Journal Article

Intermediate conformations of CD4-bound HIV-1 Env heterotrimers

Bjorkman, Pamela J., Fan, Chengcheng, Dam, Kim-Marie A., Yang, Zhi

2023

Overview

HIV-1 envelope (Env) exhibits distinct conformational changes in response to host receptor (CD4) engagement. Env, a trimer of gp120 and gp41 heterodimers, has been structurally characterized in a closed, prefusion conformation with closely associated gp120s and coreceptor binding sites on gp120 V3 hidden by V1V2 loops 1 – 4 and in fully saturated CD4-bound open Env conformations with changes including outwardly rotated gp120s and displaced V1V2 loops 3 – 9 . To investigate changes resulting from substoichiometric CD4 binding, we solved single-particle cryo-electron microscopy (cryo-EM) structures of soluble, native-like heterotrimeric Envs bound to one or two CD4 molecules. Most of the Env trimers bound to one CD4 adopted the closed, prefusion Env state, with a minority exhibiting a heterogeneous partially open Env conformation. When bound to two CD4s, the CD4-bound gp120s exhibited an open Env conformation including a four-stranded gp120 bridging sheet and displaced gp120 V1V2 loops that expose the coreceptor sites on V3. The third gp120 adopted an intermediate, occluded-open state 10 that showed gp120 outward rotation but maintained the prefusion three-stranded gp120 bridging sheet with only partial V1V2 displacement and V3 exposure. We conclude that most of the engagements with one CD4 molecule were insufficient to stimulate CD4-induced conformational changes, whereas binding two CD4 molecules led to Env opening in CD4-bound protomers only. The substoichiometric CD4-bound soluble Env heterotrimer structures resembled counterparts derived from a cryo-electron tomography study of complexes between virion-bound Envs and membrane-anchored CD4 (ref.  11 ), validating their physiological relevance. Together, these results illuminate intermediate conformations of HIV-1 Env and illustrate its structural plasticity. Single-particle cryo-electron microscopy structures of HIV-1 envelope (Env) trimers bound to one or two CD4 receptors identify intermediate Env conformations that precede host–virus fusion and inform the design of therapeutics to prevent HIV-1 infection.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 101/28 / 631/326/596/2148 / 631/535/1258/1259 / 82 / 82/80 / 82/83 / Antibodies / Binding sites / CD4 antigen / CD4 Antigens - chemistry / CD4 Antigens - metabolism / CD4 Antigens - ultrastructure / Conformation / Cryoelectron Microscopy / Electron microscopy / Glycoprotein gp41 / HIV / HIV Envelope Protein gp120 - chemistry / HIV Envelope Protein gp120 - metabolism / HIV Envelope Protein gp120 - ultrastructure / HIV-1 - chemistry / HIV-1 - ultrastructure / Human immunodeficiency virus / Humanities and Social Sciences / multidisciplinary / Mutation / Plasmids / Protein Conformation / Reproducibility of Results / Rotation / Science / Science (multidisciplinary) / Trimers / Virions