This HIVRAD program merges the complementary expertise of leading HIV-1 researchers in order to provide a fundamental advance towards an HIV-1 vaccine than can elicit broadly neutralizing antibodies (NAbs). This innovative program comprises two Research Projects: HIV-1 Env Vaccine Design (Dr. John Moore, Cornell University) and HIV-1 Trimer Crystallography (Dr. Ian Wilson, The Scripps Research Institute). The Projects are supported by scientific and administrative Cores (Dr. William Olson, Progenies Pharmaceuticals). This program leverages our recent successes in generating stable, proteolytically mature gp140 trimers (SOSIP gp140s) that mimic virion-associated Env in topology and antigenicity. As immunogens, SOSIP trimers have proven to be superior to matched gp120s in eliciting NAbs in animals. In the HIVRAD, the SOSIP template will be tailored for structural studies and for further improvements in immunogenicity in animals. Our overall goals of the HIVRAD are reflected in three major milestones: 1) determine the structure of cleaved Env trimers at <4A resolution, 2) demonstrate methods to overcome HIV-1 Env's immunosuppressive properties, and 3) identify a SOSIP trimer vaccine that elicits heterologous neutralization of diverse HIV-1 isolates. Given the present rudimentary knowledge of trimer structure, an atomic-level view has the potential to spur development of a new generation of rationally designed Env vaccines, and our preliminary studies on crystallizing SOSIP trimers provide high enthusiasm and guarded optimism for success. Parallel studies will evaluate SOSIP trimers that have been modified so as to improve presentation of NAb epitopes and/or remove Env immunosuppressive features. Animal immunogenicity studies will be complemented with in vitro studies that compare modified and unmodified forms of Env for their ability to elicit immunosuppressive responses in human dendritic cells. In addition to the primary Projects and Cores, the HIVRAD includes additional leading academic and corporate collaborators who lend specialized expertise in the areas of vaccine delivery (Aldevron, Inc.), NAb analyses (Monogram Biosciences), NAb specificity analyses (Dr. James Binley), in vitro immunogenicity studies (VaxDesign), and exploratory immunogenetics (Dr. Sunil Ahuja). Our shared goal is to overcome key structural and immunological challenges to developing a successful Env-based HIV-1 vaccine.

Public Health Relevance

Nearly 1% of the world's population is infected with HIV, and a preventive vaccine is urgently needed. Most efficacious vaccines elicit antibodies that can neutralize the pathogen, but current-generation HIV vaccines are not effective in this regard. Obstacles include our limited understanding of the structure and immunology of HIV-1 envelope trimers. This HIVRAD represents an innovative approach to addressing these challenges in order to provide a fundamental advance in our ability to elicit HIV-neutralizing antibodies with a vaccine.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI082362-05
Application #
8278038
Study Section
Special Emphasis Panel (ZAI1-EC-A (J2))
Program Officer
Pullen, Jeffrey K
Project Start
2009-06-15
Project End
2014-05-31
Budget Start
2012-06-01
Budget End
2013-05-31
Support Year
5
Fiscal Year
2012
Total Cost
$2,524,997
Indirect Cost
$820,795
Name
Weill Medical College of Cornell University
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Medina-Ramírez, Max; Sanders, Rogier W; Klasse, Per Johan (2014) Targeting B-cell germlines and focusing affinity maturation: the next hurdles in HIV-1-vaccine development? Expert Rev Vaccines 13:449-52
Guttman, Miklos; Garcia, Natalie K; Cupo, Albert et al. (2014) CD4-induced activation in a soluble HIV-1 Env trimer. Structure 22:974-84
Falkowska, Emilia; Le, Khoa M; Ramos, Alejandra et al. (2014) Broadly neutralizing HIV antibodies define a glycan-dependent epitope on the prefusion conformation of gp41 on cleaved envelope trimers. Immunity 40:657-68
Blattner, Claudia; Lee, Jeong Hyun; Sliepen, Kwinten et al. (2014) Structural delineation of a quaternary, cleavage-dependent epitope at the gp41-gp120 interface on intact HIV-1 Env trimers. Immunity 40:669-80
Isik, Gözde; van Montfort, Thijs; Chung, Nancy P Y et al. (2014) Autoantibodies induced by chimeric cytokine-HIV envelope glycoprotein immunogens. J Immunol 192:4628-35
Yasmeen, Anila; Ringe, Rajesh; Derking, Ronald et al. (2014) Differential binding of neutralizing and non-neutralizing antibodies to native-like soluble HIV-1 Env trimers, uncleaved Env proteins, and monomeric subunits. Retrovirology 11:41
Chung, Nancy P Y; Matthews, Katie; Kim, Helen J et al. (2014) Stable 293 T and CHO cell lines expressing cleaved, stable HIV-1 envelope glycoprotein trimers for structural and vaccine studies. Retrovirology 11:33
Garces, Fernando; Sok, Devin; Kong, Leopold et al. (2014) Structural evolution of glycan recognition by a family of potent HIV antibodies. Cell 159:69-79
Huang, Jinghe; Kang, Byong H; Pancera, Marie et al. (2014) Broad and potent HIV-1 neutralization by a human antibody that binds the gp41-gp120 interface. Nature 515:138-42
Murin, Charles D; Julien, Jean-Philippe; Sok, Devin et al. (2014) Structure of 2G12 Fab2 in complex with soluble and fully glycosylated HIV-1 Env by negative-stain single-particle electron microscopy. J Virol 88:10177-88

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