Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
CD4-PE40: A CHIMERIC TOXIN ACTIVE AGAINST HUMAN IMMUNODEFICIENCY VIRUS (HIV)-INFECTED CELLS
The Human Retroviruses. Gallo RC and Jay G, eds. San Diego, Academic Press, p. 379-87, 1991.. Unique Identifier : AIDSLINE ICDB/92678735 Chaudhary VK; Moss B; Berger EA; FitzGerald DJ; Pastan I; Lab. of Molecular Biology, NCI, Bethesda, MD 20892
Abstract:
The realization that HIV uses CD4 on the surface of T cells as its receptor, and later in its life cycle expresses gp120 (envelope glycoprotein) on the cell surface, has permitted the design of therapies to kill HIV-infected cells to interrupt the life cycle of the virus. To accomplish this task, a novel toxin molecule has been designed that consists of a portion of CD4 and a portion of Pseudomonas exotoxin (PE). This molecule, termed CD4-PE40, binds viral gp120 present on the surface of HIV-infected cells, is internalized, and leads to the death of the infected cells, presumably by mechanisms analogous to those for native Pseudomonas exotoxin and derivatives. This is the first example of a virally infected cell being killed by a target toxin. PE is a 66,000-mol wt enzyme secreted by Pseudomonas aeruginosa. It kills cells by catalyzing the ADP ribosylation of elongation factor 2, thus leading to its irreversible inactivation. The chimeric toxin was shown to both bind gp120 in solution and to bind to cells expressing gp120. CD4-PE40 also selectively killed T cells infected with HIV that expressed gp120 on their surfaces, while control cells not infected by the virus were not killed. Initial studies in mice have indicated that CD4-PE40 has a half-life of between 20 and 40 min. The mol wt of the molecule is about 60,000, which suggests that it should not be cleared rapidly by filtration in the kidney. Currently, the mechanism by which CD4-PE40 is removed from the circulation is not known. Because of its short half-life, therapy with CD4-PE40 probably should be carried out by continuous iv infusion to maintain an adequate blood level for extended periods. New forms of CD4-PE are being developed that may survive longer in the blood and therefore be more useful clinically. (12 Refs)
Keywords: Antigens, CD4/*GENETICS Cell Line Cell Survival/DRUG EFFECTS Exotoxins/*ADMINISTRATION & DOSAGE/GENETICS Gene Expression Regulation, Viral/*DRUG EFFECTS/PHYSIOLOGY Human HIV/*DRUG EFFECTS/GENETICS HIV Infections/GENETICS/*THERAPY Immunotoxins/*ADMINISTRATION & DOSAGE/GENETICS Recombinant Proteins/*ADMINISTRATION & DOSAGE/GENETICS MONOGRAPH REVIEW
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Important note: Information in this article was accurate in 1992. The state of the art may have changed since the publication date.
