The channel-forming toxin aerolysin neutralizes human immunodeficiency virus type 1.
Aerolysin is a channel-forming toxin secreted by Aeromonas spp. that binds to glycosyl phosphatidylinositol (GPI)-anchored proteins, such as Thy-1, on sensitive target cells. Receptor binding is followed first by oligomerization of the toxin and then by insertion of the oligomers into the membrane to form stable channels that disrupt the permeability barrier. Human immunodeficiency virus type 1 (HIV-1) produced from T cells is known to incorporate Thy-1 and other GPI-anchored proteins into its membrane. Here, we show that aerolysin is capable of neutralizing HIV-1 in a dose-dependent manner and that neutralization depends upon the presence of these proteins in the viral envelope. Pretreatment with phosphatidylinositol-specific phospholipase C to remove GPI-anchored proteins greatly reduced HIV-1 sensitivity to the toxin, and virus originating from a mutant cell line that lacks GPI-anchored proteins was not neutralized. Aerolysin variants with single amino acid changes that prevent oligomerization or insertion of the toxin were unable to inactivate the virus, implying that channel formation is necessary for neutralization to occur. These findings represent the first evidence that a pathogenic human virus can be neutralized by a bacterial toxin.
The Leukocyte Immunochemistry Laboratory, Department of Pharmacology and Molecular Sciences, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
D H
DH
Nguyen
Z
Z
Liao
J T
JT
Buckley
J E
JE
Hildreth
D019380:Anti-HIV Agents / Q000494:pharmacology*; D001427:Bacterial Toxins / Q000235:genetics / Q000494:pharmacology*; D017261:Glycosylphosphatidylinositols / Q000378:metabolism; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007473:Ion Channels / Q000378:metabolism*; D019169:Jurkat Cells; D009154:Mutation; D043265:Phosphatidylinositol Diacylglycerol-Lyase; D054801:Phosphoinositide Phospholipase C; D052899:Pore Forming Cytotoxic Proteins; D011485:Protein Binding; D010738:Type C Phospholipases / Q000378:metabolism; D014759:Viral Envelope Proteins / Q000378:metabolism
D019380:Anti-HIV Agents; D001427:Bacterial Toxins; D017261:Glycosylphosphatidylinositols; D007473:Ion Channels; D052899:Pore Forming Cytotoxic Proteins; D014759:Viral Envelope Proteins; C107096:proaerolysin; C032676:aerolysin; D010738:Type C Phospholipases; D054801:Phosphoinositide Phospholipase C; D043265:Phosphatidylinositol Diacylglycerol-Lyase