Originally created 09/05/97

Scientists create new AIDS weapon



BOSTON - Scientists have created the first virus-killing viruses, cleverly crafted microscopic missiles that zero in on AIDS-infected cells and destroy them.

The idea is to fight infection with infection. The newly created viruses target only cells that have already been captured by HIV.

The approach works well in the test tube but has not been tried yet in people or even in animals. Even though no one knows whether it will eventually help control AIDS, experts say the idea is noteworthy for its novelty alone.

"It's absolutely amazing that you can make a virus that will specifically target HIV-infected cells," said Dr. Ronald Desrosiers of the New England Regional Primate Center, who plans to begin testing one of the viruses soon on monkeys.

One version of the virus, created by Dr. John K. Rose and his research team at Yale Medical School, is a genetically altered form of vesicular stomatitis virus, or VSV, a bug that ordinarily infects livestock. Another is based on the rabies virus and was created by a team led by Dr. Karl-Klaus Conzelmann of the Federal Research Center for Virus Diseases of Animals in Tubingen, Germany.

"It's a completely new approach to limiting viral infection," Rose said. "This is the first virus that's an anti-virus."

Reports on both experiments are being published in Friday's issue of the journal Cell. An accompanying commentary by Dr. Garry P. Nolan of Stanford University called the work "highly significant" and "a leap forward."

If it works as its developers hope, the technique will stop the AIDS virus cold by employing a sort of mirror image of HIV's own sly tricks for worming its way into cells.

Each individual bit of HIV is a ball of genetic material wrapped in a protein known as gp120. This substance has a powerful chemical attraction to two other proteins called CD4 and fusin. Some types of blood cells carry CD4 and fusin on their surfaces. And the AIDS virus uses its gp120 as a magnet to attach itself to these cells.

Once gp120 latches onto these two proteins, HIV opens the cell and squirts its genetic blueprint inside. This information is then stitched into the cells' own genes, turning them into virus-building factories. Along the way, the infected cells produce more gp120 and carry it on their surfaces.

In the new experiments, the scientists built versions of rabies and VSV that are missing their original outer coats. Instead, their surfaces are made of CD4 and fusin.

Reversing the process of HIV infection, this CD4 and fusin is attracted to the gp120 on the surface of the AIDS-infected cells. The genetically engineered virus enters and takes charge. After a few hours, the cell dies, never producing HIV.

The viruses follow a trend of scientists identifying specific sites where HIV interacts with human cells and then targeting them with therapies to prevent it, such as the drug AZT, which targeted the virus' reverse transcriptase enzyme, said J. Peter Rissing, chief of infectious diseases at Medical College of Georgia. What is attractive about the discovery is how specific it is, Dr. Rissing said.

"The more specific, the fewer the side effects" from the therapy affecting other, uninfected cells, Dr. Rissing said. "That's clever engineering."

The experimental rabies virus cannot reproduce. However, Yale's bullet-shaped VSV can actually command the cell to make new versions of itself before killing it. These new bits of VSV can then spread to other HIV-infected cells, essentially becoming a self-manufacturing AIDS drug.

Dr. Edward A. Berger of the National Institute of Allergy and Infectious Diseases, who discovered fusin last year, called the approach "interesting and clever."

"This is a selective way of delivering something to the HIV-infected cell, in this case a virus that will kill the cell," he said.

In the test tube, the reproducing VSV was able to reduce levels of HIV to almost zero for three months. This means the treatment is unlikely to wipe out HIV, even if it works, but it might be used with other medicines to keep HIV infections from progressing to AIDS.

The newly created viruses are designed to attack HIV-infected cells and nothing else. However, the safety of the new approach will be one of the first questions to be answered.

Other unknowns involve whether the immune system will attack cells that are infected with the genetically engineered viruses.