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

Cai, Yongfei; Karaca-Griffin, Selen; Chen, Jia; Tian, Sai; Fredette, Nicholas; Linton, Christine; Rits-Volloch, Sophia; Lü, Jianming; Wagh, Kshitij; Theiler, James; Korber, Bette T.; Seaman, Michael S.; Harrison, Stephen C.; Carfı́, Andrea; Chen, Bing

doi:10.1073/pnas.1700634114

Cited by 19 publications

(14 citation statements)

References 41 publications

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“…The HIV-1 envelope protein (Env), a trimer of gp160 subunits activated by cleavage to (gp120-gp41) 3 , is the sole surface antigen of the virus [1,2]. Its dynamics, critical for its functions as the viral attachment protein and membrane fusogen, influence Env antigenicity by exposing epitopes inaccessible in the most stable equilibrium conformation [3][4][5][6][7]. Conformational fluctuations likewise influence the immunogenicity, both of viral Env during infection or propagation in culture, and of recombinant Env vaccine candidates.…”

Section: Introductionmentioning

confidence: 99%

“…The position of the equilibrium among these conformational states depends on Env sequence, as indicated by the early observation that sCD4 bound more readily to labadapted strains than to patient isolates and shown more completely by a recent detailed analysis of Env antigenicity [7,17,18]. The equilibrium for readily neutralized ("tier 1") Envs favors the open conformation; that for "tier 2" and "tier 3" Envs lies toward the closed conformation [6,7,19,20]. Envs that yield stable, homogeneous, trimeric, recombinant ectodomain (gp140) fall into the latter group [7,17,18].…”

Section: Introductionmentioning

confidence: 99%

“…The equilibrium for readily neutralized ("tier 1") Envs favors the open conformation; that for "tier 2" and "tier 3" Envs lies toward the closed conformation [6,7,19,20]. Envs that yield stable, homogeneous, trimeric, recombinant ectodomain (gp140) fall into the latter group [7,17,18]. Studies using fluorescence resonance energy transfer (FRET) or DEER spectroscopy have probed the ranges of relevant conformational ensembles [6,21,22].…”

Section: Introductionmentioning

confidence: 99%

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Cryo-EM structure of full-length HIV-1 Env bound with the Fab of antibody PG16

Pan¹,

Peng²,

Chen³

2019

Preprint

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The HIV-1 envelope protein (Env) is the target of neutralizing antibodies and the template for vaccine immunogen design. The dynamic conformational equilibrium of trimeric Env influences its antigenicity and potential immunogenicity. Antibodies that bind at the trimer apex stabilize a "closed" conformation characteristic of the most difficult to neutralize isolates. A goal of vaccine development is therefore to mimic the closed conformation in a designed immunogen. A disulfide-stabilized, trimeric Env ectodomain --the "SOSIP" construct --has many of the relevant properties; it is also particularly suitable for structure determination. Some singlemolecule studies have, however, suggested that the SOSIP trimer is not a good representation of Env on the surface of a virion or an infected cell. We isolated Env (fully cleaved to gp120 and gp41) from the surface of expressing cells using tagged, apex-binding Fab PG16 and determined the structure of the PG16-Env complex by cryo-EM to an overall resolution of 4.6 Å.Placing the only purification tag on the Fab ensured that the isolated Env was continuously stabilized in its closed, native conformation. The Env structure in this complex corresponds closely to the SOSIP structures determined by both x-ray crystallography and cryo-EM.Although the membrane-interacting elements are not resolved in our reconstruction, we can make inferences about the connection between ectodomain and membrane-proximal external region (MPER) by reference to the published cryo-tomography structure of an Env "spike" and the NMR structure of the MPER-transmembrane segment. We discuss these results in view of the conflicting interpretations in the literature.

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Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Cryo-EM structure of full-length HIV-1 Env bound with the Fab of antibody PG16

Pan¹,

Peng²,

Chen³

2019

Preprint

Self Cite

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“…Binding of open state Env to either chemokine co-receptor, CCR5 or CXCR (4,6,7), leads to the formation of a six-helix transmembrane bundle that drives viral fusion with the host cell membrane (8,9). Unbound Env samples the thermodynamic landscape between the prefusion closed state and the activated open state, hindering the ability to rationally design a broadly neutralizing vaccine (10)(11)(12)(13)(14)(15)(16). In addition to differences in dynamics due to mutations in the surface exposed ectodomain, conformational coupling of the gp41 transmembrane domain (TMD) to the ectodomain affects the dynamics and therefore antigenicity of Env (17,18).…”

Section: Introductionmentioning

confidence: 99%

HIV-1 Env gp41 Transmembrane Domain Dynamics are Modulated by Lipid, Water, and Ion Interactions

Hollingsworth

Lemkul

Bevan

2018

Preprint

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The gp41 transmembrane domain (TMD) of the envelope glycoprotein (Env) of the human immunodeficiency virus (HIV) modulates the conformation of the viral envelope spike, the only druggable target on the surface of the virion. Understanding of TMD dynamics is needed to better probe and target Env with small molecule and antibody therapies. However, little is known about TMD dynamics due to difficulties in describing native membrane properties. Here, we performed atomistic molecular dynamics simulations of a trimeric, prefusion TMD in a model, asymmetric viral membrane that mimics the native viral envelope. We found that water and chloride ions permeated the membrane and interacted with the highly conserved arginine bundle, (R696) 3 , at the center of the membrane and influenced TMD stability by creating a network of hydrogen bonds and electrostatic interactions. We propose that this (R696) 3 -water -anion network plays an important role in viral fusion with the host cell by modulating protein conformational changes within the membrane. Additionally, R683 and R707 at the exofacial and cytofacial membrane-water interfaces, respectively, are anchored in the lipid headgroup region and serve as a junction point for stabilization of the termini. The membrane thins as a result of the tilting of the TMD trimer, with nearby lipids increasing in volume, leading to an entropic driving force for TMD conformational change. These results provide additional detail and perspective on the influence of certain lipid types on TMD dynamics and rationale for targeting key residues of the TMD for therapeutic design. These insights into the molecular details of TMD membrane anchoring will build towards a greater understanding of dynamics that lead to viral fusion with the host cell.

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“…Tier 3 strains exhibit exceptional resistance to antibody-mediated neutralization. The neutralization tier phenotypes of HIV-1 isolates can be understood in the context of the dynamic nature of Env trimers on the virus surface (34, 46). These trimers spontaneously transition between closed, open, and at least one intermediate conformation.…”

Section: Discussionmentioning

confidence: 99%

A rare mutation in an infant derived HIV-1 envelope glycoprotein alters interprotomer stability and susceptibility to broadly neutralizing antibodies targeting the trimer apex

Mishra

Sharma

Dobhal

et al. 2020

Preprint

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Word Count: 249 13 Article Word Count: 4942 14 15 2 Abstract (249/250 words) 16The envelope glycoprotein (Env) of human immunodeficiency virus-1 (HIV-1) is the sole target of 17 broadly neutralizing antibodies (bnAbs). Several mechanisms, such as acquisition of mutations due to 18 the error prone reverse transcriptase, variability of loop length and alterations in glycan pattern are 19 employed by the virus to shield neutralizing epitopes on the env, to sustain survival and infectivity 20 within the host. Identification of mutations that can lead to viral evasion from host immune response is 21 essential for optimization and engineering of Env based trimeric immunogens. Herein, we report a 22 rare leucine to phenylalanine escape mutation (L184F) at the base of hypervariable loop 2 (population 23 frequency of 0.0045%) in a nine-month-old perinatally HIV-1 infected infant broad neutralizer. The 24L184F mutation disrupted the intramolecular interaction, stabilizing the trimer apex thereby leading to 25 viral escape from autologous plasma bnAbs and known bnAbs, targeting exclusively the N160 glycan 26 at trimer apex and not any other known epitope. The L184F amino acid change led to acquisition of a 27 relatively open trimeric configuration, often associated with tier 1 HIV-1 isolates and an increased 28 susceptibility to neutralization by polyclonal plasma antibodies of weak neutralizers. While there was 29 no impact of the L184F mutation on free virus transmission, a reduction in cell-to-cell transmission 30 was observed. In conclusion, we report a viral escape mutation that plausibly destabilized the trimer 31 apex and favoured evasion from broadly neutralizing antibodies. Such mutations, though rare, should 32 be taken into consideration while designing an immunogen, based on a stable correctly-folded HIV-1 33 Env trimer. 34Importance (148/150 words) 35Design of HIV-1 envelope-based immunogens, capable of eliciting broadly neutralizing antibodies 36 (bnAbs), are currently under active research. Some of the most potent bnAbs target the quaternary 37 epitope at the V2 apex of HIV-1 Env trimer. By studying naturally circulating viruses from an HIV-1 38 perinatally infected infant, with plasma neutralizing antibodies targeted to the V2-apex, we identified a 39 rare leucine to phenylalanine substitution in two out of six functional viral clones, that destabilized the 40 trimer apex. This single amino acid alteration impaired the interprotomeric interactions that stabilize 41 the trimer apex, resulting in an open trimer conformation, and escape from broadly neutralizing 42 autologous plasma antibodies and known V2-apex directed bnAbs, thereby favouring viral evasion of 43 the early bnAb response of the infected host. Defining the mechanisms by which viral mutations 44 3 influence the sensitivity of HIV-1 to bnAbs is crucial for the development of effective vaccines against 45 HIV-1 infection. 49 Envelope glycoprotein (Env) is a trimer of non-covalently linked heterodimers (gp120/gp41)3, and is 50 the primary target of ...

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

Cited by 19 publications

References 41 publications

Cryo-EM structure of full-length HIV-1 Env bound with the Fab of antibody PG16

Cryo-EM structure of full-length HIV-1 Env bound with the Fab of antibody PG16

HIV-1 Env gp41 Transmembrane Domain Dynamics are Modulated by Lipid, Water, and Ion Interactions

A rare mutation in an infant derived HIV-1 envelope glycoprotein alters interprotomer stability and susceptibility to broadly neutralizing antibodies targeting the trimer apex

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