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

Author:

Rawi, Reda

Rutten, Lucy

Lai, Yen-Ting

Olia, Adam S

Blokland, Sven

Juraszek, Jarek

Shen, Chen-Hsiang

Tsybovsky,Yaroslav

Verardi, Raffaello

Yang, Yongping

Zhang, Baoshan

Zhou, Tongqing

Chuang, Gwo-Yu

Kwong, Peter D

Langedijk, Johannes P M
Author Address

Vaccine Research Center, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, MD 20892, USA., Janssen Vaccines & Prevention, Archimedesweg 4-6, 2333 CN Leiden, the Netherlands., Electron Microscopy Laboratory, Cancer Research Technology Program, Frederick National Laboratory for Cancer Research sponsored by the National Cancer Institute, Frederick, MD 21701, USA., 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. Electronic address: pdkwong@nih.gov., Janssen Vaccines & Prevention, Archimedesweg 4-6, 2333 CN Leiden, the Netherlands. Electronic address: hlangedi@its.jnj.com.,

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. Published by Elsevier Inc.

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