Researchers Find Way to Cripple AIDS Virus : Surprise Discovery of Gene Removal Technique Could Pave Way for Development of Treatment

Scientists have learned for the first time how to genetically kill the AIDS virus, independent research teams at Harvard and the National Cancer Institute announced Thursday.

By removing a key gene from the HTLV-III virus in laboratory experiments, the researchers rendered the virus harmless--a major advance that may lead to new drugs or a vaccine to combat the deadly infectious disease.

Inactivating the AIDS virus came as a “big surprise,” said William A. Haseltine, leader of the Harvard team. “The virus was not only slowed down, it was stopped.”

The virus was crippled by removing a gene, called the transactivator, that greatly accelerates the production of the AIDS virus by an infected cell. Researchers only recently learned of the importance of this gene.

The scientists cautioned, however, against undue optimism. “This is not a cure for AIDS or a vaccine for AIDS,” said Flossie Wong-Staal of the institute team.

Because the transactivator gene is not present in normal cells, researchers now hope to develop drugs that can stop the spread of the virus without damaging normal tissues.

“We don’t have a drug yet, but we are pretty certain that we will be able to find drugs,” Haseltine said in a telephone interview.

Researchers also believe the crippled virus may serve as a prototype for a possible AIDS vaccine. Despite the fact that the inactivated virus can’t grow, it looks exactly like the real virus under the microscope, they said.

In another potentially significant AIDS development, a second case has come to light in which a person infected with the virus may have eliminated it without any medical treatment, according to a researcher at the University of California, San Francisco.

At a Washington meeting of the American Society for Microbiology, Jay Levy said such cases may suggest that “an individual, once infected with the virus, can control it.”

Levy said the more recent case is one of about 40 possibly similar cases being studied by UCSF.

Haseltine, also of the Dana Farber Cancer Institute in Boston, and his Harvard colleagues described their findings in a report published today in the biology journal Cell. The National Cancer Institute researchers reported their results in an article published Thursday in the British journal Nature.

The reports are part of a series of recent scientific advances in understanding the mechanisms by which the AIDS virus reproduces and grows.

The HTLV-III virus is one of many viruses called “human T-lymphotrophic viruses” that attack the body’s immune cells, leaving an infected individual vulnerable to a variety of infections and tumors.

In recent months, the Boston and National Cancer Institute research groups have increasingly focused on the tiny transactivator gene, hidden in the center of the HTLV-III virus. This unusual gene is not found in most viruses. It allows the HTLV-III virus to reproduce 100 to 1,000 times faster than many other viruses, according to Wong-Staal.

More Than Expected

When the scientists, using gene-splicing techniques, removed the key gene, they had expected simply to slow the growth of the HTLV-III virus. Instead, they blocked viral growth completely.

“In a sense, the virus is addicted to its own transactivator gene,” Haseltine said. “Without it, it won’t grow.”

The next step, he said, is to learn more about how the transactivator works so that drugs can be developed to counteract it.

Equally important, the researchers also have discovered how to make the defective virus grow again, by either restoring the key gene or supplying the protein made from the gene. These findings may allow researchers to make large quantities of the dead virus--a necessary step in developing a vaccine.

In previous studies, these researchers have explained how the transactivator gene becomes integrated into the cell’s own genetic material at the time the HTLV-III virus invades the cell. The gene helps the virus gain control over the cell’s own genetic regulatory system.

Manufactures Protein

The cell, in turn, manufactures large amounts of a protein made from the transactivator gene, which stimulates the production of large numbers of new viral particles. After the cell dies, the viral particles attack other cells.

The researchers have also learned that the transactivator gene helps the virus reproduce by an unconventional tactic.

Normally, the multiplication of viruses is regulated by the number of molecules--called “messenger” RNAs--made from a given gene. These molecules are an intermediate step in making proteins, which are the building blocks of the virus particles.

In the AIDS virus, however, the transactivator gene steps up the quantity of protein produced from each messenger RNA molecule, thus increasing the production of the virus.

Growth Interference

The experimental drugs currently used to treat some AIDS patients are designed to interfere with the usual mechanisms of viral growth or to stop the movement of viruses between cells.

Drugs directed against the trans-activator might be used in combination with other experimental agents, attacking the virus at multiple steps in its growth cycle.

In Washington, UCSF’s Levy said the man who was infected with the AIDS virus but showed no symptoms of the disease had high levels of the virus in his system a year ago, when first examined; but “six months later, we suddenly realized the virus was no longer present,” Levy said.

But scientists are not sure whether the virus had been completely removed or whether it had become latent after integrating into the genetic material of the man’s cells, Levy said. He said his researchers are conducting more sophisticated experiments to determine whether the virus is still present.

‘This Is Momentary’

“We do have to be concerned that this is momentary,” Levy said. “We don’t find it in the blood or in the cells--but we don’t know if it’s in the genome of the cells,” where genetic material is contained.

Levy said the man’s “helper” cells--those of the immune system that are destroyed by the AIDS virus--had increased, indicating a response from his immune system. Also, Levy said, the man continued to test positive for antibodies to HTLV-III.

Levy said he believes that the development of AIDS involves factors in addition to infection by the virus. And he said he believes that infected individuals could take preventive measures to avoid onset of the disease, such as practicing “low-risk” sexual behavior.

“This man said to me: ‘Dr. Levy, the greatest news you gave me was that I was infected--it made me change my life style,’ ” Levy said. “He stopped smoking. He stopped drinking. He has gone into a monogamous relationship. He is avoiding further compromise to his immune system. If the virus is latent, and remains that way, and if there are no co-factors--this man is in great shape.”

Contaminated Blood

AIDS, or acquired immune deficiency syndrome, is transmitted through sexual contact--with the exchange of bodily fluids such as semen and blood--and through the sharing of unsterilized hypodermic needles. It also has been spread through transfusions of contaminated blood or blood products, although a blood-screening procedure has considerably reduced the danger.

Those at highest risk include male homosexuals and bisexuals, their sexual partners and intravenous drug users. As of Monday, 18,576 cases and 9,865 deaths had been reported.

The San Francisco case is similar to one reported last fall by U.S. researchers at Stanford University and French scientists in Paris involving a woman who was infected with the AIDS virus by her husband, a hemophiliac who developed AIDS from contaminated blood products.

In January, 1984, the 33-year-old woman had antibodies to the virus and a decreased level of “helper” cells. In February, 1984, her husband began using a condom during sexual relations, reducing her further exposure to the virus through sexual transmission.

Ten months later, her “helper” cells had increased, and she remained healthy. However, she had no detectable level of antibodies.

Researchers said that the reason for the reversal was “unclear” but found it “noteworthy” that it occurred “after exposure to her husband’s semen was discontinued.”

The Stanford scientists said the case “suggests that avoidance of repeated exposure to (the AIDS virus) . . . may sometimes result in recovery” of normal immune function and loss of antibodies to the AIDS virus.

Steinbrook reported from Los Angeles, Cimons from Washington.