Project 2 (Structural Studies): Program Director/Principal Investigator: Moore, John P / Wilson, Ian A Abstract The goal of Project 2 in this HIVRAD proposal is to make significant advances toward the development of a HIV-1 vaccine that utilizes trimeric gp140 antigens (Env trimers). It is anticipated that such a vaccine would induce a substantial neutralizing antibody response. The role of Project 2 is to structurally characterize a wide range of SOSIP and related trimers as complexes with broadly neutralizing antibodies (bnAbs) and other ligands (receptors, small molecules) using X-ray crystallography, electron microscopy and other biophysical methods. In a truly integrative biophysical approach, we will determine the three-dimensional structures of Env trimer constructs to provide insights into design improvements intended to increase their stability, antigenicity and immunogenicity. The immediate goal of Project 2 is to capitalize on our recent exciting breakthroughs in generating stable soluble Env trimers (BG505 SOSIP.664, subtype A) that are amenable to high-resolution structure determination. We will increase the resolution of our current structural models and also determine new Env trimer structures based on a variety of genotypes (including from subtypes B and C). The resulting information will help us, working closely with Project 1 and Core A, to design a new generation of Env immunogens. To accomplish these goals, the Project 2 team will utilize a highly integrative structural biology and biophysical chemistry approach involving electron microscopy, X-ray crystallography, and a range of other biophysical tools (HDXMS, SEC-MALS, ITC, DSC, SPR), to generate high-resolution details of Env trimers and trimer- bnAb complexes. This structural information will not only provide a comprehensive view of the trimers but also define the epitopes for a diverse range of bnAbs, in the context of the trimer. This is important because many recently defined bNAb epitopes are quaternary in nature, or are otherwise not adequately described by crystal structures derived from complexes with simpler Env substrates such as gp120, gp120 outer domain, V1/V2 scaffolds, individual glycans, or linear peptides. Furthermore, we will delineate the structure and salient features of the glycan shield as the glycan moieties and composition on our SOSIP.664 trimers has been shown by our glycobiology collaborators to resemble those found on native, virion-associated trimers. Overall, we will use state-of-the-art structural and biophysical methods and our world-class structural biology facilities to generate high-resolution structures (~3-6 or better) for a variety of designed and engineered Env trimers of different genotypes, alone and in complex with bnAbs that define the main sites of vulnerability of Env. In addition, we will delineate the conformational changes that take place in Env as it transits from the closed, ground-state form to the open, fusion-active forms associated with CD4 and co-receptor binding.

Public Health Relevance

Project 2 (Structural Studies): Program Director/Principal Investigator: Moore, John P / Wilson, Ian A Narrative This project is of high relevance for design of an HIV-1 vaccine that would elicit an effective immune response to the enormous diversity of circulating strains. Achieving the Project 2 goals would be a major advance towards understanding the structure and function of the HIV-1 envelope glycoprotein complex. Specifically, high resolution HIV-1 Env trimer structures will facilitate the design of stable, native-like immunogens suitable for evaluation as vaccine candidates.

National Institute of Health (NIH)
National Institute of Allergy and Infectious Diseases (NIAID)
Research Program Projects (P01)
Project #
Application #
Study Section
Special Emphasis Panel (ZAI1)
Project Start
Project End
Budget Start
Budget End
Support Year
Fiscal Year
Total Cost
Indirect Cost
Weill Medical College of Cornell University
New York
United States
Zip Code
Ozorowski, Gabriel; Cupo, Albert; Golabek, Michael et al. (2018) Effects of Adjuvants on HIV-1 Envelope Glycoprotein SOSIP Trimers In Vitro. J Virol 92:
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 :

Showing the most recent 10 out of 51 publications