Currently available human monoclonal antibodies (mAbs) which neutralize primary isolates of HIV are directed against only a few regions of the HIV envelope glycoproteins. Some primary isolates are resistant to many of these mAbs but can be neutralized by pooled sera from HIV-infected individuals, suggesting that there may be additional neutralizing epitopes which have not yet been identified. To develop new mAbs with broad and potent neutralizing activity whose activity will complement those of previously described mAbs, which can be used for passive immunization, and whose epitopes can be characterized and incorporated into the design of candidate HIV vaccines, we propose to: (a) Produce human mAbs with potent and broad neutralizing activity against HIV-1 primary isolates that target previously unidentified epitopes. Existing human anti-HIV mAbs have been selected on the basis of their binding activity. We propose to select anti-HIV mAbs based on their function, i.e., their ability to neutralize pseudovirions containing env genes of various primary isolates. (b) Delineate the breadth of the neutralizing activity of the new mAbs selected with the neutralization screen. (c) Use a variety of immunologic, biochemical, molecular and physical techniques to identify and characterize the epitopes recognized by the broadest and most potent of the mAbs. Epitope mapping techniques will include the use of an antigen fragment library, random peptide phage display libraries, epitope excision/extraction and Arg/Lys chemical modification methods, and X-ray crystallographic analyses. These studies will elucidate the nature of the epitopes recognized by the best of the neutralizing mAbs, providing critical information about the structure of epitopes that induce protective Abs. These data will also elucidate the structure of the mAb paratopes, the intermolecular interactions between epitopes and paratopes, and the molecular basis for the cross-reactivity between diverse strains of HIV. (d) Use a """"""""focused mutagenesis"""""""" technique to engineer two selected mAbs in order to improve their potency and breadth, and subsequently determine the structure of the epitopes recognized by these engineered mAbs. The results of these studies should provide both reagents for passive immunization and data on the nature of antigenic determinants of HIV glycoproteins useful for designing immunogens that will induce broadly neutralizing Abs.

Agency
National Institute of Health (NIH)
Institute
National Heart, Lung, and Blood Institute (NHLBI)
Type
Research Project (R01)
Project #
5R01HL059725-08
Application #
6875710
Study Section
Special Emphasis Panel (ZRG1-VACC (01))
Program Officer
Barbosa, Luiz H
Project Start
2003-05-01
Project End
2008-04-30
Budget Start
2005-05-01
Budget End
2006-04-30
Support Year
8
Fiscal Year
2005
Total Cost
$629,718
Indirect Cost
Name
New York University
Department
Pathology
Type
Schools of Medicine
DUNS #
121911077
City
New York
State
NY
Country
United States
Zip Code
10016
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Li, Liuzhe; Wang, Xiao-Hong; Williams, Constance et al. (2015) A broad range of mutations in HIV-1 neutralizing human monoclonal antibodies specific for V2, V3, and the CD4 binding site. Mol Immunol 66:364-74
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Pan, Ruimin; Gorny, Miroslaw K; Zolla-Pazner, Susan et al. (2015) The V1V2 Region of HIV-1 gp120 Forms a Five-Stranded Beta Barrel. J Virol 89:8003-10
Zolla-Pazner, Susan; Edlefsen, Paul T; Rolland, Morgane et al. (2014) Vaccine-induced Human Antibodies Specific for the Third Variable Region of HIV-1 gp120 Impose Immune Pressure on Infecting Viruses. EBioMedicine 1:37-45
Klein, Florian; Nogueira, Lilian; Nishimura, Yoshiaki et al. (2014) Enhanced HIV-1 immunotherapy by commonly arising antibodies that target virus escape variants. J Exp Med 211:2361-72
Zolla-Pazner, Susan; deCamp, Allan; Gilbert, Peter B et al. (2014) Vaccine-induced IgG antibodies to V1V2 regions of multiple HIV-1 subtypes correlate with decreased risk of HIV-1 infection. PLoS One 9:e87572
Chung, Amy W; Crispin, Max; Pritchard, Laura et al. (2014) Identification of antibody glycosylation structures that predict monoclonal antibody Fc-effector function. AIDS 28:2523-30
Spurrier, Brett; Sampson, Jared; Gorny, Miroslaw K et al. (2014) Functional implications of the binding mode of a human conformation-dependent V2 monoclonal antibody against HIV. J Virol 88:4100-12

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