CD4-Pseudomonas exotoxin hybrid protein blocks the spread of human immunodeficiency virus infection in vitro and is active against cells expressing the envelope glycoproteins from diverse primate immunodeficiency retroviruses.
We previously described an unusual recombinant protein, designated CD4(178)-PE40, containing the gp120 binding region of human CD4 linked to active regions of Pseudomonas exotoxin A. The ability of this molecule to selectively inhibit protein synthesis in cells expressing the surface envelope glycoprotein of human immunodeficiency virus (HIV) suggested this molecule may be useful in treating infected individuals. To further evaluate its therapeutic potential, several in vitro properties of this hybrid toxin were examined. CD4(178)-PE40 was found to be an extremely potent cytotoxic agent, selectively killing HIV-infected cells with IC50 values around 100 pM. In a coculture system employing mixtures of HIV-infected and -uninfected cells, the hybrid toxin inhibited spread of the infection, as judged by a delay in HIV-induced cell killing and a dramatic suppression of free virus production. Experiments with control recombinant proteins indicated that this protective effect was primarily due to selective killing of the HIV-infected cells, rather than to a simple blocking effect of the CD4 moiety of the hybrid toxin. Using recombinant vaccinia viruses as expression vectors, we found the hybrid toxin to be active against cells expressing the envelope glycoproteins of divergent isolates of HIV-1, as well as HIV-2 and simian immunodeficiency virus. These results provide further support for the therapeutic potential of CD4(178)-PE40 in the treatment of HIV-infected individuals.
Berger
E A
EA
Laboratory of Viral Diseases, National Institute of Allergy and Infectious Diseases, Bethesda, MD 20852.
Clouse
K A
KA
Chaudhary
V K
VK
Chakrabarti
S
S
FitzGerald
D J
DJ
Pastan
I
I
Moss
B
B
D000998:Antiviral Agents / Q000494:pharmacology*; D001426:Bacterial Proteins / Q000494:pharmacology; D015704:CD4 Antigens; D002460:Cell Line; D002470:Cell Survival / Q000187:drug effects; D005098:Exotoxins / Q000494:pharmacology*; D006678:HIV / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D000922:Immunotoxins / Q000494:pharmacology*; D012194:RNA-Directed DNA Polymerase / Q000378:metabolism; D011994:Recombinant Proteins / Q000494:pharmacology*; D014759:Viral Envelope Proteins / Q000096:biosynthesis*
D000998:Antiviral Agents; D001426:Bacterial Proteins; D015704:CD4 Antigens; C057689:CD4-Pseudomonas toxin; D005098:Exotoxins; D000922:Immunotoxins; D011994:Recombinant Proteins; D014759:Viral Envelope Proteins; D012194:RNA-Directed DNA Polymerase