Partially Open HIV-1 Envelope Structures Exhibit Conformational Changes Relevant for Coreceptor Binding and Fusion

Haoqing Wang,Christopher O Barnes,Zhi Yang,Michel C Nussenzweig,Pamela J Bjorkman

doi:10.1016/j.chom.2018.09.003

Haoqing Wang, Christopher O Barnes + Show 3 more

Open Access

https://doi.org/10.1016/j.chom.2018.09.003

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Abstract

SummaryHIV-1 Env, a trimer of gp120-gp41 heterodimers, mediates membrane fusion after binding host receptor CD4. Receptor binding displaces V1V2 loops from Env's apex, allowing coreceptor binding and opening Env to enable gp41-mediated fusion. We present 3.54 Å and 4.06 Å cryoelectron microscopy structures of partially open soluble native-like Env trimers (SOSIPs) bound to CD4. One structure, a complex with a coreceptor-mimicking antibody that binds both CD4 and gp120, stabilizes the displaced V1V2 and reveals its structure. Comparing partially and fully open Envs with closed Envs shows that gp41 rearrangements are independent of the CD4-induced rearrangements that result in V1V2 displacement and formation of a 4-stranded bridging sheet. These findings suggest ordered conformational changes before coreceptor binding: (1) gp120 opening inducing side-chain rearrangements and a compact gp41 central helix conformation, and (2) 4-stranded bridging-sheet formation and V1V2 displacement. These analyses illuminate potential receptor-induced Env changes and inform design of therapeutics disrupting viral entry.

Highlights

The first step in HIV-1 infection is fusion of the viral and host cell lipid bilayers to allow the HIV-1 capsid and its genetic material to enter the target cell (Harrison, 2015)
An intermediate resolution (8.9 A ) single-particle cryoEM structure of an SOSIP Env complexed with soluble CD4 and the coreceptor-mimicking antibody 17b (Sullivan et al, 1998) was consistent with the electron tomography structures of CD4-bound Env on virions (Liu et al, 2008) and showed $40 Adisplacement of the V1V2 loops to the sides of the Env trimer to expose V3 (Wang et al, 2016a)
Cryo-EM Structures of Envs Complexed with soluble CD4 (sCD4), Coreceptor-Mimicking Antibodies, and 8ANC195 EM studies confirmed that recombinant native-like soluble gp140 Env trimers (SOSIPs) (Sanders et al, 2013) can adopt the closed and open architectures seen on virion-bound Env trimers (Harris et al, 2011; Sanders et al, 2013; Tran et al, 2012)

Summary

Introduction

The first step in HIV-1 infection is fusion of the viral and host cell lipid bilayers to allow the HIV-1 capsid and its genetic material to enter the target cell (Harrison, 2015). An intermediate resolution (8.9 A ) single-particle cryoEM structure of an SOSIP Env complexed with soluble CD4 (sCD4) and the coreceptor-mimicking antibody 17b (Sullivan et al, 1998) was consistent with the electron tomography structures of CD4-bound Env on virions (Liu et al, 2008) and showed $40 Adisplacement of the V1V2 loops to the sides of the Env trimer to expose V3 (Wang et al, 2016a). These results were verified and extended in a 3.7 AsCD4-and 17b-bound SOSIP structure, which described side-chain rearrangements in gp120 and gp that were visible at higher resolution, but did not show ordered density for the rearranged V1V2 loops (Ozorowski et al, 2017)

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