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Foremost among those scientific challenges: Just what does it take for a vaccine to work? Almost 2 decades after HIV was identified as the cause of AIDS, researchers are still debating which immune responses are likely to provide the best protection against the virus. The answer is proving elusive in part because experiments with monkeys are coming up with puzzling, even contradictory, data. "We're so much in the dark about what we would need for a protective vaccine," laments Ronald Desrosiers, head of Harvard University's New England Regional Primate Research Center in Southborough, Massachusetts.
Monkeys are the favored model for testing vaccine strategies. (Researchers no longer use chimps for ethical and cost reasons.) Although HIV does not infect monkeys, a cousin simian virus, SIV, does: Some two dozen African species of monkeys are now known to harbor SIV in the wild, and it causes them no harm. But when SIV infects Asian monkeys, it causes an AIDS-like disease. In the most common type of experiment, researchers vaccinate Asian rhesus macaques and then "challenge" them with either SIV or a laboratory-made hybrid of the simian and human viruses, called SHIV.
Although some researchers question whether the monkey model truly mimics HIV in humans, the field at large has embraced it as the best way to determine which vaccine strategies hold the most promise. But a slew of recent monkey experiments has raised questions about most of the vaccine approaches now being pursued.
Half a loaf
But monkey studies with AIDS vaccines have completely failed to elicit antibodies that can neutralize the virus. "I think the Holy Grail in the field of AIDS vaccine development is how to generate a broad, neutralizing antibody response," says Norman Letvin, a primate researcher based at Harvard's Beth Israel Deaconess Medical Center in Boston, "but we don't know how to do it."
As a result, many have shifted their attention to the arm of the immune system that dispatches killer cells, tiny missiles that seek infected cells and obliterate them. Because killer cells, by definition, can do their thing only if an infection has already occurred, the goal now is not prevention of infection but of disease.
Some monkey experiments have given heart to those taking this approach. Researchers at Merck Research Laboratories in West Point, Pennsylvania, working with Letvin, reported in the 17 January issue of Nature that two AIDS vaccines they used back to back in monkeys constrained SHIV and protected the animals from disease by triggering killer cell responses. The Merck data have buoyed spirits among vaccine researchers, and the vaccines now are in early human trials. But other monkey studies have raised doubts.
In the same issue of Nature, Letvin, Dan Barouch of Massachusetts General Hospital in Boston, and co-workers reported that similar vaccines initially protected eight monkeys against the identical SHIV strain Merck used, whereas unvaccinated control monkeys had high levels of virus and subsequent disease. But 6 months later, one vaccinated monkey no longer could control the virus, and by 1 year it had developed AIDS-like symptoms and died. The researchers discovered that the SHIV had mutated its way around the killer-cell response. It's an ominous development, Letvin thinks, because it threatens in time to undermine every vaccine that relies on killer cells alone.
Then again, Letvin points out, seven of the vaccinated animals are still controlling their SHIV infections, and even the animal that died fared better than the unvaccinated controls. "I'm willing to take half a loaf if that's all we have," says Letvin.
Immune conundrum. Sooty mangabeys have high viral loads of SIV, yet the virus does not make them sick.
CREDIT: NICK GORDON/OSF/ANIMALS ANIMALS
Experiments conducted by immunologist David Watkins of the Wisconsin Primate Research Center in Madison suggest that even half a loaf might be optimistic, however. Like the Merck team, Watkins and his colleagues used two vaccines back to back that triggered strong killer cell responses. Yet, as Watkins's team reported in the April issue of the Journal of Virology, when they challenged the animals with a famously nasty strain of SIV rather than SHIV, the virus was blunted for a time but ultimately ran wild. A growing number of researchers contend that this more vigorous challenge accurately reflects the way that HIV behaves in humans. "Watkins gets better cellular immunity than I've seen before, better than we can hope to get in humans, and it had a modest effect," stresses Jeffrey Lifson, a virologist at SAIC-Frederick, a company that runs the National Cancer Institute's AIDS Vaccine Program in Frederick, Maryland. "I'm very depressed by these studies," says Watkins. Killer cells by themselves, he suggests, "are not going to be protective."
In 1998, Lisa Chakrabarti, then at the Pasteur Institute, and her colleagues surprised many investigators when they reported that SIV-infected sooty mangabeys maintain terrifically high levels of the virus in their blood. If their immune system is protecting them, it's not by traditional means. Last year, Jonathan Allan of the Southwest Foundation for Biomedical Research in San Antonio, Texas, and co-workers reported that the same holds true for African green monkeys. Mark Feinberg of Emory University in Atlanta, Georgia, who collaborated with Allan and also has confirmed the French findings with sooty mangabeys, suggests that these monkeys might benefit from a sluggish immune response that keeps many immune cells--SIV's target--out of the line of fire. "More isn't necessarily better," says Feinberg. "We don't know enough to point to what are the really good immune responses and which ones aren't so good."
Two experiments that have protected Asian monkeys also raise intriguing questions. A decade ago, Desrosiers's lab reported that a vaccine made from a live, weakened version of SIV offered the best protection seen to this day--and he still cannot completely explain why (Science, 18 December 1992, p. 1938).
Another surprise has come from an experiment that resulted in substantial protection, but doesn't even involve an AIDS vaccine. Lifson of SAIC-Frederick and his co-workers, including Desrosiers, infected five monkeys with a highly lethal strain of SIV and began treating the animals the next day with tenofovir, an anti-HIV drug that also works against the monkey virus. After 28 days, they stopped all treatment. As they reported in last November's Journal of Virology, the researchers could not detect SIV in the monkeys' blood, and the animals continued to control the virus once the treatment stopped. Moreover, when the researchers challenged the monkeys with the same SIV strain more than a year later, they all beat back the challenge.
To further test the monkeys' immunity, the researchers injected the animals with antibodies that temporarily deplete CD8 cells, the family from which killer cells originate. SIV spiked, but they quickly re-established control. The investigators also upped the ante, using a different SIV strain that should be much more difficult for the animals to recognize and contain. All five monkeys substantially controlled the new virus.
Although CD8 cells appeared to play a role in the protection of some animals, the results perplexed many researchers because in other vaccine experiments, monkeys developed more impressive immune responses but still failed to contain the challenge virus. The animals in Lifson's study, Desrosiers says, "are as well protected as any vaccinated monkeys on Earth."
One lesson, says Lifson, is that blunting the initial burst of virus--whether by drugs or a vaccine-fortified immune system--is crucial, perhaps because it protects critical immune responses that otherwise would be lost for good. And he thinks this might help explain why Watkins and others could not defeat SIV with their vaccines. "None of these vaccines seem to give us enough blunting of the early viremia to allow development of an immune response that can give a good chance of solid, prolonged protection against SIV," he says.
Given the contradictory evidence from monkey studies, Desrosiers, the field's resident skeptic, says he has little hope that any of the vaccines now in human trials will work. "The breakthrough discovery that's going to lead to an AIDS vaccine hasn't been made yet," he says. "And if it happens at all, it's going to be serendipitous." Then again, many vaccines--including the one that eradicated smallpox from the world--went into widespread use long before humans had a clue how they actually worked.
Volume 296, Number 5577, Issue of 28 Jun 2002, pp. 2325-2326.
Copyright © 2002 by The American Association for the Advancement of Science. All rights reserved.