The New York Times

Friday, 20 October 2000

Vaccine Controls AIDS Virus in Early Tests on Monkeys

By GINA KOLATA

Using a new kind of vaccine, researchers report that they have been able to control a particularly lethal strain of AIDS virus in monkeys. The vaccine, made of DNA, did not prevent the animals from becoming infected, but it did prevent them from becoming ill, keeping the level of the virus so low that it was virtually undetectable in the animals' blood.

But the researchers urged caution, saying that although they were elated by the results, it could be a long and difficult path from promising data in monkeys to a vaccine that worked in humans. And even in monkeys, questions remain. It is not yet known, for example, how long the vaccine's effects will last.

"The major point that I see in this work is the concept," said Dr. Norman L. Letvin, who directed the work and is a professor of medicine at Harvard Medical School. "It might be possible with a vaccine to perhaps change the clinical course of an infection without blocking an infection."

In their study, published today in the journal Science, Dr. Letvin and his colleagues injected eight rhesus monkeys with DNA that included two AIDS virus genes. Since the genes were not a virus, the vaccine itself could not transmit disease. Having inoculated the monkeys, the scientists then infected the animals with an AIDS virus that would ordinarily destroy their immune systems in weeks and kill them in a few months.

The monkeys that were given the vaccine lived for 140 days - the length of the experiment - with no detectable virus in their blood, no deterioration in their immune systems and no signs of ill health. Dr. Letvin said he is continuing to monitor how long the effects last.

Eight monkeys injected with a sham vaccine and then with the virus became ill in weeks, with high levels of the virus in their blood and hobbled immune systems. Half were dead in 140 days.

"I think the results are very exciting," said Dr. Gary J. Nabel, the director of the vaccine research center at the National Institutes of Health, which paid for the study. "I think it shows for the first time that by vaccinating in an appropriate way we can alter the course of H.I.V. infection in terms of its ability to cause disease. We need to be a little bit cautious in extrapolating to humans," he added. But, he said, "by and large, this is good news."

Dr. David Baltimore, chairman of the AIDS Vaccine Research Committee of the National Institutes of Health, an advisory committee on vaccine science and strategy, said the results raised hope of a practical way to battle the AIDS epidemic without the high cost and debilitating side effects of today's drugs.

"We can't bring drugs to all the people of the world, but you can imagine bringing a vaccine," said Dr. Baltimore, who is also president of the California Institute of Technology. "Another way to look at this is that a vaccine of this sort, if it can reduce the viral load by orders of magnitude, offers the opportunity to break the transmission of the virus. And that's the most important thing of all."

The hope, Dr. Baltimore and other AIDS experts said, was for a DNA vaccine to be at least as effective in humans as a combination of powerful AIDS drugs but without the drugs' expense or side effects.

Uninfected people who were at high risk of infection could be vaccinated to protect them if an infection should occur. Such a vaccine could be especially important in developing countries where it could not only alleviate suffering but also, by keeping the viruses in an infected person's blood at an extremely low level, prevent the spread of AIDS.

Dr. Robert F. Siliciano, a professor of medicine and an AIDS researcher at Johns Hopkins University School of Medicine, said the study was "a very important demonstration that immunization can work," against AIDS. "The caveat is, Will we get the same effect in humans? That we don't know yet. I think it's certainly possible, but we need to do those experiments," Dr. Siliciano said.

Researchers turned to DNA vaccines for AIDS only after years of trying to make traditional vaccines to elicit antibodies to the AIDS virus. Traditional vaccines are made of proteins from microorganisms like viruses or bacteria or are made of killed or disabled microorganisms. They stimulate the immune system to make antibodies, which attach themselves to the disease-causing organisms and block them.

The problem with making such a vaccine against AIDS was that the virus had only one target for an antibody - a protein that protruded from the virus's slick fatty surface. Although vaccinated people made antibodies to that protein, the antibodies were all but useless because the virus mutated constantly, altering its surface protein and evading the antibodies.

That observation led some scientists to consider exploiting other ways that the immune system could attack the AIDS virus. They knew that when a monkey, or a person, was infected with an AIDS virus, there was an initial burst of viral replication when levels of the virus in the body shot up. Then the immune system tamps the virus down, containing the infection often for years during which there is no sign of illness. Finally, though, the virus breaks free, replicating wildly and causing sickness and death.

The challenge, then, was to figure out how the immune system normally suppressed the AIDS virus and then to enhance that natural weapon. The goal would be to make the immune system so effective that the virus would be kept at even lower levels and suppressed for even longer times.

The key, it turned out, was the killer T-cells, also known as CD8 cells. These white blood cells attack viruses in a completely different way than antibodies attack them. Instead of looking for the virus itself, killer T- cells look for cells that are infected with a virus.

When a cell is infected with a virus, like the AIDS virus, it puts fragments of viral proteins on its surface, like flags signaling distress. Killer T- cells, cruising by in the bloodstream, are drawn to those flags, kill the infected cells and start to proliferate into an army that will search for other cells with the same flags and kill them.

Over the last 15 years, scientists have steadily built a case that killer T-cells can hold the AIDS virus in check.

They found that the cells could inhibit the AIDS virus in test tubes. Then they found that killer T-cells proliferated in infected monkeys and in humans at the same time as the AIDS virus replication was brought under control. They found that the strength of an infected individual's killer T-cell response predicted how much virus would be in the person's blood and how well the person would do clinically. And they found that in monkeys, when killer T-cells were obliterated, AIDS viruses ran rampant, never coming under any sort of control and quickly killing the animals.

Encouraged by the body of evidence, Dr. Letvin and his colleagues began looking for ways to prime monkeys to make CD8 cells. The method that worked, they learned, was a DNA vaccine, some components of which were provided by Merck & Company, the pharmaceutical business.

The scientists injected the animals with two AIDS virus genes along with stimulants for cells to make an immune system hormone to speed the production of CD8 cells. Cells picked up the DNA and used those viral genes to make viral proteins. The proteins were harmless to the cells, but the cells responded as they did to any foreign proteins - they put pieces of the proteins on their surfaces, signaling killer T-cells to proliferate. The hormone amplified this process.

The result was a wave of killer cells. Ordinarily, a monkey infected with an AIDS-like virus might end up with 5 percent to 10 percent of its billions of CD8 cells dedicated to fighting the virus. But, Dr. Letvin and his colleagues found, when they used their new vaccine and then infected the monkeys with an AIDS virus, the animals would have up to 30 percent of their CD8 cells specifically designed to fight the infection with the virus.

So far, however, the study only shows that DNA vaccines are a promising approach in AIDS, not that this particular vaccine will protect people, researchers emphasized.

"This is a proof of concept," Dr. Siliciano said.

Nonetheless, he and other AIDS experts said they were hopeful.

"We're not there yet in humans in terms of having a vaccine that can do what we can do in monkeys," Dr. Letvin said. But, he added, "I think we know how to do it."