A recombinant diphtheria toxin related human CD4 fusion protein specifically kills HIV infected cells which express gp120 but selects fusion toxin resistant cells which carry HIV.
A chimeric toxin made by a genetic fusion between the DNA encoding the 389 N-terminal amino acids of diphtheria toxin and that coding for the V1 and V2 domains of human CD4 (amino acids 1-178) was produced, purified and examined for ADP ribosylation activity, gp120 binding and effects on acutely and chronically HIV infected cells. The fusion toxin DAB389CD4 possesses enzymatic activity and binds to gp120. DAB389CD4 was found to kill CEM and U937 cells infected by HIV selectively and efficiently in a dose dependent manner, however, fusion toxin treatment did not eliminate the virus from acutely infected cell cultures. In addition, treatment of chronically infected cells with DAB389CD4 rapidly led to the appearance of HIV infected cells which were resistant to the chimeric toxin. The experimental results reported here suggest that the potential use of gp120 targeted cytotoxic agents for the treatment of HIV infection should be viewed with caution.
Aullo
P
P
Unité des Toxines Microbiennes URA CNRS 557, Département de Bactériologie, Paris, France.
Alcami
J
J
Popoff
M R
MR
Klatzmann
D R
DR
Murphy
J R
JR
Boquet
P
P
D000246:Adenosine Diphosphate Ribose / Q000378:metabolism; D000595:Amino Acid Sequence; D001483:Base Sequence; D015704:CD4 Antigens / Q000235:genetics*; D016923:Cell Death / Q000187:drug effects*; D002460:Cell Line; D002472:Cell Transformation, Viral; D002678:Chimera; D004167:Diphtheria Toxin / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D006678:HIV / Q000502:physiology*; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D009838:Oligodeoxyribonucleotides; D010957:Plasmids; D011993:Recombinant Fusion Proteins / Q000378:metabolism / Q000494:pharmacology*; D015183:Restriction Mapping; D013997:Time Factors
D015704:CD4 Antigens; D004167:Diphtheria Toxin; D015699:HIV Envelope Protein gp120; D009838:Oligodeoxyribonucleotides; D011993:Recombinant Fusion Proteins; D000246:Adenosine Diphosphate Ribose