Core A (Trimer Production): Principal Investigator/Program Director: Klasse, PJ / Moore, John P. Abstract The goal of the Trimer Production Core is to support the work of the Research Projects by making appropriate quantities of high quality, cleaved, soluble envelope glycoprotein trimers and related reagents, and providing them to the Project Leaders and external collaborators. Dr. PJ Klasse will be Core Leader, with Mr. Albert Cupo directing the Core's activities on a day-to-day basis. The tasks of the Core are outlined below. Other responsibilities related to the production of trimers and other relevant antigens may arise during the life of the HIVRAD program and will be accomplished as and when appropriate.
Aim 1 : To produce milligram quantities of high quality SOSIP trimers and related Env proteins in mammalian cell lines by transient transfection. The Core will produce, in appropriate quantities, any trimers that are designed and evaluated (in small-scale production runs) by Project 1, and then selected for scale-up. The trimers will be assessed for purity and antigenic quality, in liaison with Project 1, and supplied to Projects 1 and 2 and collaborators.
Aim 2 : To create and use permanent cell lines expressing SOSIP.664 trimers. The Core will use now established methods to make stable CHO, 293T or 293S cell lines expressing wild type or epitope-tagged SOSIP.664 trimers based on various genotypes, under non-GMP conditions.
Aim 3 : To guide and facilitate the production and purification of SOSIP trimers under GMP conditions. A CMO (Catalent Inc.) will make large quantities of GMP-grade BG505 SOSIP.664 trimers under the direction of a consortium that also involves IAVI, BMGF and the Scripps CHAVI-ID. The Core will use its accumulated expertise to guide this process, including the creation and transfer of methods and the production of achievable quantities of reference standard trimers. By providing a central service to both Research Projects, and external collaborators, the Trimer Production Core will be intimately involved in the scientific program of the entire HIVRAD team.

Public Health Relevance

Core A (Trimer Production): Principal Investigator/Program Director: Klasse, PJ / Moore, John P. Narrative The overall objective of this multi-site HIVRAD application is to help develop a preventative HIV-1 vaccine based on the induction of virus neutralizing antibodies by rationally designed, structurally relevant envelope glycoprotein trimers. Core A will make the SOSIP trimers designed in Projects 1 and 2, and provide them to both project teams and external collaborators. The goals of the application are highly relevant to public health and human welfare.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI110657-02
Application #
9041515
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
2016-06-01
Budget End
2017-05-31
Support Year
2
Fiscal Year
2016
Total Cost
Indirect Cost
Name
Weill Medical College of Cornell University
Department
Type
DUNS #
060217502
City
New York
State
NY
Country
United States
Zip Code
10065
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Struwe, Weston B; Chertova, Elena; Allen, Joel D et al. (2018) Site-Specific Glycosylation of Virion-Derived HIV-1 Env Is Mimicked by a Soluble Trimeric Immunogen. Cell Rep 24:1958-1966.e5
Behrens, Anna-Janina; Kumar, Abhinav; Medina-Ramirez, Max et al. (2018) Integrity of Glycosylation Processing of a Glycan-Depleted Trimeric HIV-1 Immunogen Targeting Key B-Cell Lineages. J Proteome Res 17:987-999
Ringe, Rajesh P; Pugach, Pavel; Cottrell, Christopher A et al. (2018) Closing and opening holes in the glycan shield of HIV-1 envelope glycoprotein SOSIP trimers can redirect the neutralizing antibody response to the newly unmasked epitopes. J Virol :
Allen, Joel D; Sanders, Rogier W; Doores, Katie J et al. (2018) Harnessing post-translational modifications for next-generation HIV immunogens. Biochem Soc Trans 46:691-698
Klasse, P J; Ketas, Thomas J; Cottrell, Christopher A et al. (2018) Epitopes for neutralizing antibodies induced by HIV-1 envelope glycoprotein BG505 SOSIP trimers in rabbits and macaques. PLoS Pathog 14:e1006913
de Taeye, Steven W; de la Peña, Alba Torrents; Vecchione, Andrea et al. (2018) Stabilization of the gp120 V3 loop through hydrophobic interactions reduces the immunodominant V3-directed non-neutralizing response to HIV-1 envelope trimers. J Biol Chem 293:1688-1701
Dey, Antu K; Cupo, Albert; Ozorowski, Gabriel et al. (2018) cGMP production and analysis of BG505 SOSIP.664, an extensively glycosylated, trimeric HIV-1 envelope glycoprotein vaccine candidate. Biotechnol Bioeng 115:885-899
Torrents de la Peña, Alba; Sanders, Rogier W (2018) Stabilizing HIV-1 envelope glycoprotein trimers to induce neutralizing antibodies. Retrovirology 15:63
Medina-Ramírez, Max; Sanders, Rogier W; Sattentau, Quentin J (2017) Stabilized HIV-1 envelope glycoprotein trimers for vaccine use. Curr Opin HIV AIDS :

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