Polyanions — A Lost Chance in the Fight against HIV and other Virus Diseases?

Lüscher-Mattli, Madeleine

doi:10.1177/095632020001100401

Cited by 126 publications

(111 citation statements)

References 65 publications

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“…Desulfated HP was nonreactive. Notably, PAs were effective against EEV at concentrations orders of magnitude lower than tested against IMV, where they were largely ineffective (8,25,26). Although anionic charges are important, other polyanionic molecules, including poly-L-glutamic and poly-Laspartic acids, had no effect (Fig.…”

Section: Resultsmentioning

confidence: 98%

“…PAs ameliorate poxvirus infection by blocking actin tail formation and sensitizing EEV to anti-IMV antibody, therefore providing a significant benefit to the host even after infection has already been established. PAs have an in vitro inhibitory effect on many enveloped viruses, including HIV, herpes, influenza, respiratory syncytial, measles, and parainfluenza viruses (25,26). However, the undesirable properties such as toxicity, short half-life, and inactivity in plasma had led to failure in clinical trials (25).…”

Section: Discussionmentioning

confidence: 99%

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Ligand-induced and nonfusogenic dissolution of a viral membrane

Law

Carter²,

Roberts³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

117

118

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Hitherto, all enveloped viruses were thought to shed their lipid membrane during entry into cells by membrane fusion. The extracellular form of Vaccinia virus has two lipid envelopes surrounding the virus core, and consequently a single fusion event will not deliver a naked core into the cell. Here we report a previously underscribed mechanism in which the outer viral membrane is disrupted by a ligand-induced nonfusogenic reaction, followed by the fusion of the inner viral membrane with the plasma membrane and penetration of the virus core into the cytoplasm. The dissolution of the outer envelope depends on interactions with cellular polyanionic molecules and requires the virus glycoproteins A34 and B5. This discovery represents a remarkable example of how viruses manipulate biological membranes, solves the topological problem of how a double-enveloped virus enters cells, reveals a new effect of polyanions on viruses, and provides a therapeutic approach for treatment of poxvirus infections, such as smallpox.antiviral therapy ͉ extracellular enveloped virus ͉ membrane dissolution ͉ Vaccinia virus ͉ virus entry H itherto, membrane fusion was the only known mechanism by which enveloped viruses overcome the lipid barrier to enter and replicate in cells (1, 2). Here we show that the extracellular enveloped virus (EEV) of Vaccinia virus (VACV) sheds its outer lipid membrane by a ligand-dependent nonfusogenic mechanism.VACV replication produces several distinct virions: the intracellular mature virus (IMV), intracellular enveloped virus, cellassociated enveloped virus (CEV), and EEV (3, 4). IMV is surrounded by one lipid membrane (5-9) and is physically robust to aid virus transmission between hosts. CEV and EEV are IMV particles wrapped with an additional membrane derived from the trans-Golgi network (10) or endosomes (11) and are responsible for virus dissemination within the host (4). This extra lipid envelope (EEV membrane) and the associated virus and host membrane proteins serve to protect the IMV particle within from immune surveillance and may contribute to a broader cell tropism of the virus (4). Recently, we provided unequivocal electron micrographs showing that IMV enters by fusion with the plasma membrane (8), consistent with previous reports (6,12,13), and the recent genetic evidence for entry by fusion (14-17). Once the naked core has entered the cytoplasm, it moves deeper into the cell on microtubules (18). However, for VACV EEV, the additional EEV membrane presents an unexplained topological problem for entry, because fusion of the EEV outer envelope with the plasma membrane or the membrane of an intracellular vesicle will release only an IMV, instead of a naked core, into the cytosol. For a recent review of VACV entry, see ref.19.Here we studied the entry of EEV by immuno-EM and demonstrated that the EEV outer membrane is disrupted at the point of cell contact after binding. This enables the IMV within to enter the cell by fusion with the plasma membrane. The ligands required for membrane rupture were ...

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Section: Resultsmentioning

confidence: 98%

Section: Discussionmentioning

confidence: 99%

Ligand-induced and nonfusogenic dissolution of a viral membrane

Law

Carter²,

Roberts³

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

117

118

View full text Add to dashboard Cite

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“…Large (Ն5 kDa) polyanionic molecules have been shown to be excellent in vitro inhibitors of attachment and entry for several enveloped viruses, including herpesviruses, retroviruses, orthomyxoviruses, and paramyxoviruses (11,32). For many of these viruses, this has been shown to be due to the blocking of important charge-charge interactions involved in the binding of the virus to its cellular receptor(s).…”

Section: Discussionmentioning

confidence: 99%

“…For many of these viruses, this has been shown to be due to the blocking of important charge-charge interactions involved in the binding of the virus to its cellular receptor(s). Such an inhibition is generally dependent upon the molecular weight and extent of the negative charge of the polyanions used and is somewhat nonspecific, in the sense that the interactions are thought to be largely charge mediated and of low affinity and may involve several sites on a particular viral or cellular protein (32). The inhibition of human immunodeficiency virus (HIV) by dextran sulfate, for example, has been shown to involve the association of dextran sulfate with several positively charged regions of the surface glycoprotein gp120 (7,14,22,37,39) and to interfere with the binding of gp160 to its receptor (30,35), coreceptor (39), and cell surface heparan sulfate (38,45).…”

Section: Discussionmentioning

confidence: 99%

“…Whether there are host cell proteins on the surfaces of virions that may also contribute to viral attachment has not been reported, although it has been shown that the presence of heparin-like molecules on the virus surface is important for viral entry (4). Given the importance of sulfated GAGs for RSV entry, it is not surprising that many natural and synthetic polyanions, which are capable of competing with the binding of RSV to these sulfated moieties, have been shown to inhibit RSV infection (25,32).…”

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confidence: 99%

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RhoA-Derived Peptide Dimers Share Mechanistic Properties with Other Polyanionic Inhibitors of Respiratory Syncytial Virus (RSV), Including Disruption of Viral Attachment and Dependence on RSV G

Budge

Beeler

et al. 2004

J Virol

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Large polyanionic molecules, such as sulfated polysaccharides (including soluble heparin and dextran sulfate), synthetic polyanionic polymers, and negatively charged proteins, have been shown to broadly inhibit several enveloped viruses. We recently reported the antiviral activity of a peptide derived from amino acids 77 to 95 of a potential binding partner of respiratory syncytial virus F protein (RSV F), the GTPase RhoA. A subsequent study with a truncated peptide (amino acids 80 to 94) revealed that optimal antiviral activity required dimerization via intermolecular disulfide bonds. We report here that the net negative charge of this peptide is also a determining factor for its antiviral activity and that it, like other polyanions, inhibits virus attachment. In a flow cytometry-based binding assay, peptide 80-94, heparin, and dextran sulfate inhibited the attachment of virus to cells at 4°C at the same effective concentrations at which they prevent viral infectivity. Interestingly, time-of-addition experiments revealed that peptide 80-94 and soluble heparin were also able to inhibit the infectivity of a virus that had been prebound to cells at 4°C, as had previously been shown for dextran sulfate, suggesting a potential role for postattachment effects of polyanions on RSV entry. Neutralization experiments with recombinant viruses showed that the antiviral activities of peptide 80-94 and dextran sulfate were diminished in the absence of the RSV attachment glycoprotein (G). Taken together, these data indicate that the antiviral activity of RhoA-derived peptides is functionally similar to that of other polyanions, is dependent on RSV G, and does not specifically relate to a protein-protein interaction between F and RhoA.

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