Inhibitory Effect of Simple Aliphatic Amines on Influenza Virus in Tissue Culture

Jensen, Elizabeth; Liu, O. C.

doi:10.3181/00379727-112-28076

Cited by 23 publications

(8 citation statements)

References 2 publications

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“…We find that infection of MDCK cells by fowl plague virus is inhibited by ammonium chloride and chloroquine . Similar results have been previously reported for ammonium chloride, alkylamines, and amantadine in other cell systems (12)(13)(14)(15)(16)(39)(40)(41)(42)(43)(44)(45) . All these drugs are less effective if added 1 h after infection and do not significantly change virus binding or internalization .…”

Section: Role Of Lysosomes In Infectionsupporting

confidence: 91%

“…On the basis of our studies with Semliki Forest virus, we have suggested that the inhibition depends on the lysosomotropic character of the agents (5,6,47) ; they are known to accumulate in the lysosomes, to elevate the lysosomal pH, and to inhibit many of the lysosomal hydrolases (48,49) . We have here studied the effects of ammonium chloride and chloroquine on fowl plague virus infection in MDCK cells, thereby confirming and extending the previous findings obtained with other influenza viruses (12)(13)(14)(15)(16)(39)(40)(41)(42)(43)(44)(45) .…”

Section: Inhibition By Lysosomotropicagentssupporting

confidence: 88%

“…A number of studies have shown that lipophilic weak bases such as ammonium chloride and amantadine inhibit the entry of influenza virus into their host cells and block infection (12)(13)(14)(15)(16)(39)(40)(41)(42)(43)(44)(45). Similar inhibitory effects of lipophilic amines have been reported in other virus systems (5,6,46,47).…”

Section: Inhibition By Lysosomotropicagentsmentioning

confidence: 59%

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Infectious entry pathway of influenza virus in a canine kidney cell line.

Matlin¹,

Reggio²,

Helenius³

et al. 1981

The Journal of Cell Biology

647

483

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The entry of fowl plague virus, an avian influenza A virus, into Madin-Darby canine kidney (MDCK) cells was examined both biochemically and morphologically . At low multiplicity and 0°C, viruses bound to the cell surface but were not internalized . Binding was not greatly dependent on the pH of the medium and reached an equilibrium level in 60-90 min. Over 90% of the bound viruses were removed by neuraminidase but not by proteases. When cells with prebound virus were warmed to 37°C, part of the virus became resistant to removal by neuraminidase, with a half-time of 10-15 min. After a brief lag period, degraded viral material was released into the medium . The neuraminidase-resistant virus was capable of infecting the cells and probably did so by an intracellular route, since ammonium chloride, a lysosomotropic agent, blocked both the infection and the degradation of viral protein.When the entry process was observed by electron microscopy, viruses were seen bound primarily to microvilli on the cell surface at 0°C and, after warming at 37°C, were endocytosed in coated pits, coated vesicles, and large smooth-surfaced vacuoles . Viruses were also present in smooth-surfaced invaginations and small smooth-surfaced vesicles at both temperatures .

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Section: Role Of Lysosomes In Infectionsupporting

confidence: 91%

Section: Inhibition By Lysosomotropicagentssupporting

confidence: 88%

Section: Inhibition By Lysosomotropicagentsmentioning

confidence: 59%

See 1 more Smart Citation

Infectious entry pathway of influenza virus in a canine kidney cell line.

Matlin¹,

Reggio²,

Helenius³

et al. 1981

The Journal of Cell Biology

647

483

View full text Add to dashboard Cite

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“…The effect of ammonium ions on influenza virus infection was described independently by Jensen et al (1961) and Eaton & Scala (1961), and was later extended to a large number of aliphatic amines (Jensen & Liu, 1963;Fletcher et al, 1965). The inhibitory effect of chloroquine has been reported with myxoviruses (Inglot, 1969;Schimizu et al, 1972;Matlin et al, 1981), rhabdoviruses (Schimizu et al, 1972;, retroviruses (Pazmino et al, 1974), togaviruses (Inglot, 1969, Helenius et al, 1980aTalbot & Vance, 1980), paramyxoviruses (Inglot, 1969;Schimizu et al, 1972;Durand et al, 1970), herpes viruses (Lancz et al, 1971;Banfield & Kirsch, 1973) and mouse hepatitis virus (Malucci, 1966).…”

Section: Discussionmentioning

confidence: 99%

Inhibition of Semliki Forest Virus Penetration by Lysosomotropic Weak Bases

Helenius

Marsh

White

1982

Journal of General Virology

240

157

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SUMMARYThe effect of five lysosomotropic weak bases (chloroquine, amantadine, tributylamine, methylamine and NH4CI) on Semliki Forest virus (SFV) infection has been studied in BHK-21 cells. When present at concentrations equal to or greater than 0-1, 0.5, 2, 15 and 15 mM respectively, the agents inhibited SFV infection by more than 90%. The effect was reversible and involved a process occurring within the first 60 min of virus-cell contact. The agents did not have a direct virucidal effect nor did they affect virus binding to the cells, receptor-mediated endocytosis of prebound virus, intracellular distribution of virus after endocytosis, or the low pH-induced membrane fusion activity of the virus spike glycoproteins. The step blocked by chloroquine and NH4CI occurred intracellularly and was identified as the release of the virus nucleocapsid into the cytoplasm or the uncoating process. On the basis of these results, our previous studies on SFV entry, and the known effects of lipophilic amines on lysosomes, we conclude that the agents affect entry by a common mechanism: they prevent the transfer of the virus nucleocapsid into the cytoplasm by increasing the lysosomal pH above the critical value needed to trigger a low pH-dependent fusion reaction between the membranes of the tysosome and the virus.

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“…Chloroquine had no direct effect on the virus particles nor did it inhibit binding, endocytosis, or uptake of SFV into intracellular vacuoles and lysosomes. The lysosomotropic agents we tested, and others similar to them, have been previously reported to inhibit infections by several enveloped viruses including myxo, oncorna, rubella, and paramyxo viruses (10,13,15,26,27,32,36,39,50,54) . Where studied, the mechanism of action of these agents appears strikingly similar to that of chloroquine on SFV .…”

Section: Penetrationmentioning

confidence: 99%

On the entry of semliki forest virus into BHK-21 cells

Helenius¹,

Kartenbeck²,

Simons³

et al. 1980

The Journal of Cell Biology

762

542

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The pathway by which Semliki Forest virus (SFV), a membrane-containing animal virus, enters BHK-21 cells was studied morphologically and biochemically . After attaching to the cell surface, the majority of viruses was rapidly trapped into coated pits, internalized by endocytosis in coated vesicles, and sequestered into intracellular vacuoles and lysosomes . Direct penetration of viruses through the plasma membrane was never observed .To assess the possible involvement of lysosomes in the release of the genome into the cytoplasm, the effect of five lysosomotropic agents, known to increase the lysosomal pH, was tested. All of these agents inhibited SFV infectivity and one, chloroquine (the agent studied in most detail), inhibited a very early step in the infection but had no effect on binding, endocytosis, or intracellular distribution of SFV . Thus, the inhibitory effect was concluded to be either on penetration of the nucleocapsid into the cytoplasm or on uncoating of the viral RNA .Possible mechanisms for the penetration of the genome into the cytoplasm were studied in vitro, using phospholipid-cholesterol liposomes and isolated SFV . When the pH was 6 .0 or lower, efficient fusion of the viral membranes and the liposomal membranes occurred, resulting in the transfer of the nucleocapsid into the liposomes . Infection of cells could also be induced by brief low pH treatment of cells with bound SFV under conditions where the normal infection route was blocked .The results suggest that the penetration of the viral genome into the cytosol takes place intracellularly through fusion between the limiting membrane of intracellular vacuoles and the membrane of viruses contained within them . The low pH required for fusion together with the inhibitory effect of lysosomotropic agents implicate lysosomes, or other intracellular vacuoles with sufficiently low pH, as the main sites of penetration . KEY WORDS coated vesicleslysosomes " from the extracellular space to the cytosol . This endocytosis -membrane fusion process requires transport through one or more lysosomotropic agents membrane barriers . For animal viruses the mechanisms involved are poorly understood . Data from To infect a cell, a virus must transfer its genome electron microscopy suggest that penetration oc-404 J . CELL BIOLOGY

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Inhibitory Effect of Simple Aliphatic Amines on Influenza Virus in Tissue Culture

Cited by 23 publications

References 2 publications

Infectious entry pathway of influenza virus in a canine kidney cell line.

Infectious entry pathway of influenza virus in a canine kidney cell line.

Inhibition of Semliki Forest Virus Penetration by Lysosomotropic Weak Bases

On the entry of semliki forest virus into BHK-21 cells

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