The Role of the N-Terminal Heptad Repeat of HIV-1 in the Actual Lipid Mixing Step as Revealed by Its Substitution with Distant Coiled Coils†

Biochemistry ◽  
2005 ◽  
Vol 44 (15) ◽  
pp. 5853-5861 ◽  
Author(s):  
Yael Wexler-Cohen ◽  
Kelly Sackett ◽  
Yechiel Shai
Keyword(s):  
Coiled Coils ◽  
Heptad Repeat ◽  
Hiv 1

scholarly journals Neutralizing Antibodies Targeting HIV-1 gp41

Viruses ◽  
2020 ◽  
Vol 12 (11) ◽  
pp. 1210
Author(s):  
Christophe Caillat ◽  
Delphine Guilligay ◽  
Guidenn Sulbaran ◽  
Winfried Weissenhorn
Keyword(s):  
Conformational Changes ◽  
Neutralizing Antibodies ◽  
Somatic Mutations ◽  
Heptad Repeat ◽  
Broadly Neutralizing Antibodies ◽  
Vaccine Research ◽  
Membrane Components ◽  
And Function ◽  
Hiv 1

HIV-1 vaccine research has obtained an enormous boost since the discovery of many broadly neutralizing antibodies (bnAbs) targeting all accessible sites on the HIV-1 envelope glycoprotein (Env). This in turn facilitated high-resolution structures of the Env glycoprotein in complex with bnAbs. Here we focus on gp41, its highly conserved heptad repeat region 1 (HR1), the fusion peptide (FP) and the membrane-proximal external region (MPER). Notably, the broadest neutralizing antibodies target MPER. Both gp41 HR1 and MPER are only fully accessible once receptor-induced conformational changes have taken place, although some studies suggest access to MPER in the close to native Env conformation. We summarize the data on the structure and function of neutralizing antibodies targeting gp41 HR1, FP and MPER and we review their access to Env and their complex formation with gp41 HR1, MPER peptides and FP within native Env. We further discuss MPER bnAb binding to lipids and the role of somatic mutations in recognizing a bipartite epitope composed of the conserved MPER sequence and membrane components. The problematic of gp41 HR1 access and MPER bnAb auto- and polyreactivity is developed in the light of inducing such antibodies by vaccination.

scholarly journals Extremely Thermostabilizing Core Mutations in Coiled-Coil Mimetic Proteins of HIV-1 gp41 Produce Diverse Effects on Target Binding but Do Not Affect Their Inhibitory Activity

Biomolecules ◽  
2021 ◽  
Vol 11 (4) ◽  
pp. 566
Author(s):  
Mario Cano-Muñoz ◽  
Samuele Cesaro ◽  
Bertrand Morel ◽  
Julie Lucas ◽  
Christiane Moog ◽  
...  
Keyword(s):  
Inhibitory Activity ◽  
Coiled Coil ◽  
Helical Structure ◽  
Heptad Repeat ◽  
Single Chain ◽  
Cell Infection ◽  
Polar Residues ◽  
Hiv 1

A promising strategy to neutralize HIV-1 is to target the gp41 spike subunit to block membrane fusion with the cell. We previously designed a series of single-chain proteins (named covNHR) that mimic the trimeric coiled-coil structure of the gp41 N-terminal heptad repeat (NHR) region and potently inhibit HIV-1 cell infection by avidly binding the complementary C-terminal heptad repeat (CHR) region. These proteins constitute excellent tools to understand the structural and thermodynamic features of this therapeutically important interaction. Gp41, as with many coiled-coil proteins, contains in core positions of the NHR trimer several highly conserved, buried polar residues, the role of which in gp41 structure and function is unclear. Here we produced three covNHR mutants by substituting each triad of polar residues for the canonical isoleucine. The mutants preserve their helical structure and show an extremely increased thermal stability. However, increased hydrophobicity enhances their self-association. Calorimetric analyses show a marked influence of mutations on the binding thermodynamics of CHR-derived peptides. The mutations do not affect however the in vitro HIV-1 inhibitory activity of the proteins. The results support a role of buried core polar residues in maintaining structural uniqueness and promoting an energetic coupling between conformational stability and NHR–CHR binding.

Role of Cations in the Interaction of Pradimicins with HIV-1 Envelope gp120

2013 ◽  
Vol 13 (16) ◽  
pp. 1907-1915 ◽  
Author(s):  
Bart Hoorelbeke ◽  
Youngju Kim ◽  
Toshikazu Oki ◽  
Yasuhiro Igarashi ◽  
Jan Balzarini
Keyword(s):  
Hiv 1 ◽  
Envelope Gp120

Role of HIV-1 Envelope Glycoproteins Conformation and Accessory Proteins on ADCC Responses

2015 ◽  
Vol 14 (1) ◽  
pp. 9-23 ◽  
Author(s):  
Maxime Veillette ◽  
Jonathan Richard ◽  
Marzena Pazgier ◽  
George K. Lewis ◽  
Matthew S. Parsons ◽  
...  
Keyword(s):  
Envelope Glycoproteins ◽  
Accessory Proteins ◽  
Hiv 1

Pivotal Role of the Genital Epithelial Cells in HIV-1 Transmission

2015 ◽  
Vol 13 (6) ◽  
pp. 479-489
Author(s):  
Amelie Saint Jean ◽  
Thomas Bourlet ◽  
Olivier Delezay
Keyword(s):  
Epithelial Cells ◽  
Pivotal Role ◽  
Hiv 1

scholarly journals The Role of Capsid in HIV-1 Nuclear Entry

Viruses ◽  
2021 ◽  
Vol 13 (8) ◽  
pp. 1425
Author(s):  
Anabel Guedán ◽  
Eve R. Caroe ◽  
Genevieve C. R. Barr ◽  
Kate N. Bishop
Keyword(s):  
Nuclear Pore ◽  
Outer Face ◽  
Nuclear Entry ◽  
Nuclear Compartment ◽  
Critical Step ◽  
Technological Advances ◽  
Dividing Cells ◽  
Hiv 1 ◽  
Gain Access

HIV-1 can infect non-dividing cells. The nuclear envelope therefore represents a barrier that HIV-1 must traverse in order to gain access to the host cell chromatin for integration. Hence, nuclear entry is a critical step in the early stages of HIV-1 replication. Following membrane fusion, the viral capsid (CA) lattice, which forms the outer face of the retroviral core, makes numerous interactions with cellular proteins that orchestrate the progress of HIV-1 through the replication cycle. The ability of CA to interact with nuclear pore proteins and other host factors around the nuclear pore determines whether nuclear entry occurs. Uncoating, the process by which the CA lattice opens and/or disassembles, is another critical step that must occur prior to integration. Both early and delayed uncoating have detrimental effects on viral infectivity. How uncoating relates to nuclear entry is currently hotly debated. Recent technological advances have led to intense discussions about the timing, location, and requirements for uncoating and have prompted the field to consider alternative uncoating scenarios that presently focus on uncoating at the nuclear pore and within the nuclear compartment. This review describes recent advances in the study of HIV-1 nuclear entry, outlines the interactions of the retroviral CA protein, and discusses the challenges of investigating HIV-1 uncoating.

scholarly journals Specificity of the HIV-1 Protease on Substrates Representing the Cleavage Site in the Proximal Zinc-Finger of HIV-1 Nucleocapsid Protein

Viruses ◽  
2021 ◽  
Vol 13 (6) ◽  
pp. 1092
Author(s):  
János András Mótyán ◽  
Márió Miczi ◽  
Stephen Oroszlan ◽  
József Tőzsér
Keyword(s):  
Amino Acid ◽  
Zinc Finger ◽  
Cleavage Site ◽  
Potential Role ◽  
Binding Mode ◽  
Interaction Energies ◽  
Vitro Assay ◽  
Hiv 1

To explore the sequence context-dependent nature of the human immunodeficiency virus type 1 (HIV-1) protease’s specificity and to provide a rationale for viral mutagenesis to study the potential role of the nucleocapsid (NC) processing in HIV-1 replication, synthetic oligopeptide substrates representing the wild-type and modified versions of the proximal cleavage site of HIV-1 NC were assayed as substrates of the HIV-1 protease (PR). The S1′ substrate binding site of HIV-1 PR was studied by an in vitro assay using KIVKCF↓NCGK decapeptides having amino acid substitutions of N17 residue of the cleavage site of the first zinc-finger domain, and in silico calculations were also performed to investigate amino acid preferences of S1′ site. Second site substitutions have also been designed to produce “revertant” substrates and convert a non-hydrolysable sequence (having glycine in place of N17) to a substrate. The specificity constants obtained for peptides containing non-charged P1′ substitutions correlated well with the residue volume, while the correlation with the calculated interaction energies showed the importance of hydrophobicity: interaction energies with polar residues were related to substantially lower specificity constants. Cleavable “revertants” showed one residue shift of cleavage position due to an alternative productive binding mode, and surprisingly, a double cleavage of a substrate was also observed. The results revealed the importance of alternative binding possibilities of substrates into the HIV-1 PR. The introduction of the “revertant” mutations into infectious virus clones may provide further insights into the potential role of NC processing in the early phase of the viral life-cycle.

The Role of Conserved Residues in the DEDDh Motif: the Proton-Transfer Mechanism of HIV-1 RNase H

ACS Catalysis ◽  
2021 ◽  
pp. 7915-7927
Author(s):  
Simon L. Dürr ◽  
Olga Bohuszewicz ◽  
Dénes Berta ◽  
Reynier Suardiaz ◽  
Pablo G. Jambrina ◽  
...  
Keyword(s):  
Proton Transfer ◽  
Rnase H ◽  
Transfer Mechanism ◽  
Conserved Residues ◽  
Hiv 1
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