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Special Issue "Virus-Induced Membrane Fusion"

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A special issue of Viruses (ISSN 1999-4915). This special issue belongs to the section "Animal Viruses".

Deadline for manuscript submissions: closed (31 May 2012)

Special Issue Editor

Guest Editor
Dr. Rebecca Dutch (Website)

Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, B171 BBSRB, 741 S. Limestone St., Lexington, KY, 40536 USA
Interests: paramyxoviruses; viral entry; membrane fusion; viral fusion proteins; glycoprotein folding and trafficking

Published Papers (10 papers)

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Review

Open AccessReview Influenza Virus-Mediated Membrane Fusion: Determinants of Hemagglutinin Fusogenic Activity and Experimental Approaches for Assessing Virus Fusion
Viruses 2012, 4(7), 1144-1168; doi:10.3390/v4071144
Received: 7 June 2012 / Revised: 11 July 2012 / Accepted: 17 July 2012 / Published: 24 July 2012
Cited by 27 | PDF Full-text (889 KB) | HTML Full-text | XML Full-text
Abstract
Hemagglutinin (HA) is the viral protein that facilitates the entry of influenza viruses into host cells. This protein controls two critical aspects of entry: virus binding and membrane fusion. In order for HA to carry out these functions, it must first undergo [...] Read more.
Hemagglutinin (HA) is the viral protein that facilitates the entry of influenza viruses into host cells. This protein controls two critical aspects of entry: virus binding and membrane fusion. In order for HA to carry out these functions, it must first undergo a priming step, proteolytic cleavage, which renders it fusion competent. Membrane fusion commences from inside the endosome after a drop in lumenal pH and an ensuing conformational change in HA that leads to the hemifusion of the outer membrane leaflets of the virus and endosome, the formation of a stalk between them, followed by pore formation. Thus, the fusion machinery is an excellent target for antiviral compounds, especially those that target the conserved stem region of the protein. However, traditional ensemble fusion assays provide a somewhat limited ability to directly quantify fusion partly due to the inherent averaging of individual fusion events resulting from experimental constraints. Inspired by the gains achieved by single molecule experiments and analysis of stochastic events, recently-developed individual virion imaging techniques and analysis of single fusion events has provided critical information about individual virion behavior, discriminated intermediate fusion steps within a single virion, and allowed the study of the overall population dynamics without the loss of discrete, individual information. In this article, we first start by reviewing the determinants of HA fusogenic activity and the viral entry process, highlight some open questions, and then describe the experimental approaches for assaying fusion that will be useful in developing the most effective therapies in the future. Full article
(This article belongs to the Special Issue Virus-Induced Membrane Fusion)
Open AccessReview Herpes Virus Fusion and Entry: A Story with Many Characters
Viruses 2012, 4(5), 800-832; doi:10.3390/v4050800
Received: 25 April 2012 / Revised: 4 May 2012 / Accepted: 9 May 2012 / Published: 10 May 2012
Cited by 93 | PDF Full-text (1244 KB) | HTML Full-text | XML Full-text | Supplementary Files
Abstract
Herpesviridae comprise a large family of enveloped DNA viruses all of whom employ orthologs of the same three glycoproteins, gB, gH and gL. Additionally, herpesviruses often employ accessory proteins to bind receptors and/or bind the heterodimer gH/gL or even to determine cell [...] Read more.
Herpesviridae comprise a large family of enveloped DNA viruses all of whom employ orthologs of the same three glycoproteins, gB, gH and gL. Additionally, herpesviruses often employ accessory proteins to bind receptors and/or bind the heterodimer gH/gL or even to determine cell tropism. Sorting out how these proteins function has been resolved to a large extent by structural biology coupled with supporting biochemical and biologic evidence. Together with the G protein of vesicular stomatitis virus, gB is a charter member of the Class III fusion proteins. Unlike VSV G, gB only functions when partnered with gH/gL. However, gH/gL does not resemble any known viral fusion protein and there is evidence that its function is to upregulate the fusogenic activity of gB. In the case of herpes simplex virus, gH/gL itself is upregulated into an active state by the conformational change that occurs when gD, the receptor binding protein, binds one of its receptors. In this review we focus primarily on prototypes of the three subfamilies of herpesviruses. We will present our model for how herpes simplex virus (HSV) regulates fusion in series of highly regulated steps. Our model highlights what is known and also provides a framework to address mechanistic questions about fusion by HSV and herpesviruses in general. Full article
(This article belongs to the Special Issue Virus-Induced Membrane Fusion)
Open AccessReview Poxvirus Cell Entry: How Many Proteins Does it Take?
Viruses 2012, 4(5), 688-707; doi:10.3390/v4050688
Received: 10 April 2012 / Revised: 21 April 2012 / Accepted: 23 April 2012 / Published: 27 April 2012
Cited by 29 | PDF Full-text (694 KB) | HTML Full-text | XML Full-text
Abstract
For many viruses, one or two proteins enable cell binding, membrane fusion and entry. The large number of proteins employed by poxviruses is unprecedented and may be related to their ability to infect a wide range of cells. There are two main [...] Read more.
For many viruses, one or two proteins enable cell binding, membrane fusion and entry. The large number of proteins employed by poxviruses is unprecedented and may be related to their ability to infect a wide range of cells. There are two main infectious forms of vaccinia virus, the prototype poxvirus: the mature virion (MV), which has a single membrane, and the extracellular enveloped virion (EV), which has an additional outer membrane that is disrupted prior to fusion. Four viral proteins associated with the MV membrane facilitate attachment by binding to glycosaminoglycans or laminin on the cell surface, whereas EV attachment proteins have not yet been identified. Entry can occur at the plasma membrane or in acidified endosomes following macropinocytosis and involves actin dynamics and cell signaling. Regardless of the pathway or whether the MV or EV mediates infection, fusion is dependent on 11 to 12 non-glycosylated, transmembrane proteins ranging in size from 4- to 43-kDa that are associated in a complex. These proteins are conserved in poxviruses making it likely that a common entry mechanism exists. Biochemical studies support a two-step process in which lipid mixing of viral and cellular membranes is followed by pore expansion and core penetration. Full article
(This article belongs to the Special Issue Virus-Induced Membrane Fusion)
Open AccessReview Paramyxovirus Fusion and Entry: Multiple Paths to a Common End
Viruses 2012, 4(4), 613-636; doi:10.3390/v4040613
Received: 8 March 2012 / Revised: 10 March 2012 / Accepted: 12 April 2012 / Published: 19 April 2012
Cited by 55 | PDF Full-text (2429 KB) | HTML Full-text | XML Full-text
Abstract
The paramyxovirus family contains many common human pathogenic viruses, including measles, mumps, the parainfluenza viruses, respiratory syncytial virus, human metapneumovirus, and the zoonotic henipaviruses, Hendra and Nipah. While the expression of a type 1 fusion protein and a type 2 attachment protein [...] Read more.
The paramyxovirus family contains many common human pathogenic viruses, including measles, mumps, the parainfluenza viruses, respiratory syncytial virus, human metapneumovirus, and the zoonotic henipaviruses, Hendra and Nipah. While the expression of a type 1 fusion protein and a type 2 attachment protein is common to all paramyxoviruses, there is considerable variation in viral attachment, the activation and triggering of the fusion protein, and the process of viral entry. In this review, we discuss recent advances in the understanding of paramyxovirus F protein-mediated membrane fusion, an essential process in viral infectivity. We also review the role of the other surface glycoproteins in receptor binding and viral entry, and the implications for viral infection. Throughout, we concentrate on the commonalities and differences in fusion triggering and viral entry among the members of the family. Finally, we highlight key unanswered questions and how further studies can identify novel targets for the development of therapeutic treatments against these human pathogens. Full article
(This article belongs to the Special Issue Virus-Induced Membrane Fusion)
Open AccessReview Ready, Set, Fuse! The Coronavirus Spike Protein and Acquisition of Fusion Competence
Viruses 2012, 4(4), 557-580; doi:10.3390/v4040557
Received: 15 March 2012 / Revised: 29 March 2012 / Accepted: 2 April 2012 / Published: 12 April 2012
Cited by 28 | PDF Full-text (692 KB) | HTML Full-text | XML Full-text
Abstract
Coronavirus-cell entry programs involve virus-cell membrane fusions mediated by viral spike (S) proteins. Coronavirus S proteins acquire membrane fusion competence by receptor interactions, proteolysis, and acidification in endosomes. This review describes our current understanding of the S proteins, their interactions with and [...] Read more.
Coronavirus-cell entry programs involve virus-cell membrane fusions mediated by viral spike (S) proteins. Coronavirus S proteins acquire membrane fusion competence by receptor interactions, proteolysis, and acidification in endosomes. This review describes our current understanding of the S proteins, their interactions with and their responses to these entry triggers. We focus on receptors and proteases in prompting entry and highlight the type II transmembrane serine proteases (TTSPs) known to activate several virus fusion proteins. These and other proteases are essential cofactors permitting coronavirus infection, conceivably being in proximity to cell-surface receptors and thus poised to split entering spike proteins into the fragments that refold to mediate membrane fusion. The review concludes by noting how understanding of coronavirus entry informs antiviral therapies. Full article
(This article belongs to the Special Issue Virus-Induced Membrane Fusion)
Open AccessReview Novel Approaches to Inhibit HIV Entry
Viruses 2012, 4(2), 309-324; doi:10.3390/v4020309
Received: 16 December 2011 / Revised: 17 January 2012 / Accepted: 7 February 2012 / Published: 21 February 2012
Cited by 29 | PDF Full-text (913 KB) | HTML Full-text | XML Full-text
Abstract
Human Immunodeficiency Virus (HIV) entry into target cells is a multi-step process involving binding of the viral glycoprotein, Env, to its receptor CD4 and a coreceptor—either CCR5 or CXCR4. Understanding the means by which HIV enters cells has led to the identification [...] Read more.
Human Immunodeficiency Virus (HIV) entry into target cells is a multi-step process involving binding of the viral glycoprotein, Env, to its receptor CD4 and a coreceptor—either CCR5 or CXCR4. Understanding the means by which HIV enters cells has led to the identification of genetic polymorphisms, such as the 32 base-pair deletion in the ccr5 gene (ccr5∆32) that confers resistance to infection in homozygous individuals, and has also resulted in the development of entry inhibitors—small molecule antagonists that block infection at the entry step. The recent demonstration of long-term control of HIV infection in a leukemic patient following a hematopoietic stem cell transplant using cells from a ccr5∆32 homozygous donor highlights the important role of the HIV entry in maintaining an established infection and has led to a number of attempts to treat HIV infection by genetically modifying the ccr5 gene. In this review, we describe the HIV entry process and provide an overview of the different classes of approved HIV entry inhibitors while highlighting novel genetic strategies aimed at blocking HIV infection at the level of entry. Full article
(This article belongs to the Special Issue Virus-Induced Membrane Fusion)
Open AccessReview Henipavirus Mediated Membrane Fusion, Virus Entry and Targeted Therapeutics
Viruses 2012, 4(2), 280-308; doi:10.3390/v4020280
Received: 30 December 2011 / Revised: 30 January 2012 / Accepted: 30 January 2012 / Published: 13 February 2012
Cited by 18 | PDF Full-text (2277 KB) | HTML Full-text | XML Full-text
Abstract
The Paramyxoviridae genus Henipavirus is presently represented by the type species Hendra and Nipah viruses which are both recently emerged zoonotic viral pathogens responsible for repeated outbreaks associated with high morbidity and mortality in Australia, Southeast Asia, India and Bangladesh. These enveloped [...] Read more.
The Paramyxoviridae genus Henipavirus is presently represented by the type species Hendra and Nipah viruses which are both recently emerged zoonotic viral pathogens responsible for repeated outbreaks associated with high morbidity and mortality in Australia, Southeast Asia, India and Bangladesh. These enveloped viruses bind and enter host target cells through the coordinated activities of their attachment (G) and class I fusion (F) envelope glycoproteins. The henipavirus G glycoprotein interacts with host cellular B class ephrins, triggering conformational alterations in G that lead to the activation of the F glycoprotein, which facilitates the membrane fusion process. Using the recently published structures of HeV-G and NiV-G and other paramyxovirus glycoproteins, we review the features of the henipavirus envelope glycoproteins that appear essential for mediating the viral fusion process, including receptor binding, G-F interaction, F activation, with an emphasis on G and the mutations that disrupt viral infectivity. Finally, recent candidate therapeutics for henipavirus-mediated disease are summarized in light of their ability to inhibit HeV and NiV entry by targeting their G and F glycoproteins. Full article
(This article belongs to the Special Issue Virus-Induced Membrane Fusion)
Open AccessReview Filovirus Entry: A Novelty in the Viral Fusion World
Viruses 2012, 4(2), 258-275; doi:10.3390/v4020258
Received: 23 December 2011 / Revised: 24 January 2012 / Accepted: 30 January 2012 / Published: 7 February 2012
Cited by 30 | PDF Full-text (1888 KB) | HTML Full-text | XML Full-text
Abstract
Ebolavirus (EBOV) and Marburgvirus (MARV) that compose the filovirus family of negative strand RNA viruses infect a broad range of mammalian cells. Recent studies indicate that cellular entry of this family of viruses requires a series of cellular protein interactions and molecular [...] Read more.
Ebolavirus (EBOV) and Marburgvirus (MARV) that compose the filovirus family of negative strand RNA viruses infect a broad range of mammalian cells. Recent studies indicate that cellular entry of this family of viruses requires a series of cellular protein interactions and molecular mechanisms, some of which are unique to filoviruses and others are commonly used by all viral glycoproteins. Details of this entry pathway are highlighted here. Virus entry into cells is initiated by the interaction of the viral glycoprotein1 subunit (GP1) with both adherence factors and one or more receptors on the surface of host cells. On epithelial cells, we recently demonstrated that TIM-1 serves as a receptor for this family of viruses, but the cell surface receptors in other cell types remain unidentified. Upon receptor binding, the virus is internalized into endosomes primarily via macropinocytosis, but perhaps by other mechanisms as well. Within the acidified endosome, the heavily glycosylated GP1 is cleaved to a smaller form by the low pH-dependent cellular proteases Cathepsin L and B, exposing residues in the receptor binding site (RBS). Details of the molecular events following cathepsin-dependent trimming of GP1 are currently incomplete; however, the processed GP1 specifically interacts with endosomal/lysosomal membranes that contain the Niemann Pick C1 (NPC1) protein and expression of NPC1 is required for productive infection, suggesting that GP/NPC1 interactions may be an important late step in the entry process. Additional events such as further GP1 processing and/or reducing events may also be required to generate a fusion-ready form of the glycoprotein. Once this has been achieved, sequences in the filovirus GP2 subunit mediate viral/cellular membrane fusion via mechanisms similar to those previously described for other enveloped viruses. This multi-step entry pathway highlights the complex and highly orchestrated path of internalization and fusion that appears unique for filoviruses. Full article
(This article belongs to the Special Issue Virus-Induced Membrane Fusion)
Open AccessReview Molecular and Cellular Aspects of Rhabdovirus Entry
Viruses 2012, 4(1), 117-139; doi:10.3390/v4010117
Received: 25 November 2011 / Revised: 5 January 2012 / Accepted: 10 January 2012 / Published: 18 January 2012
Cited by 26 | PDF Full-text (1983 KB) | HTML Full-text | XML Full-text
Abstract
Rhabdoviruses enter the cell via the endocytic pathway and subsequently fuse with a cellular membrane within the acidic environment of the endosome. Both receptor recognition and membrane fusion are mediated by a single transmembrane viral glycoprotein (G). Fusion is triggered via a [...] Read more.
Rhabdoviruses enter the cell via the endocytic pathway and subsequently fuse with a cellular membrane within the acidic environment of the endosome. Both receptor recognition and membrane fusion are mediated by a single transmembrane viral glycoprotein (G). Fusion is triggered via a low-pH induced structural rearrangement. G is an atypical fusion protein as there is a pH-dependent equilibrium between its pre- and post-fusion conformations. The elucidation of the atomic structures of these two conformations for the vesicular stomatitis virus (VSV) G has revealed that it is different from the previously characterized class I and class II fusion proteins. In this review, the pre- and post-fusion VSV G structures are presented in detail demonstrating that G combines the features of the class I and class II fusion proteins. In addition to these similarities, these G structures also reveal some particularities that expand our understanding of the working of fusion machineries. Combined with data from recent studies that revealed the cellular aspects of the initial stages of rhabdovirus infection, all these data give an integrated view of the entry pathway of rhabdoviruses into their host cell. Full article
(This article belongs to the Special Issue Virus-Induced Membrane Fusion)
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Open AccessReview The Curious Case of Arenavirus Entry, and Its Inhibition
Viruses 2012, 4(1), 83-101; doi:10.3390/v4010083
Received: 28 October 2011 / Revised: 7 December 2011 / Accepted: 5 January 2012 / Published: 13 January 2012
Cited by 23 | PDF Full-text (698 KB) | HTML Full-text | XML Full-text
Abstract
Arenaviruses comprise a diverse family of enveloped negative-strand RNA viruses that are endemic to specific rodent hosts worldwide. Several arenaviruses cause severe hemorrhagic fevers in humans, including Junín and Machupo viruses in South America and Lassa fever virus in western Africa. Arenavirus [...] Read more.
Arenaviruses comprise a diverse family of enveloped negative-strand RNA viruses that are endemic to specific rodent hosts worldwide. Several arenaviruses cause severe hemorrhagic fevers in humans, including Junín and Machupo viruses in South America and Lassa fever virus in western Africa. Arenavirus entry into the host cell is mediated by the envelope glycoprotein complex, GPC. The virion is endocytosed on binding to a cell-surface receptor, and membrane fusion is initiated in response to physiological acidification of the endosome. As with other class I virus fusion proteins, GPC-mediated membrane fusion is promoted through a regulated sequence of conformational changes leading to formation of the classical postfusion trimer-of-hairpins structure. GPC is, however, unique among the class I fusion proteins in that the mature complex retains a stable signal peptide (SSP) as a third subunit, in addition to the canonical receptor-binding and fusion proteins. We will review the curious properties of the tripartite GPC complex and describe evidence that SSP interacts with the fusion subunit to modulate pH-induced activation of membrane fusion. This unusual solution to maintaining the metastable prefusion state of GPC on the virion and activating the class I fusion cascade at acidic pH provides novel targets for antiviral intervention. Full article
(This article belongs to the Special Issue Virus-Induced Membrane Fusion)
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