scholarly journals The Membrane Proximal External Region of the HIV-1 Envelope Glycoprotein gp41 Contributes to the Stabilization of the Six-Helix Bundle Formed with a Matching N′ Peptide†

Biochemistry ◽  
2008 ◽  
Vol 47 (26) ◽  
pp. 6782-6792 ◽  
Author(s):  
Eran Noah ◽  
Zohar Biron ◽  
Fred Naider ◽  
Boris Arshava ◽  
Jacob Anglister
Keyword(s):  
Envelope Glycoprotein ◽  
External Region ◽  
Membrane Proximal External Region ◽  
Helix Bundle ◽  
Glycoprotein Gp41 ◽  
Hiv 1

Exposure of the Membrane-Proximal External Region of HIV-1 gp41 in the Course of HIV-1 Envelope Glycoprotein-Mediated Fusion†

Biochemistry ◽  
2007 ◽  
Vol 46 (5) ◽  
pp. 1398-1401 ◽  
Author(s):  
Antony S. Dimitrov ◽  
Amy Jacobs ◽  
Catherine M. Finnegan ◽  
Gabriela Stiegler ◽  
Hermann Katinger ◽  
...  
Keyword(s):  
Envelope Glycoprotein ◽  
External Region ◽  
Membrane Proximal External Region ◽  
Hiv 1

scholarly journals Modulating immunogenic properties of HIV-1 gp41 membrane-proximal external region by destabilizing six-helix bundle structure

Virology ◽  
2016 ◽  
Vol 490 ◽  
pp. 17-26 ◽  
Author(s):  
Saikat Banerjee ◽  
Heliang Shi ◽  
Habtom H. Habte ◽  
Yali Qin ◽  
Michael W. Cho
Keyword(s):  
External Region ◽  
Membrane Proximal External Region ◽  
Helix Bundle ◽  
Immunogenic Properties ◽  
Hiv 1 ◽  
Bundle Structure

scholarly journals Structure of the membrane proximal external region of HIV-1 envelope glycoprotein

2018 ◽  
Vol 115 (38) ◽  
pp. E8892-E8899 ◽  
Author(s):  
Qingshan Fu ◽  
Md Munan Shaik ◽  
Yongfei Cai ◽  
Fadi Ghantous ◽  
Alessandro Piai ◽  
...  
Keyword(s):  
Lipid Bilayer ◽  
Envelope Glycoprotein ◽  
Neutralizing Antibodies ◽  
Transmembrane Domain ◽  
Bilayer Membrane ◽  
Antigenic Analysis ◽  
External Region ◽  
Membrane Proximal External Region ◽  
Electron Cryotomography ◽  
Hiv 1

The membrane-proximal external region (MPER) of the HIV-1 envelope glycoprotein (Env) bears epitopes of broadly neutralizing antibodies (bnAbs) from infected individuals; it is thus a potential vaccine target. We report an NMR structure of the MPER and its adjacent transmembrane domain in bicelles that mimic a lipid-bilayer membrane. The MPER lies largely outside the lipid bilayer. It folds into a threefold cluster, stabilized mainly by conserved hydrophobic residues and potentially by interaction with phospholipid headgroups. Antigenic analysis and comparison with published images from electron cryotomography of HIV-1 Env on the virion surface suggest that the structure may represent a prefusion conformation of the MPER, distinct from the fusion-intermediate state targeted by several well-studied bnAbs. Very slow bnAb binding indicates that infrequent fluctuations of the MPER structure give these antibodies occasional access to alternative conformations of MPER epitopes. Mutations in the MPER not only impede membrane fusion but also influence presentation of bnAb epitopes in other regions. These results suggest strategies for developing MPER-based vaccine candidates.

scholarly journals Structural insights into the conformational plasticity of the full-length trimeric HIV-1 envelope glycoprotein precursor

2018 ◽  
Author(s):  
Shijian Zhang ◽  
Wei Li Wang ◽  
Shuobing Chen ◽  
Maolin Lu ◽  
Eden P. Go ◽  
...  
Keyword(s):  
Viral Entry ◽  
Envelope Glycoprotein ◽  
Structural Data ◽  
Full Length ◽  
Heptad Repeat ◽  
Structural Basis ◽  
Glycoprotein Precursor ◽  
Helix Bundle ◽  
Conformational Plasticity ◽  
Hiv 1

SummaryThe human immunodeficiency virus (HIV-1) envelope glycoprotein (Env) trimer mediates viral entry into cells and is the major target for the host antibody response. In infected cells, the mature Env [(gp120/gp41)3] is produced by cleavage of a trimeric gp160 precursor. Proteolytic cleavage decreases Env conformational flexibility, allowing the mature Env to resist antibody binding to conserved elements. The conformational plasticity of the Env precursor skews the humoral immune response towards the elicitation of ineffectual antibodies, contributing to HIV-1 persistence in the infected host. The structural basis for the plasticity of the Env precursor remains elusive. Here we use cryo-electron microscopy to visualize two coexisting conformational states of the full-length Env precursor at nominal resolutions of 5.5 and 8.0 Å. The State-P2 conformation features a three-helix bundle of the gp41 heptad repeat region in the core, but has disordered membrane-interactive regions. State-P1 trimers lack the three-helix bundle and instead retain ordered transmembrane and membrane-proximal external regions embracing a central cavity. Our structural data shed light on the unusual plasticity of the Env precursor and provide new clues to Env immunogen discovery.

scholarly journals Destabilization of Highly Rigid Bilayers Enriched in Cholesterol by the Membrane-Proximal External Region of HIV-1 gp41

2011 ◽  
Vol 100 (3) ◽  
pp. 634a
Author(s):  
Beatriz Apellaniz ◽  
Andrey Ivankin ◽  
David Gidalevitz ◽  
Jose L. Nieva
Keyword(s):  
External Region ◽  
Membrane Proximal External Region ◽  
Hiv 1

The interaction between the membrane-proximal external region and the N-trimer region of HIV-1 gp41: Involvement in viral fusion

2009 ◽  
Vol 54 (10) ◽  
pp. 1707-1712
Author(s):  
Jing Li ◽  
Lu Lu ◽  
Fan Wu ◽  
Xi Chen ◽  
Ben Niu ◽  
...  
Keyword(s):  
Viral Fusion ◽  
External Region ◽  
Membrane Proximal External Region ◽  
Hiv 1

scholarly journals Anti-V3/Glycan and Anti-MPER Neutralizing Antibodies, but Not Anti-V2/Glycan Site Antibodies, Are Strongly Associated with Greater Anti-HIV-1 Neutralization Breadth and Potency

2015 ◽  
Vol 89 (10) ◽  
pp. 5264-5275 ◽  
Author(s):  
Rajesh Abraham Jacob ◽  
Thandeka Moyo ◽  
Michael Schomaker ◽  
Fatima Abrahams ◽  
Berta Grau Pujol ◽  
...  
Keyword(s):  
Neutralizing Antibodies ◽  
Prediction Interval ◽  
Vaccine Design ◽  
Broadly Neutralizing Antibodies ◽  
External Region ◽  
Membrane Proximal External Region ◽  
Site Recognition ◽  
Anti Hiv ◽  
Glycan Site ◽  
Hiv 1

ABSTRACTThe membrane-proximal external region (MPER), the V2/glycan site (initially defined by PG9 and PG16 antibodies), and the V3/glycans (initially defined by PGT121–128 antibodies) are targets of broadly neutralizing antibodies and potential targets for anti-HIV-1 antibody-based vaccines. Recent evidence shows that antibodies with moderate neutralization breadth are frequently attainable, with 50% of sera from chronically infected individuals neutralizing ≥50% of a large, diverse set of viruses. Nonetheless, there is little systematic information addressing which specificities are preferentially targeted among such commonly found, moderately broadly neutralizing sera. We explored associations between neutralization breadth and potency and the presence of neutralizing antibodies targeting the MPER, V2/glycan site, and V3/glycans in sera from 177 antiretroviral-naive HIV-1-infected (>1 year) individuals. Recognition of both MPER and V3/glycans was associated with increased breadth and potency. MPER-recognizing sera neutralized 4.62 more panel viruses than MPER-negative sera (95% prediction interval [95% PI], 4.41 to 5.20), and V3/glycan-recognizing sera neutralized 3.24 more panel viruses than V3/glycan-negative sera (95% PI, 3.15 to 3.52). In contrast, V2/glycan site-recognizing sera neutralized only 0.38 more panel viruses (95% PI, 0.20 to 0.45) than V2/glycan site-negative sera and no association between V2/glycan site recognition and breadth or potency was observed. Despite autoreactivity of many neutralizing antibodies recognizing MPER and V3/glycans, antibodies to these sites are major contributors to neutralization breadth and potency in this cohort. It may therefore be appropriate to focus on developing immunogens based upon the MPER and V3/glycans.IMPORTANCEPrevious candidate HIV vaccines have failed either to induce wide-coverage neutralizing antibodies or to substantially protect vaccinees. Therefore, current efforts focus on novel approaches never before successfully used in vaccine design, including modeling epitopes. Candidate immunogen models identified by broadly neutralizing antibodies include the membrane-proximal external region (MPER), V3/glycans, and the V2/glycan site. Autoreactivity and polyreactivity of anti-MPER and anti-V3/glycan antibodies are thought to pose both direct and indirect barriers to achieving neutralization breadth. We found that antibodies to the MPER and the V3/glycans contribute substantially to neutralization breadth and potency. In contrast, antibodies to the V2/glycan site were not associated with neutralization breadth/potency. This suggests that the autoreactivity effect is not critical and that the MPER and the V3/glycans should remain high-priority vaccine candidates. The V2/glycan site result is surprising because broadly neutralizing antibodies to this site have been repeatedly observed. Vaccine design priorities should shift toward the MPER and V3/glycans.

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