Elimination of infectious human immunodeficiency virus from human T-cell cultures by synergistic action of CD4-Pseudomonas exotoxin and reverse transcriptase inhibitors.
We have previously described a recombinant protein, designated CD4(178)-PE40, consisting of the human immunodeficiency virus (HIV) envelope glycoprotein-binding region of human CD4 linked to the translocation and ADP-ribosylation domains of Pseudomonas aeruginosa exotoxin A. By virtue of its affinity for gp120 (the external subunit of the HIV envelope glycoprotein), the hybrid toxin selectively binds to and kills HIV-1-infected human T cells expressing surface envelope glycoprotein and also inhibits HIV-1 spread in mixed cultures of infected and uninfected cells. We now report that CD4(178)-PE40 and reverse transcriptase inhibitors exert highly synergistic effects against HIV-1 spread in cultured human primary T cells. Furthermore, combination treatment can completely eliminate infectious HIV-1 from cultures of human T-cell lines. This conclusion is based on protection of a susceptible cell population from HIV-induced killing, complete inhibition of virus protein accumulation, and elimination of HIV DNA (as judged by quantitative polymerase chain reaction analysis). The results highlight the therapeutic potential of treatment regimens involving combination of a virostatic drug that inhibits virus replication plus an agent that selectively kills HIV-infected cells.
Laboratory of Viral Diseases, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892.
P
P
Ashorn
B
B
Moss
J N
JN
Weinstein
V K
VK
Chaudhary
D J
DJ
FitzGerald
I
I
Pastan
E A
EA
Berger
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D015704:CD4 Antigens / Q000008:administration & dosage / Q000737:chemistry*; D002478:Cells, Cultured; D016049:Didanosine / Q000008:administration & dosage; D004357:Drug Synergism; D005098:Exotoxins / Q000008:administration & dosage* / Q000737:chemistry; D006678:HIV / Q000254:growth & development; D015658:HIV Infections / Q000628:therapy*; D006801:Humans; D000922:Immunotoxins; D066298:In Vitro Techniques; D018894:Reverse Transcriptase Inhibitors; D013601:T-Lymphocytes / Q000382:microbiology*; D037521:Virulence Factors; D014779:Virus Replication / Q000187:drug effects; D015215:Zidovudine / Q000008:administration & dosage; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D001427:Bacterial Toxins; D015704:CD4 Antigens; D016049:Didanosine; D005098:Exotoxins; D000922:Immunotoxins; D018894:Reverse Transcriptase Inhibitors; D037521:Virulence Factors; D015215:Zidovudine; D000097668:Pseudomonas aeruginosa Exotoxin A