Cell Entry of Enveloped Viruses

Abstract

Enveloped viruses penetrate their cell targets following the merging of their membrane with that of the cell. This fusion process is catalyzed by one or several viral glycoproteins incorporated on the membrane of the virus. These envelope glycoproteins (EnvGP) evolved in order to combine two features. First, they acquired a domain to bind to a specific cellular protein, named "receptor." Second, they developed, with the help of cellular proteins, a function of finely controlled fusion to optimize the replication and preserve the integrity of the cell, specific to the genus of the virus. Following the activation of the EnvGP either by binding to their receptors and/or sometimes the acid pH of the endosomes, many changes of conformation permit ultimately the action of a specific hydrophobic domain, the fusion peptide, which destabilizes the cell membrane and leads to the opening of the lipidic membrane. The comprehension of these mechanisms is essential to develop medicines of the therapeutic class of entry inhibitor like enfuvirtide (Fuzeon) against human immunodeficiency virus (HIV). In this chapter, we will summarize the different envelope glycoprotein structures that viruses develop to achieve membrane fusion and the entry of the virus. We will describe the different entry pathways and cellular proteins that viruses have subverted to allow infection of the cell and the receptors that are used. Finally, we will illustrate more precisely the recent discoveries that have been made within the field of the entry process, with a focus on the use of pseudoparticles. These pseudoparticles are suitable for high-throughput screenings that help in the development of natural or artificial inhibitors as new therapeutics of the class of entry inhibitors.

Acid-Activated Structural Reorganization of the Rift Valley Fever Virus Gc Fusion Protein

“…Activation of fusion proteins generally triggers the exposure of a hydrophobic "fusion peptide" which normally functions by inserting into the host membrane and initiating fusion, which might explain the observed acid-induced virus aggregation. Typically, fusion proteins are trimeric in this fusionactive state (8,17). Hence, we assume that the RVFV Gc stable oligomer is also made up of three Gc molecules, but further research is needed to confirm this hypothesis.…”

“…This membrane fusion process is driven by structural rearrangements in the metastable viral fusion protein which are triggered by receptor binding, proteolytic cleavage, or the acidic pH of endosomes, allowing fusion to occur at the right time and place (8). Viral fusion proteins have been divided into three classes (classes I, II, and III) based on their structural features (67).…”

Paleovirology of ‘ syncytins ’, retroviral env genes exapted for a role in placentation

“…The envelope glycoprotein (Env) of enveloped viruses is essential for viral entry by recognizing susceptible cells and inducing fusion of the virion envelope with the cell plasma membrane, allowing the release of the nucleocapsid into the cell cytoplasm [24]. The env gene of retroviruses encodes a precursor protein which is cleaved, during transport through the host cell secretory pathway, by a cellular furin protease to generate two fragments, the surface (SU) and the transmembrane (TM) subunits (figure 2a) [25].…”

Targeted Entry via Somatostatin Receptors Using a Novel Modified Retrovirus Glycoprotein That Delivers Genes at Levels Comparable to Those of Wild-Type Viral Glycoproteins

“…Early efforts used insertion of ligands into the glycoprotein surface subunit (SU), the subunit of the retroviral envelope protein (Env) that binds the natural virus receptor. These chimeras reproducibly exhibited specific vector attachment but very poor or no transduction in the cells bearing the target receptor and lacking the natural virus receptor (2,13). More recent efforts used nonretroviral glycoproteins.…”

“…T he lack of methods for targeting entry to achieve gene delivery in specific cell types and tissues in vivo remains a major technical barrier to in vivo human gene therapy (13,53). Retroviral and lentiviral vectors for gene delivery have most commonly used vesicular stomatitis virus (VSV) G protein or envelope Env glycoprotein (Env) from gammaretroviruses, including amphotropic murine leukemia virus (MLV) and gibbon ape leukemia virus.…”