Automated Design by Structure-Based Stabilization and Consensus Repair to Achieve Prefusion-Closed Envelope Trimers in a Wide Variety of HIV Strains

Cell Reports, vol. 33, pp. 108432

Abstract

Soluble envelope (Env) trimers, stabilized in a prefusion-closed conformation, can elicit neutralizing responses against HIV-1 strains closely related to the immunizing trimer. However, to date such stabilization has succeeded with only a limited number of HIV-1 strains. To address this issue, here we develop ADROITrimer, an automated procedure involving structure-based stabilization and consensus repair, and generate "RnS-DS-SOSIP"-stabilized Envs from 180 diverse Env sequences. The vast majority of these RnS-DS-SOSIP Envs fold into prefusion-closed conformations as judged by antigenic analysis and size exclusion chromatography. Additionally, representative strains from clades AE, B, and C are stabilized in prefusion-closed conformations as shown by negative-stain electron microscopy, and the crystal structure of a clade A strain MI369.A5 Env trimer provides 3.5 Å resolution detail into stabilization and repair mutations. The automated procedure reported herein that yields well-behaved, soluble, prefusion-closed Env trimers from a majority of HIV-1 strains could have substantial impact on the development of an HIV-1 vaccine.

Authors 15

1. Reda Rawi

   National Institutes of Health · National Institute of Allergy and Infectious Diseases · Vaccine Research Center

   Affiliation as printed

   Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

2. Lucy Rutten Aachen Janssen Vaccines & Prevention

   Janssen (Netherlands)

   Affiliation as printed

   Janssen Vaccines & Prevention, Archimedesweg 4-6, 2333 CN Leiden, the Netherlands

3. Yen‐Ting Lai

   National Institutes of Health · National Institute of Allergy and Infectious Diseases · Vaccine Research Center

   Affiliation as printed

   Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

4. Adam S. Olia

   National Institutes of Health · National Institute of Allergy and Infectious Diseases · Vaccine Research Center

   Affiliation as printed

   Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

5. Sven Blokland Aachen Janssen Vaccines & Prevention

   Janssen (Netherlands)

   Affiliation as printed

   Janssen Vaccines & Prevention, Archimedesweg 4-6, 2333 CN Leiden, the Netherlands

6. Jarek Juraszek Aachen Janssen Vaccines & Prevention

   Janssen (Netherlands)

   Affiliation as printed

   Janssen Vaccines & Prevention, Archimedesweg 4-6, 2333 CN Leiden, the Netherlands

7. Chen‐Hsiang Shen

   National Institutes of Health · National Institute of Allergy and Infectious Diseases · Vaccine Research Center

   Affiliation as printed

   Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

8. Yaroslav Tsybovsky

   Frederick National Laboratory for Cancer Research · National Cancer Institute

   Affiliation as printed

   Electron Microscopy Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD 21701, USA

9. Raffaello Verardi

   National Institutes of Health · National Institute of Allergy and Infectious Diseases · Vaccine Research Center

   Affiliation as printed

   Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

10. Yongping Yang

    National Institutes of Health · National Institute of Allergy and Infectious Diseases · Vaccine Research Center

    Affiliation as printed

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

11. Baoshan Zhang

    National Institutes of Health · National Institute of Allergy and Infectious Diseases · Vaccine Research Center

    Affiliation as printed

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

12. Tongqing Zhou

    National Institutes of Health · National Institute of Allergy and Infectious Diseases · Vaccine Research Center

    Affiliation as printed

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

13. Gwo‐Yu Chuang corresponding

    National Institutes of Health · National Institute of Allergy and Infectious Diseases · Vaccine Research Center

    Affiliation as printed

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: gwo-yu.chuang@nih.gov

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

14. Peter D. Kwong corresponding

    National Institutes of Health · National Institute of Allergy and Infectious Diseases · Vaccine Research Center

    Affiliation as printed

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA. Electronic address: pdkwong@nih.gov

    Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA

15. Johannes P. M. Langedijk corresponding Aachen Janssen Vaccines & Prevention

    Janssen (Netherlands)

    Affiliation as printed

    Janssen Vaccines & Prevention, Archimedesweg 4-6, 2333 CN Leiden, the Netherlands. Electronic address: hlangedi@its.jnj.com

    Janssen Vaccines & Prevention, Archimedesweg 4-6, 2333 CN Leiden, the Netherlands