scholarly journals Super Potent Bispecific Llama VHH Antibodies Neutralize HIV via a Combination of gp41 and gp120 Epitopes

Antibodies ◽  
2019 ◽  
Vol 8 (2) ◽  
pp. 38 ◽  
Author(s):  
Nika M. Strokappe ◽  
Miriam Hock ◽  
Lucy Rutten ◽  
Laura E. Mccoy ◽  
Jaap W. Back ◽  
...  
Keyword(s):  
Heptad Repeat ◽  
Therapeutic Approaches ◽  
Structural Details ◽  
Cd4 Binding Site ◽  
Enhanced Strain ◽  
Single Domain Antibodies ◽  
Vhh Antibodies ◽  
Phage Libraries ◽  
The Individual ◽  
Hiv 1

Broad and potent neutralizing llama single domain antibodies (VHH) against HIV-1 targeting the CD4 binding site (CD4bs) have previously been isolated upon llama immunization. Here we describe the epitopes of three additional VHH groups selected from phage libraries. The 2E7 group binds to a new linear epitope in the first heptad repeat of gp41 that is only exposed in the fusion-intermediate conformation. The 1B5 group competes with co-receptor binding and the 1F10 group interacts with the crown of the gp120 V3 loop, occluded in native Env. We present biophysical and structural details on the 2E7 interaction with gp41. In order to further increase breadth and potency, we constructed bi-specific VHH. The combination of CD4bs VHH (J3/3E3) with 2E7 group VHH enhanced strain-specific neutralization with potencies up to 1400-fold higher than the mixture of the individual VHHs. Thus, these new bivalent VHH are potent new tools to develop therapeutic approaches or microbicide intervention.

scholarly journals Inhibition of Human Immunodeficiency Virus Type 1 Entry in Cells Expressing gp41-Derived Peptides

2004 ◽  
Vol 78 (2) ◽  
pp. 568-575 ◽  
Author(s):  
Marc Egelhofer ◽  
Gunda Brandenburg ◽  
Holger Martinius ◽  
Patricia Schult-Dietrich ◽  
Gregory Melikyan ◽  
...  
Keyword(s):  
Human Immunodeficiency Virus ◽  
Heptad Repeat ◽  
Therapeutic Approaches ◽  
Transmembrane Glycoprotein ◽  
Antiretroviral Drug ◽  
Immunodeficiency Virus ◽  
Hiv Type 1 ◽  
Hiv 1 ◽  
Maximal Expression

ABSTRACT As the limitations of antiretroviral drug therapy, such as toxicity and resistance, become evident, interest in alternative therapeutic approaches for human immunodeficiency virus (HIV) infection is growing. We developed the first gene therapeutic strategy targeting entry of a broad range of HIV type 1 (HIV-1) variants. Infection was inhibited at the level of membrane fusion by retroviral expression of a membrane-anchored peptide derived from the second heptad repeat of the HIV-1 gp41 transmembrane glycoprotein. To achieve maximal expression and antiviral activity, the peptide itself, the scaffold for presentation of the peptide on the cell surface, and the retroviral vector backbone were optimized. This optimized construct effectively inhibited virus replication in cell lines and primary blood lymphocytes. The membrane-anchored C-peptide was also shown to bind to free gp41 N peptides, suggesting that membrane-anchored antiviral C peptides have a mode of action similar to that of free gp41 C peptides. Preclinical toxicity and efficacy studies of this antiviral vector have been completed, and clinical trials are in preparation.

System Effects in Generic Risk-Based Inspection Planning

2004 ◽  
Vol 126 (3) ◽  
pp. 265-271 ◽  
Author(s):  
Daniel Straub ◽  
Michael Havbro Faber
Keyword(s):  
Reliability Analysis ◽  
Hot Spots ◽  
Value Of Information ◽  
Structural Reliability ◽  
Inspection Planning ◽  
The Past ◽  
Structural Reliability Analysis ◽  
Structural Details ◽  
The Individual ◽  
Consistent Approach

Reliability and risk-based inspection planning (RBI) has been developed in the past for single structural details subject to fatigue, based on structural reliability analysis. This paper extends the methodology to systems with a stochastic dependency between the individual fatigue hot spots. It addresses the general decision theoretic problems that arise when dealing with RBI of systems. The differences to inspection planning for individual hot spots are listed and discussed. Using a generic format for single hot spots, a consistent approach to the problem is proposed, based on the concept of Value of Information. Possible applications of the methodology are outlined.

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 Trimeric heptad repeat synthetic peptides HR1 and HR2 efficiently inhibit HIV-1 entry

2019 ◽  
Vol 39 (9) ◽  
Author(s):  
Olfa Mzoughi ◽  
Meritxell Teixido ◽  
Rémi Planès ◽  
Manutea Serrero ◽  
Ibtissem Hamimed ◽  
...  
Keyword(s):  
Antiviral Activity ◽  
Heptad Repeat ◽  
Fusion Activity ◽  
Helical Structures ◽  
Fusion Inhibitors ◽  
Immunodeficiency Virus ◽  
Antiviral Activities ◽  
Physical Interactions ◽  
Kinetics Of ◽  
Hiv 1

Abstract The trimeric heptad repeat domains HR1 and HR2 of the human immunodeficiency virus 1 (HIV-1) gp41 play a key role in HIV-1-entry by membrane fusion. To develop efficient inhibitors against this step, the corresponding trimeric-N36 and C34 peptides were designed and synthesized. Analysis by circular dichroism of monomeric and trimeric N36 and C34 peptides showed their capacities to adopt α-helical structures and to establish physical interactions. At the virological level, while trimeric-C34 conserves the same high anti-fusion activity as monomeric-C34, trimerization of N36-peptide induced a significant increase, reaching 500-times higher in anti-fusion activity, against R5-tropic virus-mediated fusion. This result was associated with increased stability of the N36 trimer peptide with respect to the monomeric form, as demonstrated by the comparative kinetics of their antiviral activities during 6-day incubation in a physiological medium. Collectively, our findings demonstrate that while the trimerization of C34 peptide had no beneficial effect on its stability and antiviral activity, the trimerization of N36 peptide strengthened both stability and antiviral activity. This approach, promotes trimers as new promising HIV-1 inhibitors and point to future development aimed toward innovative peptide fusion inhibitors, microbicides or as immunogens.

scholarly journals Neutralizing antibodies induced by first-generation gp41-stabilized HIV-1 envelope trimers and nanoparticles

2020 ◽  
Author(s):  
Sonu Kumar ◽  
Xiaohe Lin ◽  
Timothy Ngo ◽  
Benjamin Shapero ◽  
Cindy Sou ◽  
...  
Keyword(s):  
Cell Sorting ◽  
Neutralizing Antibodies ◽  
First Generation ◽  
Heptad Repeat ◽  
X Ray ◽  
X Ray Crystallography ◽  
Clade C ◽  
Next Generation Sequencing Ngs ◽  
Generation Sequencing ◽  
Hiv 1

ABSTRACTAntigen-specific B-cell sorting and next-generation sequencing (NGS) were combined to isolate HIV-1 neutralizing antibodies (NAbs) from mice and rabbits immunized with BG505 trimers and nanoparticles. Three mouse NAbs potently neutralize BG505.T332N and recognize a glycan epitope centered at the C3/V4 region, as revealed by electron microscopy (EM), x-ray crystallography, and epitope mapping. Three potent NAbs were sorted from rabbit B cells that target glycan holes on the BG505 envelope glycoprotein (Env) and account for a significant portion of autologous NAb response. We then determined a 3.4Å-resolution crystal structure for the clade C transmitted/founder Du172.17 Env with a redesigned heptad repeat 1 (HR1) bend. This clade C Env, as a soluble trimer and attached to a ferritin nanoparticle, along with a clade A Q482-d12 Env trimer, elicited distinct NAb responses in rabbits. Our study demonstrates that nanoparticles presenting gp41-stabilized trimers can induce potent NAb responses in mice and rabbits with Env-dependent breadth.TEASERMouse and rabbit NAbs elicited by gp41-stabilized trimers and nanoparticles neutralize autologous HIV-1 by targeting different epitopes

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