AIDS Warriors: Fighting for Every Inch

Frustrated at so many points, researchers report progress in developing a vaccine that won't itself turn deadly

It has been more than 20 years since the AIDS epidemic began, and the latest numbers, presented at the 8th Annual Conference on Retroviruses in Chicago, are staggering. More than 20 million people have died of the disease already. Thirty six million more harbor HIV, the deadly virus that causes the disease -- and new infections are appearing at the rate of 5.3 million per year.

The terrible scourge continues to hit the hardest in Africa. "It is Africa's greatest catastrophe since slavery," said Dr. Kevin M. DeCock, director of the U.S. Centers for Disease Control's activities in Kenya, at the conference on Feb. 4. In many parts of the continent, the lifetime risk of dying from AIDS is 60%, which means that the majority of today's teenagers will die of the disease.

Even in the U.S, where powerful new drugs have been developed to keep the virus at bay, the story is still grim. An estimated 900,000 Americans are infected, and as many as 250,000 of them aren't even aware that they have the virus. As a result, they may be continuing to transmit it to others, helping to explain why new infections continue to appear at the high rate of 40,000 a year. In fact, there's disturbing new evidence that people with HIV are beginning to forget the lessons of the past. They're increasingly having unprotected sex or engaging in other high-risk activities, raising the specter of an even more rapidly spreading epidemic.


  At the same time, the wonder drugs aren't working as well as originally hoped. They cause serious, potentially life-threatening side effects, such as heart disease. And the wily virus has been able to quickly develop resistance to many of the new medicines.

That's why scientists are still battling HIV on a number of different fronts, from designing new drugs to devising better ways of spreading the message of prevention. At this year's conference, the world's preeminent scientific meeting on AIDS, hundreds of new studies are peeling back the mysteries of the virus. "There has been great progress on a wide range of fronts," says Dr. Constance A. Benson of the University of Chicago, the chair of the conference's scientific-program committee. But she hastens to add that the progress is incremental. Science is still a long way from breaking the back of the epidemic, researchers say.

Turns out that the standard routes to vaccines for other diseases don't work for AIDS

One good example of this combination of progress and frustration is the long saga of Ronald Desrosiers, professor of microbiology at Harvard Medical School and director of the New England Regional Primate Research Center. For years, Desrosiers has been working on the ultimate weapon against HIV -- a vaccine. Back in the 1980s, he thought it might be possible to follow one of the standard routes used to develop vaccines for other diseases.

The idea: Modify the bug so that it's too weak to cause disease. Then, inject the weakened microbe into the body. Since the bug is still alive, it's able to stimulate a far stronger immune response than a vaccine made just from inanimate parts. And since it's too weak to cause disease, it's harmless. After all, a weakened strain of polio was one of the vaccines used to tame that terrible disease.


  Working with the monkey equivalent of HIV -- simian immunodeficiency virus, or SIV -- Desrosiers plucked out a key gene from the virus to weaken it. Then he injected it into monkeys and let the immune system respond, before challenging the animals with the deadly version of the virus.

At first, the results were enormously promising. Desrosiers' so-called live-attenuated vaccine consistently prevented monkeys from getting infected by the virus. But it was also enormously risky. Scientists feared that the weakened strain used in the vaccine could mutate to become more virulent. If that happened, using it as a vaccine could make the epidemic worse.

The fears were borne out. Additional monkey studies by Desrosiers and other scientists showed that the vaccine could indeed turn more deadly. Clearly, a live-attenuated virus was far too dangerous to use as a vaccine in people.

AIDS is diabolical. It keeps its most vulnerable parts hidden from antibodies

But how could scientists make a safer vaccine that worked? They tried all sorts of approaches, from selecting pieces of HIV's outer envelope to slipping a few HIV genes into other harmless viruses. The central problem is that it's very difficult to stimulate an immune response that's capable of neutralizing the virus. Normally, when a microbe invades, it prompts the immune system to make antibodies that can bind to and neutralize the invader. The immune system also makes killer T-cells that attack cells in the body that are infected by the microbe. That's why humans can easily rid themselves of nasty bugs like the cold virus.


  But HIV is more diabolical, scientists have learned. Yes, the immune system makes large amounts of antibodies when HIV invades. But these antibodies are useless against the virus. The reason, researchers have learned, is that the virus keeps its most vulnerable parts carefully cloaked -- the parts that bind to and infect cells. The virus keeps them hidden until the brief moment of infection, so that the immune system doesn't have time to make antibodies capable of hitting these targets. "The virus has developed strategies to evade the immune system," Desrosiers explains. "The bottom line is that in monkeys and people, the antibodies are not able to do the job of neutralizing the virus."

That new knowledge prompted Desrosiers to go down a different path. Instead of stripping out genes to make the virus weaker, he has been trying to modify the virus so that its vulnerable sites are more visible to the immune system. And at the Retrovirus Conference, he reported on promising new strategies. "We've been able to tweak the system to make the virus easier to neutralize," he says.

In order to infect a cell, the virus must be able to attach its own envelope to receptors on the surface of the cell it's targeting. That requires very specific binding regions on the envelope that fit into the receptor like a key into a lock. But to prevent the immune system from seeing -- and thus being able to create antibodies to block -- the binding sites, the virus cloaks these key regions with a coat of sugars and a loop of protein.


  What Desrosiers did was create strains of virus that lack the sugar coating or the extra covering loop of protein. The resulting strains are still able to infect cells, he found, but they also prompt the immune system to make the correct type of antibodies. In monkey tests, Desrosiers immunized the animals with the modified strains. Then he challenged them with a virulent virus. The results were impressive: "The animals were well protected -- as well protected as any with the attenuated virus," he explains.

Of course, Desrosiers adds, an effective vaccine is still a long way off. "We shouldn't have false hopes," he cautions. After all, these modified viruses are still too dangerous to use as vaccines. But they do point the way to the development of better vaccines, he says. What scientists need to do now is figure out how to give the immune system a better look at the virus's vulnerable binding sites without using an actual live strain of the virus.

The work is already well under way. Scientists at biotech company Chiron Corp., for instance, are using a combination vaccine that includes pieces of the viral envelope that have been stripped of the covering protein loop. Those pieces, reports Chiron's Susan Barnett, are able to stimulate the immune system to make potent neutralizing antibodies. And when boosted with other vaccines, these envelope pieces are able to partially protect monkeys from infection, she says. That means it could be used by those already harboring HIV to help their immune systems better fight the virus, she suggests.

It's not a major victory yet against this deadly scourge. But this sort of progress has scientists hopeful that some of the battles can eventually be won.

By John Carey in Chicago

Edited by Douglas Harbrecht

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