Overall Abstract This HIVRAD Program Project renewal application is made in response to PAR-18-319. It contains two Research Projects, one Scientific Core and an Administrative Core, under the direction of Principal Investigator, John P. Moore, PhD (Weill Cornell Medical College; WCMC) and co-Principal Investigator, Ian A. Wilson, PhD (The Scripps Research Institute; TSRI). The goal of the project is to further develop stable, soluble, cleaved trimeric mimics of the native Env spike (SOSIP trimers) as antigens for structural studies and as immunogens for the development of vaccines aimed at inducing broadly neutralizing antibodies (bNAbs). Our central hypothesis is that a proteolytically cleaved, soluble, trimeric form of HIV-1 Env is an appropriate structural antigen for high resolution x-ray crystallography and electron microscopy studies, and a suitable immunogen for vaccine research aimed at the induction of bNAbs. Our intent is to use structure-based information to help develop an effective, prophylactic HIV-1 vaccine (or component of a more complex vaccine) that is based on the concept of inducing sufficient titers of bNAbs. We believe that one way to accomplish this goal is to make soluble recombinant protein mimics of the native, trimeric Env spike that is present on virions, that mediates virus entry into cells and that is the target for all known bNAbs. SOSIP trimers have the desired properties and can be produced efficiently, including in the amounts and qualities required for human clinical trials. This HIVRAD project team has made excellent progress during the past 4 years, and now seeks support to continue to work together. Its research plan involves the following sub-components. Project 1: John P. Moore (and Rogier W. Sanders): Design of SOSIP trimers Project 2: Ian A. Wilson (and Andrew B. Ward): Structural studies of SOSIP trimers Core B: PJ Klasse: Production of SOSIP trimers Core A: John P. Moore: Administrative support Rogier W. Sanders of the Amsterdam University Medical Centers, Amsterdam will direct a sub-component of Project 1. Andrew B. Ward of The Scripps Research Institute will be the co-leader of Project 2. As well as the integral components of the HIVRAD team, we propose to maintain and expand an extensive network of research collaborations, and we will continue to provide SOSIP trimers and related reagents to the many scientists who request our support.

Public Health Relevance

A vaccine to prevent HIV-1 infection is only likely to be effective if it includes components that are able to stimulate the human immune system into producing antibodies (designated bNAbs) that can neutralize the infectivity of multiple strains of the HIV-1 virus. To stimulate the production of bNAbs, we make proteins known as SOSIP trimers that are based on the only part of the virus that is targeted by bNAbs, the envelope glycoprotein (Env) on the viral surface. In this project, we propose to continue to make and study new and better versions of the SOSIP trimer, for our own research, to provide to collaborators and to donate to other scientists who now use SOSIP trimer designs for their own vaccine-development or related research programs.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
3P01AI110657-06S1
Application #
10336283
Study Section
Special Emphasis Panel (ZAI1)
Program Officer
Chakrabarti, Bimal Kumar
Project Start
2015-06-01
Project End
2021-05-31
Budget Start
2021-02-24
Budget End
2021-05-31
Support Year
6
Fiscal Year
2021
Total Cost
Indirect Cost
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
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
van Haaren, Marlies M; van den Kerkhof, Tom L G M; van Gils, Marit J (2017) Natural infection as a blueprint for rational HIV vaccine design. Hum Vaccin Immunother 13:229-236

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