Activity of CD4-Pseudomonas exotoxin against cells expressing diverse forms of the HIV and SIV envelope glycoproteins.
CD4(178)-PE40 is a genetically engineered hybrid toxin containing a portion of human CD4 linked to the translocation and ADP-ribosylation domains of Pseudomonas exotoxin A. In vitro, the molecule has been shown to selectively kill cells expressing the envelope glycoproteins of human immunodeficiency virus (HIV) or simian immunodeficiency virus (SIV), and to inhibit HIV spread. In this report we examine the activity of the hybrid toxin against cells expressing diverse forms of the HIV and SIV envelope glycoproteins, encoded by recombinant vaccinia virus vectors. The activity of CD4(178)-PE40 was found to be unaffected by mutations in the HIV-1 or HIV-2 envelope glycoprotein genes, which prevent normal proteolytic processing of the corresponding gp160 precursor molecules. Cells expressing a mutant HIV-1 envelope glycoprotein lacking most of the cytoplasmic tail of the gp41 transmembrane subunit were also sensitive to the hybrid toxin. Most interestingly, HIV-1, HIV-2, and SIVmac envelope glycoprotein molecules known to have widely differing affinities for CD4 were found to be comparably effective at mediating sensitivity to CD4(178)-PE40. By virtue of its ability to kill infected cells, the hybrid toxin inhibited the spread of SIVmac in vitro. These results indicate that CD4(178)-PE40 is active against cells expressing HIV and SIV envelope glycoproteins with a diverse array of structural differences.
Ashorn
P
P
Department of Biomedical Sciences, University of Tampere, Finland.
Moss
B
B
Berger
E A
EA
D036002:ADP Ribose Transferases; D000818:Animals; D001427:Bacterial Toxins; D015704:CD4 Antigens / Q000633:toxicity*; D002460:Cell Line; D005098:Exotoxins / Q000633:toxicity*; D015967:Gene Expression Regulation, Viral; D015686:Gene Products, env / Q000096:biosynthesis / Q000235:genetics*; D006678:HIV / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D015497:HIV-1 / Q000187:drug effects / Q000235:genetics; D015498:HIV-2 / Q000187:drug effects / Q000235:genetics; D006801:Humans; D000922:Immunotoxins / Q000633:toxicity*; D011994:Recombinant Proteins / Q000633:toxicity*; D015302:Simian Immunodeficiency Virus / Q000187:drug effects* / Q000235:genetics / Q000502:physiology; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D015704:CD4 Antigens; D005098:Exotoxins; D015686:Gene Products, env; D000922:Immunotoxins; D011994:Recombinant Proteins; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A; C057689:CD4-Pseudomonas toxin