Structural basis for membrane anchoring of HIV-1 envelope spike

Dev, Jyoti; Park, Donghyun; Fu, Qing; Chen, Jia; Ha, Heather Jiwon; Ghantous, Fadi; Herrmann, Tobias; Chang, Wei‐Ting; Liu, Zhijun; Frey, Gary; Seaman, Michael S.; Chen, Bing; Chou, James J.

doi:10.1126/science.aaf7066

Cited by 172 publications

(270 citation statements)

References 49 publications

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“…Both the gp41 membrane-proximal external region and the transmembrane segment are disordered in the PGT151-EnvΔCT complex structure (48). As both of these gp41 regions have been implicated in maintaining the conformation of the native HIV-1 Env in state 1 (35,41,55,(82)(83)(84), the observed disorder makes it unlikely that the state 1 conformation is represented by the EnvΔCT structure (or, on the basis of its close resemblance, by the soluble gp140 SOSIP.664 structure).…”

Section: Discussionmentioning

confidence: 97%

Residues in the gp41 Ectodomain Regulate HIV-1 Envelope Glycoprotein Conformational Transitions Induced by gp120-Directed Inhibitors

Pacheco

Alsahafi

Débbeche

et al. 2017

J Virol

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Interactions between the gp120 and gp41 subunits of the human immunodeficiency virus type 1 (HIV-1) envelope glycoprotein (Env) trimer maintain the metastable unliganded form of the viral spike. Binding of gp120 to the receptor, CD4, changes the Env conformation to promote gp120 interaction with the second receptor, CCR5 or CXCR4. CD4 binding also induces the transformation of Env into the prehairpin intermediate, in which the gp41 heptad repeat 1 (HR1) coiled coil is assembled at the trimer axis. In nature, HIV-1 Envs must balance the requirements to maintain the noncovalent association of gp120 with gp41 and to evade the host antibody response with the need to respond to CD4 binding. Here we show that the gp41 HR1 region contributes to gp120 association with the unliganded Env trimer. Changes in particular amino acid residues in the gp41 HR1 region decreased the efficiency with which Env moved from the unliganded state. Thus, these gp41 changes decreased the sensitivity of HIV-1 to cold inactivation and ligands that require Env conformational changes to bind efficiently. Conversely, these gp41 changes increased HIV-1 sensitivity to small-molecule entry inhibitors that block Env conformational changes induced by CD4. Changes in particular gp41 HR1 amino acid residues can apparently affect the relative stability of the unliganded state and CD4-induced conformations. Thus, the gp41 HR1 region contributes to the association with gp120 and regulates Env transitions from the unliganded state to downstream conformations.IMPORTANCE The development of an efficient vaccine able to prevent HIV infection is a worldwide priority. Knowledge of the envelope glycoprotein structure and the conformational changes that occur after receptor engagement will help researchers to develop an immunogen able to elicit antibodies that block HIV-1 transmission. Here we identify residues in the HIV-1 transmembrane envelope glycoprotein that stabilize the unliganded state by modulating the transitions from the unliganded state to the CD4-bound state.

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Section: Discussionmentioning

confidence: 97%

Residues in the gp41 Ectodomain Regulate HIV-1 Envelope Glycoprotein Conformational Transitions Induced by gp120-Directed Inhibitors

Pacheco

Alsahafi

Débbeche

et al. 2017

J Virol

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“…A proposed nuclear magnetic resonance (NMR) structure identified the tyrosine-based YXXL sorting signal as being located within a hydrophilic core of transmembrane domain (TMD) of gp41, contributing to stabilize the trimeric structure TMD. Mutation of this motif is suggested to destabilize the hydrophilic core of TMD trimer, altering the antigenic surfaces of the ectodomain of gp120 (67). Thus, an attractive model to explain the changes in the neutralization sensitivity of the YXXL mutant viruses is that this membrane-proximal internal motif is involved in allosteric modulation of gp120.…”

Section: Discussionmentioning

confidence: 99%

Reduced Potency and Incomplete Neutralization of Broadly Neutralizing Antibodies against Cell-to-Cell Transmission of HIV-1 with Transmitted Founder Envs

Zony

Chen

et al. 2017

J Virol

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Broadly neutralizing antibodies (bNAbs) have been isolated from HIV-1 patients and can potently block infection of a wide spectrum of HIV-1 subtypes. These antibodies define common epitopes shared by many viral isolates. While bNAbs potently antagonize infection with cell-free virus, inhibition of HIV-1 transmission from infected to uninfected CD4 ϩ T cells through virological synapses (VS) has been found to require greater amounts of antibody. In this study, we examined two well-studied molecular clones and two transmitted/founder (T/F) clones for their sensitivities to a panel of bNAbs in cell-free and cell-to-cell infection assays. We observed resistance of cell-to-cell transmission to antibody neutralization that was reflected not only by reductions of antibody potency but also by decreases in maximum neutralization capacity relative to the levels seen with cell-free infections. BNAbs targeting different epitopes exhibited incomplete neutralization against cellassociated virus with T/F Envs, which was not observed with the cell-free form of the same virus. We further identified the membrane-proximal internal tyrosine-based sorting motif as a determinant that can affect the incomplete neutralization of these T/F clones in cell-to-cell infection. These findings indicate that the signal that affects surface expression and/or internalization of Env from the plasma membrane can modulate the presentation of neutralizing epitopes on infected cells. These results highlight that a fraction of virus can escape from high concentrations of antibody through cell-to-cell infection while remaining sensitive to neutralization in cell-free infection. The ability to fully inhibit cell-to-cell transmission may represent an important consideration in the development of antibodies for treatment or prophylaxis.

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“…Thus, like many other soluble Env preparations (12,29), it does not fully recapitulate the antigenic structure of virion-borne Env. Our recent observation that the TMD of HIV-1 Env is a structural component critical for the stability of the functional Env spike provides a plausible explanation for why the antigenic properties of most recombinant, soluble Env preparations with the TMD deleted deviate from those of the native protein (14,39). We therefore must take the structural constraints imposed by the TMD on the ectodomain into consideration when designing a soluble immunogen, e.g., by mutating surface-exposed, lipid-interacting hydrophobic residues on the TMD while maintaining the trimeric structure seen in the high-resolution structure (14,40).…”

Section: Discussionmentioning

confidence: 99%

“…We found that deletion of the CT has minimal impact on the membrane-fusion function of the Env trimer but has an unexpectedly large influence on the antigenic properties of the ectodomain (10). Moreover, to understand the physical coupling between the CT and the ectodomain, we then determined an atomic structure of the transmembrane domain (TMD) (14). The TMD forms a well-ordered trimer.…”

mentioning

confidence: 99%

Antigenicity-defined conformations of an extremely neutralization-resistant HIV-1 envelope spike

Cai

Karaca-Griffin

Chen

et al. 2017

Proc. Natl. Acad. Sci. U.S.A.

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The extraordinary genetic diversity of the HIV-1 envelope spike [Env; trimeric (gp160) 3 , cleaved to (gp120/gp41) 3 ] poses challenges for vaccine development. Envs of different clinical isolates exhibit different sensitivities to antibody-mediated neutralization. Envs of difficult-to-neutralize viruses are thought to be more stable and conformationally homogeneous trimers than those of easyto-neutralize viruses, thereby providing more effective concealment of conserved, functionally critical sites. In this study we have characterized the antigenic properties of an Env derived from one of the most neutralization-resistant HIV-1 isolates, CH120.6. Sequence variation at neutralizing epitopes does not fully account for its exceptional resistance to antibodies. The full-length, membrane-bound CH120.6 Env is indeed stable and conformationally homogeneous. Its antigenicity correlates closely with its neutralization sensitivity, and major changes in antigenicity upon CD4 engagement appear to be restricted to the coreceptor site. The CH120.6 gp140 trimer, the soluble and uncleaved ectodomain of (gp160) 3 , retains many antigenic properties of the intact Env, consistent with a conformation close to that of Env spikes on a virion, whereas its monomeric gp120 exposes many nonneutralizing or strain-specific epitopes. Thus, trimer organization and stability are important determinants not only for occluding many epitopes but also for conferring resistance to neutralization by all but a small set of antibodies. Env preparations derived from neutralization-resistant viruses may induce irrelevant antibody responses less frequently than do other Envs and may be excellent templates for developing soluble immunogens.HIV-1 gp160 | neutralizing antibodies | vaccine design

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Structural basis for membrane anchoring of HIV-1 envelope spike

Cited by 172 publications

References 49 publications

Residues in the gp41 Ectodomain Regulate HIV-1 Envelope Glycoprotein Conformational Transitions Induced by gp120-Directed Inhibitors

Residues in the gp41 Ectodomain Regulate HIV-1 Envelope Glycoprotein Conformational Transitions Induced by gp120-Directed Inhibitors

Reduced Potency and Incomplete Neutralization of Broadly Neutralizing Antibodies against Cell-to-Cell Transmission of HIV-1 with Transmitted Founder Envs

Antigenicity-defined conformations of an extremely neutralization-resistant HIV-1 envelope spike

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