + and CD8 + T cells. When this targeting is coupled with a DC maturation stimulus, mice develop unusually strong and long lasting effector T cell responses, i.e., Th1 type CD4 + T cells and cytolytic CD8 + T cells. The responses are much greater than prior """"""""gold standards,"""""""" like complete Freund's adjuvant. The mice resist challenge to antigen in recombinant vaccinia virus delivered via the lung and growing tumors in the skin. We will move this vaccine strategy into monkeys and human, using a new monoclonal reactive with monkey/human DEC-205, which is expressed at high levels on DCs in human and monkey lymph nodes and spleen. The heavy chains of anti-DEC-205 antibodies have already been engineered to express several peptides and HIV gag p24 protein. We will verify that anti-human DEC-205 mediates efficient presentation of engineered antigens on the MHC class I and II products of human DCs. We will simultaneously compare several methods for maturing DCs in vivo in mice, to achieve optimal presentation and strong effector and memory T cell responses after targeting by anti-DEC- 205: antigen conjugates. We will engineer microbial proteins, not just peptides, into DEC-205 antibodies to test that human and monkey DCs present viral proteins including proteins from HIV and SIV gag proteins. Then we can begin to immunize macaques with engineered, DC-targeting antibody plus a maturation stimulus, to assess combined CD4 + and CD8 + T cell immunity and memory. In this way the concepts of antigen targeting coupled with DC maturation can be assessed as a new vaccination strategy for nonhuman primates.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Project (R01)
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AIDS Immunology and Pathogenesis Study Section (AIP)
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D'Souza, Patricia D
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Rockefeller University
Other Domestic Higher Education
New York
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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
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
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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