A new player in the puzzle of filovirus entry

White, Judith M.; Schornberg, Kathryn L.

doi:10.1038/nrmicro2764

Cited by 77 publications

(83 citation statements)

References 59 publications

(119 reference statements)

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“…More importantly, we identified HR2, the prevalent heptad repeat sequence comprising an alpha-helical coil anchored in viral membranes 15,16 , as a site accessible to triterpenoids that antagonize Ebola virus-cell fusion. Furthermore, as a critical element of the trimerof-hairpins, HR2 was identified as a common target in the triterpenoid-mediated inhibition on viral entry of influenza virus and HIV, potentially extending to an increasingly diverse array of viruses.…”

Section: Introductionmentioning

confidence: 99%

Triterpenoids Manipulate a Broad Range of Virus-Host Fusion via Wrapping the HR2 Domain Prevalent in Viral Envelopes

Si¹,

Meng²,

Tian³

et al. 2018

Preprint

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Recent years have witnessed a breakthrough in identification of a trimer-ofhairpins motif within viral envelopes that triggers a broad range of virus-host fusion.Identifying a domain capable of controlling virus-host fusion remains a challenge due to sequence diversity, heavy glycan shielding and multiple conformations. Here, we report that HR2, a prevalent heptad repeat sequence comprising an alpha-helical coil anchored in viral membranes, is an accessible site to triterpenes, a class of widely distributed natural products. Triterpenes and their derivatives inhibit the entry of Ebola, HIV, and influenza A viruses with distinct structure-activity relationships. Specifically, triterpenoid probes, upon activation by ultraviolet light, capture the viral envelope via crosslinking the HR2 coil. Profiling the Ebola HR2 sequence using amino acid substitution, surface plasmon resonance (SPR) and nuclear magnetic resonance (NMR) spectroscopy disclosed six constitutive residues that are accessible to triterpenoids, leading to wrapping of the hydrophobic helix by triterpenoids and blocking of the HR1-HR2 interaction, which is critical in the trimer-of-hairpins formation. This finding was also observed in the envelopes of HIV and influenza A viruses and might potentially extend to a broader variety of viruses. Our findings might translate into a shared mechanism that host utilize natural product triterpenoids to antagonize membrane fusion of respective viruses, complementing the current repertoire of antiviral agents.

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Section: Introductionmentioning

confidence: 99%

Triterpenoids Manipulate a Broad Range of Virus-Host Fusion via Wrapping the HR2 Domain Prevalent in Viral Envelopes

Si¹,

Meng²,

Tian³

et al. 2018

Preprint

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“…Binding of the RBD to a host receptor then triggers GP 2 to insert its fusion loop into the host cell membrane, at which point a series of conformational changes bring the host and viral membranes together, resulting in fusion (12). While the definitive host receptor has not yet been determined, recent studies have identified the Niemann-Pick cholesterol transporter NPC1 as indispensable for the escape of virus from the acidified endosome following internalization (13)(14)(15)(16).…”

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confidence: 99%

Less Is More: Ebola Virus Surface Glycoprotein Expression Levels Regulate Virus Production and Infectivity

Mohan

et al. 2015

J Virol

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The Ebola virus (EBOV) surface glycoprotein (GP 1,2 ) mediates host cell attachment and fusion and is the primary target for host neutralizing antibodies. Expression of GP 1,2 at high levels disrupts normal cell physiology, and EBOV uses an RNA-editing mechanism to regulate expression of the GP gene. In this study, we demonstrate that high levels of GP 1,2 expression impair production and release of EBOV virus-like particles (VLPs) as well as infectivity of GP 1,2 -pseudotyped viruses. We further show that this effect is mediated through two mechanisms. First, high levels of GP 1,2 expression reduce synthesis of other proteins needed for virus assembly. Second, viruses containing high levels of GP 1,2 are intrinsically less infectious, possibly due to impaired receptor binding or endosomal processing. Importantly, proteolysis can rescue the infectivity of high-GP 1,2 -containing viruses. Taken together, our findings indicate that GP 1,2 expression levels have a profound effect on factors that contribute to virus fitness and that RNA editing may be an important mechanism employed by EBOV to regulate GP 1,2 expression in order to optimize virus production and infectivity. IMPORTANCEThe Ebola virus (EBOV), as well as other members of the Filoviridae family, causes severe hemorrhagic fever that is highly lethal, with up to 90% mortality. The EBOV surface glycoprotein (GP 1,2 ) plays important roles in virus infection and pathogenesis, and its expression is tightly regulated by an RNA-editing mechanism during virus replication. Our study demonstrates that the level of GP 1,2 expression profoundly affects virus particle production and release and uncovers a new mechanism by which Ebola virus infectivity is regulated by the level of GP 1,2 expression. These findings extend our understanding of EBOV infection and replication in adaptation of host environments, which will aid the development of countermeasures against EBOV infection.

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“…Entry of Ebov is mediated by glycoprotein (GP) spikes that protrude from the virus particle (4)(5)(6)(7)(8). Like most other class I viral fusion proteins, GP is composed of a receptor binding unit (GP1) and a fusion (GP2) subunit.…”

mentioning

confidence: 99%

Ebolavirus Entry Requires a Compact Hydrophobic Fist at the Tip of the Fusion Loop

Gregory

Larsson

Nelson

et al. 2014

J Virol

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Ebolavirus is an enveloped virus causing severe hemorrhagic fever. Its surface glycoproteins undergo proteolytic cleavage and rearrangements to permit membrane fusion and cell entry. Here we focus on the glycoprotein's internal fusion loop (FL), critical for lowpH-triggered fusion in the endosome. Alanine mutations at L529 and I544 and particularly the L529 I544 double mutation compromised viral entry and fusion. The nuclear magnetic resonance (NMR) structures of the I544A and L529A I544A mutants in lipid environments showed significant disruption of a three-residue scaffold that is required for the formation of a consolidated fusogenic hydrophobic surface at the tip of the FL. Biophysical experiments and molecular simulation revealed the position of the wild-type (WT) FL in membranes and showed the inability of the inactive double mutant to reach this position. Consolidation of hydrophobic residues at the tip of FLs may be a common requirement for internal FLs of class I, II, and III fusion proteins. IMPORTANCEMany class I, II, and III viral fusion proteins bear fusion loops for target membrane insertion and fusion. We determined structures of the Ebolavirus fusion loop and found residues critical for forming a consolidated hydrophobic surface, membrane insertion, and viral entry. E bolavirus (Ebov) is a filovirus that causes severe hemorrhagic fever with mortality rates of between 25 and 90% (1, 2). Outbreaks involving human fatalities have occurred in sub-Saharan Africa since 1976, the last three being in Uganda and the Democratic Republic of the Congo in 2012 and in Guinea and Liberia in 2014 (3). Ebolavirus is also a much feared potential agent of bioterrorism. However, there are still no FDA-approved treatments or vaccines for this devastatingly morbid infectious agent. One area of therapeutic interest is to target the viral entry machinery that governs virus-host membrane fusion. This would halt infection before initiation of viral replication and subsequent cell destruction. To guide therapeutic design, a detailed knowledge of Ebov entry and membrane fusion is needed, and currently little is known about Ebov virus-host membrane interactions.Entry of Ebov is mediated by glycoprotein (GP) spikes that protrude from the virus particle (4-8). Like most other class I viral fusion proteins, GP is composed of a receptor binding unit (GP1) and a fusion (GP2) subunit. After binding to cell surface receptors, GP mediates virus uptake through a macropinocytosis-like process (9, 10). Viral fusion ultimately occurs in endosomes, where GP1 is cleaved by cathepsins B and L to an ϳ19-kDa species (11, 12), which engages Niemann-Pick C1, a late endosomal protein essential for Ebov entry (13-15). A final unknown trigger causes conformational changes in GP (16, 17) that expose the fusion loop (FL) in GP2. The Ebov FL is clamped by a disulfide bond and has a hydrophobic region at its tip. It is thought to be functionally equivalent to the linear hydrophobic and glycine-rich fusion peptides found at the N termini of mo...

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A new player in the puzzle of filovirus entry

Cited by 77 publications

References 59 publications

Triterpenoids Manipulate a Broad Range of Virus-Host Fusion via Wrapping the HR2 Domain Prevalent in Viral Envelopes

Triterpenoids Manipulate a Broad Range of Virus-Host Fusion via Wrapping the HR2 Domain Prevalent in Viral Envelopes

Less Is More: Ebola Virus Surface Glycoprotein Expression Levels Regulate Virus Production and Infectivity

Ebolavirus Entry Requires a Compact Hydrophobic Fist at the Tip of the Fusion Loop

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