scholarly journals Single-Molecule FRET Imaging of Virus Spike–Host Interactions

Viruses ◽  
2021 ◽  
Vol 13 (2) ◽  
pp. 332
Author(s):  
Maolin Lu
Keyword(s):  
Structure Function ◽  
Membrane Fusion ◽  
Single Molecule ◽  
Conformational Changes ◽  
Virus Entry ◽  
Surface Glycoprotein ◽  
Therapeutic Interventions ◽  
Spike Protein ◽  
Viral Membrane ◽  
Viral Membrane Fusion

As a major surface glycoprotein of enveloped viruses, the virus spike protein is a primary target for vaccines and anti-viral treatments. Current vaccines aiming at controlling the COVID-19 pandemic are mostly directed against the SARS-CoV-2 spike protein. To promote virus entry and facilitate immune evasion, spikes must be dynamic. Interactions with host receptors and coreceptors trigger a cascade of conformational changes/structural rearrangements in spikes, which bring virus and host membranes in proximity for membrane fusion required for virus entry. Spike-mediated viral membrane fusion is a dynamic, multi-step process, and understanding the structure–function-dynamics paradigm of virus spikes is essential to elucidate viral membrane fusion, with the ultimate goal of interventions. However, our understanding of this process primarily relies on individual structural snapshots of endpoints. How these endpoints are connected in a time-resolved manner, and the order and frequency of conformational events underlying virus entry, remain largely elusive. Single-molecule Förster resonance energy transfer (smFRET) has provided a powerful platform to connect structure–function in motion, revealing dynamic aspects of spikes for several viruses: SARS-CoV-2, HIV-1, influenza, and Ebola. This review focuses on how smFRET imaging has advanced our understanding of virus spikes’ dynamic nature, receptor-binding events, and mechanism of antibody neutralization, thereby informing therapeutic interventions.

scholarly journals Physical Aspects of Viral Membrane Fusion

2009 ◽  
Vol 9 ◽  
pp. 764-780 ◽  
Author(s):  
Laura Wessels ◽  
Keith Weninger
Keyword(s):  
Fusion Protein ◽  
Membrane Fusion ◽  
Conformational Changes ◽  
Genetic Material ◽  
Computational Techniques ◽  
Cell Penetration ◽  
Viral Membrane ◽  
Membrane Fusion Protein ◽  
Viral Membrane Fusion

Enveloped viruses commonly employ membrane fusion during cell penetration in order to deliver their genetic material across the cell boundary. Large conformational changes in the proteins embedded in the viral membrane play a fundamental role in the membrane fusion process. Despite the tremendously wide variety of viruses that contain membranes, it appears that they all contain membrane fusion protein machinery with a remarkably conserved mechanism of action. Much of our current biochemical understanding of viral membrane fusion has been derived from high-resolution structural studies and solution-basedin vitroassays in which viruses fuse with liposomes or cells. Recently, single-particle experiments have been used to provide measurements of details not available in the bulk assays. Here we focus our discussion on the key dynamical aspects of fusion protein structure, along with some of the experimental and computational techniques presently being used to investigate viral-mediated membrane fusion.

scholarly journals Viral membrane fusion

Virology ◽  
2015 ◽  
Vol 479-480 ◽  
pp. 498-507 ◽  
Author(s):  
Stephen C. Harrison
Keyword(s):  
Membrane Fusion ◽  
Viral Membrane ◽  
Viral Membrane Fusion

scholarly journals Treatment of influenza virus with Beta-propiolactone alters viral membrane fusion

2014 ◽  
Vol 1838 (1) ◽  
pp. 355-363 ◽  
Author(s):  
Pierre Bonnafous ◽  
Marie-Claire Nicolaï ◽  
Jean-Christophe Taveau ◽  
Michel Chevalier ◽  
Fabienne Barrière ◽  
...  
Keyword(s):  
Influenza Virus ◽  
Membrane Fusion ◽  
Viral Membrane ◽  
Viral Membrane Fusion

Insights into a Structure-Based Mechanism of Viral Membrane Fusion

2000 ◽  
Vol 20 (6) ◽  
pp. 557-570 ◽  
Author(s):  
Danika L. LeDuc ◽  
Yeon-Kyun Shin
Keyword(s):  
Membrane Fusion ◽  
General Structure ◽  
Viral Membrane ◽  
Induced Membrane ◽  
Alternative Scenario ◽  
Influenza Hemagglutinin ◽  
Hiv Gp120 ◽  
Viral Membrane Fusion ◽  
Spike Proteins

A number of different viral spike proteins, responsible for membrane fusion, show striking similarities in their core structures. The prospect of developing a general structure-based mechanism seems plausible in light of these newly determined structures. Influenza hemagglutinin (HA) is the best-studied fusion machine, whose action has previously been described by a hypothetical “spring-loaded” model. This model has recently been extended to explain the mechanism of other systems, such as HIV gp120–gp41. However, evidence supporting this idea is insufficient, requiring re-examination of the mechanism of HA-induced membrane fusion. Recent experiments with a shortened construct of HA, which is able to induce lipid mixing, have provided evidence for an alternative scenario for HA-induced membrane fusion and perhaps that of other viral systems.

scholarly journals The Role of Histidine Residues in Low-pH-Mediated Viral Membrane Fusion

Structure ◽  
2006 ◽  
Vol 14 (10) ◽  
pp. 1481-1487 ◽  
Author(s):  
Thorsten Kampmann ◽  
Daniela S. Mueller ◽  
Alan E. Mark ◽  
Paul R. Young ◽  
Bostjan Kobe
Keyword(s):  
Membrane Fusion ◽  
Low Ph ◽  
Viral Membrane ◽  
Histidine Residues ◽  
Viral Membrane Fusion

scholarly journals Hemagglutinin-Mediated Membrane Fusion: A Biophysical Perspective

2018 ◽  
Vol 47 (1) ◽  
pp. 153-173 ◽  
Author(s):  
Sander Boonstra ◽  
Jelle S. Blijleven ◽  
Wouter H. Roos ◽  
Patrick R. Onck ◽  
Erik van der Giessen ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Host Cell ◽  
Conformational Changes ◽  
Fusion Process ◽  
Host Cell Membrane ◽  
Activation Barriers ◽  
Viral Membrane ◽  
Influenza Hemagglutinin ◽  
Working Together

Influenza hemagglutinin (HA) is a viral membrane protein responsible for the initial steps of the entry of influenza virus into the host cell. It mediates binding of the virus particle to the host-cell membrane and catalyzes fusion of the viral membrane with that of the host. HA is therefore a major target in the development of antiviral strategies. The fusion of two membranes involves high activation barriers and proceeds through several intermediate states. Here, we provide a biophysical description of the membrane fusion process, relating its kinetic and thermodynamic properties to the large conformational changes taking place in HA and placing these in the context of multiple HA proteins working together to mediate fusion. Furthermore, we highlight the role of novel single-particle experiments and computational approaches in understanding the fusion process and their complementarity with other biophysical approaches.

scholarly journals P2X1 Selective Antagonists Block HIV-1 Infection through Inhibition of Envelope Conformation-Dependent Fusion

2019 ◽  
Vol 94 (6) ◽  
Author(s):  
Alexandra Y. Soare ◽  
Hagerah S. Malik ◽  
Natasha D. Durham ◽  
Tracey L. Freeman ◽  
Raymond Alvarez ◽  
...  
Keyword(s):  
Membrane Fusion ◽  
Chronic Inflammation ◽  
Neutralizing Antibody ◽  
Extracellular Nucleotides ◽  
Productive Infection ◽  
Variable Regions ◽  
Viral Membrane ◽  
P2x1 Receptor ◽  
Viral Membrane Fusion ◽  
Hiv 1

ABSTRACT Purinergic receptors are well-established modulators of inflammatory processes, primarily through detection of extracellular nucleotides that are released by dying or infected cells. Emerging literature has demonstrated that inhibition of these inflammatory receptors can block HIV-1 productive infection and HIV-1-associated inflammation. The specificity of receptor type and mechanism of interaction has not yet been determined. Here, we characterize the inhibitory activity of P2X1 receptor antagonists, NF279 and NF449, in cell lines, primary cells, and a variety of HIV-1 envelope (Env) clades. NF279 and NF449 blocked productive infection at the level of viral membrane fusion, with a range of inhibitory activities against different HIV-1 Env isolates. A mutant virus carrying a truncation deletion of the C-terminal tail of HIV-1 Env glycoprotein 41 (gp41) showed reduced sensitivity to P2X1 antagonists, indicating that the sensitivity of inhibition by these molecules may be modulated by Env conformation. In contrast, a P2X7 antagonist, A438079, had a limited effect on productive infection and fusion. NF279 and NF449 interfered with the ability of the gp120 variable regions 1 and 2 (V1V2)-targeted broadly neutralizing antibody PG9 to block productive infection, suggesting that these drugs may antagonize HIV-1 Env at gp120 V1V2 to block viral membrane fusion. Our observations indicate that P2X1 antagonism can inhibit HIV-1 replication at the level of viral membrane fusion through interaction with Env. Future studies will probe the nature of these compounds in inhibiting HIV-1 fusion and the development of small molecules to block HIV-1 entry via this mechanism. IMPORTANCE While effective treatment can lower the severe morbidity and mortality associated with HIV-1 infection, patients infected with HIV-1 suffer from significantly higher rates of noncommunicable comorbidities associated with chronic inflammation. Emerging literature suggests a key role for P2X1 receptors in mediating this chronic inflammation, but the mechanism is still unknown. Here, we demonstrate that HIV-1 infection is reduced by P2X1 receptor antagonism. This inhibition is mediated by interference with HIV-1 Env and can impact a variety of viral clades. These observations highlight the importance of P2X1 antagonists as potential novel therapeutics that could serve to block a variety of different viral clades with additional benefits for their anti-inflammatory properties.

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