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Designer genes. Monkeys given a virus that holds the DNA for lab-made antibodies dodged SIV.

Malcolm Linton

Designer Antibodies Derail Monkey AIDS Virus

Researchers are reporting that a new antiviral strategy powerfully protects monkeys from SIV, the simian cousin of HIV. The approach combines elements of vaccines and gene therapy, and experts say the development could eventually lead to a vaccinelike weapon against AIDS--a goal that has thus far proved elusive.

Vaccines work by priming the "adaptive" immune system to recognize and attack a specific invader. But despite 2 decades of research, several potential AIDS vaccines have failed to teach the immune system to produce antibodies that can stop HIV. Still, some progress has been made: Researchers have isolated a handful of antibodies from HIV-infected humans that stymie HIV in test-tube studies. Intensive efforts have attempted to find the proteins or peptides that could teach the immune system to produce these powerful antibodies, yet none has made progress.

AIDS vaccine researcher Philip Johnson came up with a workaround: Bypass the immune response and just deliver the antibodies. "We're taking what Mother Nature has given us in terms of molecules and antibodies, and we're leapfrogging the adaptive immune system, which is not very effective against HIV," he says.

Johnson's group at Children's Hospital of Philadelphia in Pennsylvania decided to test the idea in the monkey SIV model to see if it had promise. The researchers first created what amounts to designer antibodies: They linked together pieces of antibody to construct "immunoadhesins." These molecules derailed SIV in test-tube studies and can remain in the blood at high concentrations. They then stitched the genes for these immunoadhesins into an adeno-associated virus (AAV), a "vector" used in human gene therapy experiments to deliver foreign DNA into the body's cells.

Nine monkeys received injections into their muscles of AAVs that carried three different immunoadhesins. Four weeks later, the researchers "challenged" the monkeys with injections of SIV. Six of the nine animals did not become infected, whereas all six control animals, which did not receive the immunoadhesins, did. The team reports its findings online this week in Nature Medicine.

"It's a great paper," says Nobel Prize-winning virologist David Baltimore, whose own lab at the California Institute of Technology in Pasadena is doing similar work. "Phil Johnson has gone for the throat with these anti-SIV immunoadhesins rather than natural antibodies. It's a hopeful opportunity to make a vaccine by a very different principle than what we've seen before."

Several practical questions still loom large. The three monkeys that were not protected by the immunoadhesins all had immune responses that attacked these artificial antibodies. Why did some monkey immune systems go after the designer antibodies whereas others did not? "We don't have a clue," says Johnson.

What's more, unlike a vaccine, which builds long-lasting immunological memory against a pathogen, the designer antibody approach depends on the viral vector persisting and continuing to pump out the immunoadhesins. Although Johnson says the monkeys continue to produce the immunoadhesins 80 weeks out, it's unclear how long the AAV will survive. Another potential problem is that prolonged exposure to the immunoadhesins or the vector itself could lead to immune responses against them later.

Then there's the question of SIV compared with HIV. Immunologist Dennis Burton of the Scripps Research Institute in San Diego, California, notes that the particular SIV used to challenge the monkeys is "very, very sensitive" to antibodies. "With HIV, it would be quite difficult to get those levels of neutralization with the antibodies we know about," he says.

Johnson recognizes the limitations, including the substantial regulatory hurdles that must be cleared before the new approach can be tested in humans, but he is confident that it will move forward. "Some people think it's nice monkey work but not translatable," says Johnson. "My favorite line is, 'Okay, so what's your idea?'"