This HIVRAD program builds upon our recent successes in generating stable, proteolytically mature gp140 trimers (SOSIP gp140s) that mimic virion-associated envelope (Env) in topology and antigenicity. The overall goals of this HIVRAD program 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. These goals are reliant on the preparative production of novel SOSIP trimers in highly purified, homogeneous form. SOSIP trimers are exceptionally complex biomolecules whose production requires a high level of technical expertise, and Core B lends this expertise to the HIVRAD in order to support the goals of Project 1 (HIV-1 Env Vaccine Design, Dr. Moore) and Project 2 (HIV-1 Env Trimer Crystallography, Dr. Wilson). The overall role of Core B is expressed in terms of four Specific Aims: 1) Produce and characterize Env proteins for crystallography studies;2) Produce and characterize Env proteins for immunogenicity studies;3) Evaluate the immunogenicity of Env proteins in small animals, 4) Evaluate Env proteins for effects on human dendritic cells and antigen presentation in vitro. In addition to producing SOSIP trimers, Core B provides a central resource for additional high-quality materials (e.g., gp120 monomers, control antigen, CD4-based proteins, antibody Fabs) that are required by Project 1 and Project 2. Core B also possesses significant experience in vaccine testing and thus will be responsible for performing small-animal immunogenicity studies in collaboration with Project 1. Lastly, Core B will collaborate with external groups to explore and understand the interactions of HIV-1 Env with human dendritic cells in vitro. In addition, Core B will serve as a central point of contact and will manage consortial/contractual agreements with several leading academic and corporate collaborators who lend specialized expertise in the areas of vaccine delivery (Aldevron, Fargo, ND), NAb analyses (Monogram Biosciences, South San Francisco, CA), NAb specificity analyses (Dr. James Binley, Torrey Pines Institute for Molecular Studies, San Diego, CA), in vitro immunogenicity studies (VaxDesign, Orlando, FL), and exploratory immunogenetics (Dr. Sunil Ahuja, University of Texas). In fulfilling these roles, Core B represents an integral element of this innovative, multidisciplinary HIVRAD program.

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 #
5P01AI082362-06
Application #
8475549
Study Section
Special Emphasis Panel (ZAI1-EC-A)
Project Start
Project End
Budget Start
2013-06-01
Budget End
2014-05-31
Support Year
6
Fiscal Year
2013
Total Cost
$966,147
Indirect Cost
$314,063
Name
Weill Medical College of Cornell University
Department
Type
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
Go, Eden P; Cupo, Albert; Ringe, Rajesh et al. (2016) Native Conformation and Canonical Disulfide Bond Formation Are Interlinked Properties of HIV-1 Env Glycoproteins. J Virol 90:2884-94
Klasse, P J; LaBranche, Celia C; Ketas, Thomas J et al. (2016) Sequential and Simultaneous Immunization of Rabbits with HIV-1 Envelope Glycoprotein SOSIP.664 Trimers from Clades A, B and C. PLoS Pathog 12:e1005864
Dosenovic, Pia; von Boehmer, Lotta; Escolano, Amelia et al. (2015) Immunization for HIV-1 Broadly Neutralizing Antibodies in Human Ig Knockin Mice. Cell 161:1505-15
Schiffner, Torben; de Val, Natalia; Russell, Rebecca A et al. (2015) Chemical Cross-Linking Stabilizes Native-Like HIV-1 Envelope Glycoprotein Trimer Antigens. J Virol 90:813-28
Lee, Jeong Hyun; Leaman, Daniel P; Kim, Arthur S et al. (2015) Antibodies to a conformational epitope on gp41 neutralize HIV-1 by destabilizing the Env spike. Nat Commun 6:8167
Alexander, Marina R; Ringe, Rajesh; Sanders, Rogier W et al. (2015) What Do Chaotrope-Based Avidity Assays for Antibodies to HIV-1 Envelope Glycoproteins Measure? J Virol 89:5981-95
Garces, Fernando; Lee, Jeong Hyun; de Val, Natalia et al. (2015) Affinity Maturation of a Potent Family of HIV Antibodies Is Primarily Focused on Accommodating or Avoiding Glycans. Immunity 43:1053-63
Ringe, Rajesh P; Yasmeen, Anila; Ozorowski, Gabriel et al. (2015) Influences on the Design and Purification of Soluble, Recombinant Native-Like HIV-1 Envelope Glycoprotein Trimers. J Virol 89:12189-210
Sanders, Rogier W; van Gils, Marit J; Derking, Ronald et al. (2015) HIV-1 VACCINES. HIV-1 neutralizing antibodies induced by native-like envelope trimers. Science 349:aac4223
Sliepen, Kwinten; Ozorowski, Gabriel; Burger, Judith A et al. (2015) Presenting native-like HIV-1 envelope trimers on ferritin nanoparticles improves their immunogenicity. Retrovirology 12:82

Showing the most recent 10 out of 54 publications