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

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.

journal_name

Cell Rep

journal_title

Cell reports

authors

Rawi R,Rutten L,Lai YT,Olia AS,Blokland S,Juraszek J,Shen CH,Tsybovsky Y,Verardi R,Yang Y,Zhang B,Zhou T,Chuang GY,Kwong PD,Langedijk JPM

doi

10.1016/j.celrep.2020.108432

subject

Has Abstract

pub_date

2020-11-24 00:00:00

pages

108432

issue

8

issn

2211-1247

pii

S2211-1247(20)31421-2

journal_volume

33

pub_type

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