Inhibition of HIV-1 RNA production by the diphtheria toxin-related IL-2 fusion proteins DAB486IL-2 and DAB389IL-2.
Productive infection of cells by human immunodeficiency virus type 1 (HIV-1) is associated with the activation state of the cell and its obligatory expression of the interleukin-2 receptor (IL-2R), the latter providing a new target for antiviral therapy. A quantitative RNA-RNA hybridization assay is employed to detect production of HIV-1 RNA and to show that two IL-2 diphtheria toxin-related fusion proteins (DAB486IL-2 and its more potent, truncated form DAB389IL-2) inhibit HIV-1 RNA production in infected cells. A mutant form of DAB486IL-2 containing a single point mutation that inactivates the adenosine diphosphate ribosyltransferase activity of the toxin does not inhibit HIV RNA production, even though the molecule binds to the IL-2R. The active fusion proteins inhibit viral RNA replication in cells infected with HIV-1 clinical isolates as well as with a ZDV-resistant strain of HIV-1. These results indicate that IL-2 receptor-targeted fusion proteins can be utilized to inhibit HIV-1 replication effectively in infected human lymphocytes.
Zhang
L
L
Division of Infectious Diseases, Beth Israel Hospital, Harvard Medical School, Boston, MA 02215.
Waters
C
C
Nichols
J
J
Crumpacker
C
C
D000998:Antiviral Agents / Q000494:pharmacology*; D015152:Blotting, Northern; D002478:Cells, Cultured; D004167:Diphtheria Toxin / Q000494:pharmacology*; D015497:HIV-1 / Q000187:drug effects* / Q000235:genetics; D006801:Humans; D007376:Interleukin-2 / Q000494:pharmacology*; D011500:Protein Synthesis Inhibitors / Q000494:pharmacology; D015347:RNA Probes; D016372:RNA, Antisense; D012367:RNA, Viral / Q000096:biosynthesis*; D011993:Recombinant Fusion Proteins / Q000494:pharmacology; D014764:Viral Proteins / Q000096:biosynthesis; D015215:Zidovudine / Q000494:pharmacology
D000998:Antiviral Agents; C054780:DAB(486)-interleukin 2; D004167:Diphtheria Toxin; D007376:Interleukin-2; D011500:Protein Synthesis Inhibitors; D015347:RNA Probes; D016372:RNA, Antisense; D012367:RNA, Viral; D011993:Recombinant Fusion Proteins; D014764:Viral Proteins; C078456:denileukin diftitox; D015215:Zidovudine