Broadly neutralizing anfibodies to HIV have the ability to prevent HIV infection in animal models and therefore it has been proposed that vaccines that elicit such antibodies might also be highly effective in humans. However, despite numerous efforts very few broadly neutralizing anfibodies have been identified to date. Several of these most potent broadly neutralizing antibodies are also polyreactive, i.e. they react with more than two other defined antigens, a property that has been attributed to long and hydrophobic or charged immunoglobulin heavy chain complementarity determining region 3 (CDR3). We have developed techniques to clone antibodies from single human B cells and studied thousands of antibodies obtained from B cells in defined stages of development. In these studies we showed that although polyreactivity is a normal feature of antibodies produced by nascent B cells in the bone marrow, this is normally selected against as B cells develop. It has been suggested that this selection is in part responsible for the rarity of broadly neutralizing anfibodies against HIV. The object ofthe proposed research is to use the human anfibody cloning technology we developed to determine whether B cells that produce broadly neutralizing anti-HIV anfibodies are selecfively deleted during B cell development and if so at which developmental stage. In addifion we propose to study B cells and antibodies from individuals that produce broadly neutralizing anfibodies to determine whether these patients show altered selection against polyreactive anfibodies.
A third aim i s to identify individuals with high titers of broadly neutralizing antibodies in their serum and to clone and characterize these anfibodies using our single cell methods. The long-term goals are to understand the genesis of anti-HIV anfibodies and to define additional anfigenic epitopes to be used in efficient vaccines developed by the Steinman and Ravetch laboratories to elicit protective anti-HIV antibodies

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI081677-04
Application #
8381090
Study Section
Special Emphasis Panel (ZAI1-KS-I)
Project Start
Project End
Budget Start
2012-09-01
Budget End
2013-08-31
Support Year
4
Fiscal Year
2012
Total Cost
$422,978
Indirect Cost
$165,735
Name
Rockefeller University
Department
Type
DUNS #
071037113
City
New York
State
NY
Country
United States
Zip Code
10065
Bournazos, Stylianos; Gazumyan, Anna; Seaman, Michael S et al. (2016) Bispecific Anti-HIV-1 Antibodies with Enhanced Breadth and Potency. Cell 165:1609-20
Lu, Ching-Lan; Murakowski, Dariusz K; Bournazos, Stylianos et al. (2016) Enhanced clearance of HIV-1-infected cells by broadly neutralizing antibodies against HIV-1 in vivo. Science 352:1001-4
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
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
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
DiLillo, David J; Tan, Gene S; Palese, Peter et al. (2014) Broadly neutralizing hemagglutinin stalk-specific antibodies require FcγR interactions for protection against influenza virus in vivo. Nat Med 20:143-51
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
Klein, Florian; Mouquet, Hugo; Dosenovic, Pia et al. (2013) Antibodies in HIV-1 vaccine development and therapy. Science 341:1199-204

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