Tailored toxin targets HIV-laden cells.

Tailored toxin targets HIV-laden cells

A genetically engineered "guided missile" shows promise as a chemical weapon against cells invaded by the AIDS-causing HIV virus. Preliminary tests on cultured, HIV-infected cells show they are "very sensitive" to the engineered toxin, which has been designed to bind selectively only to cells actively producing HIV components. The strategy builds upon several recent advances in scientists' understanding of the molecular biology of AIDS, and in principle resembles some experimental cancer therapies.

Researchers report in the Sept. 22 NATURE the successful engineering of a bacterium to produce a hybrid protein that includes an HIV-binding molecule linked to a cell-killing toxin. The toxin is not aimed at the AIDS virus itself, since the virus typically hides -- and reproduces -- within the body's immune system cells. Instead, the researchers' approach takes advantage of the fact that HIV-infected cells produce on their cell surface a particular protein characteristic of the HIV outer shell, or envelope. That protein, called gp120, serves as a molecular marker of an otherwise clandestine HIV factory.

Vijay K. Chaudhary of the National Cancer Institute, Edward A. Berger of the National Institute of Allergy and Infectious Diseases (NIAID) and their colleagues designed the toxic protein to include a portion of the so-called CD4 molecule that binds to gp120. To do so, they rewrote parts of the genetic code in an E. coli bacterium to make it manufacture a hybrid protein containing both the truncated CD4 molecule and the potent portion of a toxin normally produced by another bacterium, Pseudomonas. The "fusion protein" binds to cells expressing the gp120 protein, then sabotages their protein-making machinery. Similar, experimental approaches have been used to target and kill malignant tumors.

"What we've done is to remove the cell-binding site from the Pseudomonas toxin and substitute a portion of CD4," says NIAID researcher Bernard Moss. "As long as the cell is infected with HIV and is making envelope, then the toxin should kill it."

Experiments show the engineered toxin is deadly to cultured monkey kidney cells infected with a recombinant virus that mimics HIV, and to cultured, HIV-infected human white blood cells. In preliminary experiments, noninfected immune cells appear unharmed. Moss says the group is conducting further tests to determine the toxin's effectiveness against a variety of HIV-infected cells.

Toxicity studies on animals must precede any clinical trials in humans.