The virion glycoproteins of Ebola viruses are encoded in two reading frames and are expressed through transcriptional editing.

Sanchez, Anthony; Trappier, Sam G.; Mahy, Brian W. J.; Peters, C. J.; Nichol, Stuart T.

doi:10.1073/pnas.93.8.3602

Cited by 513 publications

(480 citation statements)

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“…All filovirus glycoproteins follow a classical secretory pathway for secretion outside of the infected cell; in addition, infected cells have been shown to increase the expression of a surface enzyme capable of cleaving and thus releasing a portion of the surface-bound structural form GP (known as shed GP) before it is incorporated into virions. These scenarios are thought to contribute to pathogenesis by providing an immunological decoy of sorts that is capable of consuming circulating filovirus GP-specific antibodies, as antibodies to GP isolated from human survivors of Ebolavirus infection also bind the soluble forms 99 . The production of the different glycoproteins from the same gene is dependent on the insertion of one or two additional uridine (U) residues in the GP gene editing site such that the non-edited mRNA expresses sGP and the 8Uand 9U mRNA species produce the structural form GP and soluble form ssGP, respectively.…”

Section: Box 4 | Screening Systems For Drug Developmentmentioning

confidence: 99%

“…GP requires post-translational modifications in the endoplasmic reticulum and Golgi processes and hence follows a different trafficking pathway to the plasma membrane than do the other viral proteins [95][96][97] . Unique to members of the Ebolavirus genus, an artefact of transcriptional editing of the GP gene allows for the production of several nonstructural GP derivatives, each of which is thought to contribute to pathogenesis in a different way, some of which may have direct relevance to interventions specific to Ebolavirus infections [97][98][99][100][101] . …”

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confidence: 99%

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Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

107

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| The filoviruses -Ebola virus and Marburg virus -cause lethal haemorrhagic fever in humans and non-human primates (NHPs). Filoviruses present a global health threat both as naturally acquired diseases and as potential agents of bioterrorism. In the recent 2013-2016 outbreak of Ebola virus, the most promising therapies for post-exposure use with demonstrated efficacy in the gold-standard NHP models of filovirus disease were unable to show statistically significant protection in patients infected with Ebola virus. This Review briefly discusses these failures and what has been learned from these experiences, and summarizes the current status of post-exposure medical countermeasures in development, including antibodies, small interfering RNA and small molecules. We outline how our current knowledge could be applied to the identification of novel interventions and ways to use interventions more effectively. R E V I E W SNATURE REVIEWS | DRUG DISCOVERY VOLUME 17 | JUNE 2018 | 413 © 2 0 1 8 M a c m i l l a n P u b l i s h e r s L i m i t e d , p a r t o f S p r i n g e r N a t u r e . A l l r i g h t s r e s e r v e d . AstheniaMuscular weakness. MyalgiaMuscular pain. ArthralgiaJoint pain. LeukopeniaA condition of having a low number of circulating leukocytes, including neutrophils, eosinophils, basophils, lymphocytes and monocytes. LymphocytopeniaA condition of having a low number of circulating leukocytes, including natural killer cells, T cells and B cells. ThrombocytopeniaA condition of having a low number of circulating thrombocytes, also known as platelets.and Ebolavirus. The Marburgvirus genus contains a single species, Marburg marburgvirus, which contains two members, Marburg virus (MARV) and Ravn virus (RAVV). The Ebolavirus genus consists of five distinct species: Bundibugyo ebolavirus (BDBV), Reston ebolavirus (RESTV), Sudan ebolavirus (SUDV), Tai Forest ebolavirus (TAFV; previously termed 'Côte d'Ivoire ebolavirus' but more commonly known as 'Ivory Coast ebolavirus') and Zaire ebolavirus (EBOV). MARV, RAVV, BDBV, SUDV and EBOV are important human pathogens, with case fatality rates often up to 90% for MARV, RAVV and EBOV, and around 55% for SUDV 8,10 . On the basis of two small outbreaks in 2007 and 2012, BDBV seems to be the least pathogenic, with a case fatality rate of about 40-48% 11,12 . In 1994, TAFV was associated with a number of deaths in chimpanzees and a single symptomatic but non-lethal human infection in the Republic of Côte d'Ivoire 13,14 . RESTV is lethal for macaques but is not thought to cause disease in humans 15 . An outbreak of RESTV was reported in pigs in the Philippines in 2008; however, it remains uncertain whether the disease observed in the pigs was caused by RESTV or other agents reported to have co-infected the animals 16 . Clinical manifestationsClinical and laboratory signs of disease caused by filovirus infection are nonspecific and usually associated with an incubation period of 2-21 days (mean 4-10 days) 8,17 . Illness begins with an abrupt onset of fever, astheni...

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Section: Box 4 | Screening Systems For Drug Developmentmentioning

confidence: 99%

mentioning

confidence: 99%

Post-exposure treatments for Ebola and Marburg virus infections

Cross

Mire

Feldmann

et al. 2018

Nat Rev Drug Discov

107

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“…Homotrimers of GP 1 -GP 2 form the virion spikes. The primary gene product of the EBOV GP gene is not the GP, but rather a smaller nonstructural secreted GP (sGP), which is efficiently released from infected cells (Refs 19,20). The function of sGP has not been fully delineated, but it appears that expression of sGP might protect against cytotoxicity (Ref.…”

Section: Ebov: Structure and Protein Functionsmentioning

confidence: 99%

Ebola virus: new insights into disease aetiopathology and possible therapeutic interventions

Geisbert

Hensley

2004

Expert Rev. Mol. Med.

111

106

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Ebola virus (EBOV) gained public notoriety in the last decade largely as a consequence of the highly publicised isolation of a new EBOV species in a suburb of Washington, DC, in 1989, together with the dramatic clinical presentation of EBOV infection and high case-fatality rate in Africa (near 90% in some outbreaks), and the unusual and striking morphology of the virus. Furthermore, there are no vaccines or effective therapies currently available. Progress in understanding the origins of the pathophysiological changes that make EBOV infections of humans so devastating has been slow, primarily because these viruses require special containment for safe research. However, an increasing understanding of the mechanisms of EBOV pathogenesis, facilitated by the development of new tools to elucidate critical regulatory elements in the viral life cycle, is providing new targets that can be exploited for therapeutic interventions. Notably, identifying factors triggering the haemorrhagic complications that characterise EBOV infections led to the development of a strategy to modulate coagulopathy; this therapeutic modality successfully mitigated the effects of EBOV haemorrhagic fever in nonhuman primates. This review summarises our current understanding of EBOV pathogenesis and discusses various approaches to therapeutic intervention based on our current understanding of how EBOV produces a lethal infection.

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“…Hydrophobic 4-3 heptad repeats, characteristic of coiledcoil sequences, are frequently observed within the extracellular domains of viral envelope proteins that mediate fusion of the envelope with cell surface or endosomal membranes during the infectious process (Buckland and Wild, 1989). Examples of this motif are encoded in the human immunodeficiency virus (HIV) GP41, paramyxovirus F, Ebola GP, and baculovirus GP64 membrane proteins (Blissard and Rohrmann, 1989;Whitford et al, 1989;Chambers et al, 1990;Sanchez et al, 1996;Weissenhorn et al, 1998). X-ray crystallographic studies on a number of viral fusion proteins have revealed a common theme of a central trimeric amino-terminal core sequence stabilized by coiled-coil packing, with an antiparallel packing of a second ␣ helix against this central core.…”

Section: Introductionmentioning

confidence: 99%

A Discrete Stage of Baculovirus GP64-mediated Membrane Fusion

Kingsley

Behbahani

Rashtian

et al. 1999

MBoC

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Viral fusion protein trimers can play a critical role in limiting lipids in membrane fusion. Because the trimeric oligomer of many viral fusion proteins is often stabilized by hydrophobic 4-3 heptad repeats, higher-order oligomers might be stabilized by similar sequences. There is a hydrophobic 4-3 heptad repeat contiguous to a putative oligomerization domain of Autographa californica multicapsid nucleopolyhedrovirus envelope glycoprotein GP64. We performed mutagenesis and peptide inhibition studies to determine if this sequence might play a role in catalysis of membrane fusion. First, leucine-to-alanine mutants within and flanking the amino terminus of the hydrophobic 4-3 heptad repeat motif that oligomerize into trimers and traffic to insect Sf9 cell surfaces were identified. These mutants retained their wild-type conformation at neutral pH and changed conformation in acidic conditions, as judged by the reactivity of a conformationally sensitive mAb. These mutants, however, were defective for membrane fusion. Second, a peptide encoding the portion flanking the GP64 hydrophobic 4-3 heptad repeat was synthesized. Adding peptide led to inhibition of membrane fusion, which occurred only when the peptide was present during low pH application. The presence of peptide during low pH application did not prevent low pH-induced conformational changes, as determined by the loss of a conformationally sensitive epitope. In control experiments, a peptide of identical composition but different sequence, or a peptide encoding a portion of the Ebola GP heptad motif, had no effect on GP64-mediated fusion. Furthermore, when the hemagglutinin (X31 strain) fusion protein of influenza was functionally expressed in Sf9 cells, no effect on hemagglutinin-mediated fusion was observed, suggesting that the peptide does not exert nonspecific effects on other fusion proteins or cell membranes. Collectively, these studies suggest that the specific peptide sequences of GP64 that are adjacent to and include portions of the hydrophobic 4-3 heptad repeat play a dynamic role in membrane fusion at a stage that is downstream of the initiation of protein conformational changes but upstream of lipid mixing. INTRODUCTIONThe mechanism of membrane fusion is currently a field of intense investigation, both for intracellular trafficking and enveloped viral infection. For viral fusion protein function, we have previously suggested that fusion protein oligomers form transient and cooperative higher-order structures or rings . These transient ring structures are proposed to facilitate conversion of kinetic energy, released during protein conformational change, into work on the target and host membranes required for membrane fusion. Indeed, biochemical evidence for baculovirus GP64 aggregates during membrane fusion has recently been reported (Markovic et al. 1998). Whether and how viral fusion proteins might function in a coordinated and cooperative manner is a major question in the field of membrane fusion. Because hydrophobic 4-3 heptad repeats are observed...

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The virion glycoproteins of Ebola viruses are encoded in two reading frames and are expressed through transcriptional editing.

Abstract: In late 1994 and early 1995

Cited by 513 publications

References 21 publications

Post-exposure treatments for Ebola and Marburg virus infections

Post-exposure treatments for Ebola and Marburg virus infections

Ebola virus: new insights into disease aetiopathology and possible therapeutic interventions

A Discrete Stage of Baculovirus GP64-mediated Membrane Fusion

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