This program project grant is a new proposal to develop vaccines by the Steinman-Nussenzweig-Ravetch laboratories. It is focused on investigating the hypothesis that antigens delivered directly to dendritic cells in conjunction with a maturation stimulus will enhance immunity and elicit productive immune responses to vaccine antigens. The program will exploit the principles of dendritic cell biology and immunology more broadly to design and develop vaccines, including phase I studies in humans.
Specific aims are: 1) Develop DNA vaccines that incorporate dendritic cell targeting strategies and test the vaccines in humans 2) Regulate FcR signaling on DC subsets as a means of controlling DC maturation and the generation of antigen-specific immnunity. 3) Identify antigens that induce broadly neutralizing anti-HIV-1 antibodies by cloning such antibodies from single B cells from rare individuals that control their HIV-I infection and controls that do not All of the projects proposed in this program will address these three areas using the complementary strategies outlined in the proposal. The information generated by each project will allow the group as a whole to adjust its strategy accordingly. Thus, the strength of the proposed program project lies in the expertise of the investigators, the proven record of their collaborations with other members of the program, and the close relationship each project has to the overall goals of the program.
|Pantel, Austin; Teixeira, Angela; Haddad, Elias et al. (2014) Direct type I IFN but not MDA5/TLR3 activation of dendritic cells is required for maturation and metabolic shift to glycolysis after poly IC stimulation. PLoS Biol 12:e1001759|
|DiLillo, David J; Tan, Gene S; Palese, Peter et al. (2014) Broadly neutralizing hemagglutinin stalk-specific antibodies require Fc?R interactions for protection against influenza virus in vivo. Nat Med 20:143-51|
|Halper-Stromberg, Ariel; Lu, Ching-Lan; Klein, Florian et al. (2014) Broadly neutralizing antibodies and viral inducers decrease rebound from HIV-1 latent reservoirs in humanized mice. Cell 158:989-99|
|Bournazos, Stylianos; Klein, Florian; Pietzsch, John et al. (2014) Broadly neutralizing anti-HIV-1 antibodies require Fc effector functions for in vivo activity. Cell 158:1243-53|
|Anandasabapathy, Niroshana; Feder, Rachel; Mollah, Shamim et al. (2014) Classical Flt3L-dependent dendritic cells control immunity to protein vaccine. J Exp Med 211:1875-91|
|Mollah, Shamim A; Dobrin, Joseph S; Feder, Rachel E et al. (2014) Flt3L dependence helps define an uncharacterized subset of murine cutaneous dendritic cells. J Invest Dermatol 134:1265-75|
|Gruell, Henning; Bournazos, Stylianos; Ravetch, Jeffrey V et al. (2013) Antibody and antiretroviral preexposure prophylaxis prevent cervicovaginal HIV-1 infection in a transgenic mouse model. J Virol 87:8535-44|
|Gaebler, Christian; Gruell, Henning; Velinzon, Klara et al. (2013) Isolation of HIV-1-reactive antibodies using cell surface-expressed gp160ýýc(BaL.). J Immunol Methods 397:47-54|
|Klein, Florian; Diskin, Ron; Scheid, Johannes F et al. (2013) Somatic mutations of the immunoglobulin framework are generally required for broad and potent HIV-1 neutralization. Cell 153:126-38|
|Mouquet, Hugo; Warncke, Malte; Scheid, Johannes F et al. (2012) Enhanced HIV-1 neutralization by antibody heteroligation. Proc Natl Acad Sci U S A 109:875-80|
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