Unsung AIDS Advance
In celebrating a major milestone in AIDS vaccine research last week, the media overlooked a second equally important and closely related advance. Indeed, the second breakthrough could lead more quickly to human studies of experimental vaccines.
Heralded on the front pages of the New York Times and Los Angeles Times, the first milestone was the exquisite, atom-by-atom, three-dimensional X-ray picture of a protein on the surface of HIV--called gp120--as it attaches to the T-cell it is about to infect. This scientific tour de force culminated a decade of trying--and it will help researchers target specific molecular approaches for drugs and vaccines.
The gp120 protein acts like the hand of a robber, picking the lock on the cell's door so that HIV can get inside. It is also crucial for a vaccine, because, sticking out of HIV's surface, it makes a perfect target for antibodies.
The research team, led by Harvard's Joseph Sodroski and Columbia's Wayne Hendrickson, showed how gp120's critical machinery is cloaked with a thick layer of sugars. The immune system does not make antibodies against sugars, so this cloak allows gp120 to elude the body's counterattack.
Even if the immune system were to make antibodies to gp120's critical core, many scientists have assumed those antibodies would have trouble latching onto the protein because of its slippery icing of sugars. But this assumption might not be right--and, in fact, the second discovery gives tremendous hope that when the right antibodies are induced, they can be quite active against gp120, able to snare it despite its protective sugars.
While Sodroski and Hendrickson have given the world a detailed model of gp120, researchers already knew the raw fact that the protein is covered in sugars. So Harvard's Ronald Desrosiers decided to conduct a simple test: try a vaccine with the sugars removed from gp120.
Vaccines do not attack viruses directly. Instead, they train the immune system to fight off the invader, and to do that, they must be very similar to the actual virus. So vaccines are made from killed viruses (like the Salk polio vaccine), or from live viruses that have had disease-causing portions deleted (like the Sabin vaccine), or from harmless but immune-activating portions of viruses.
Desrosiers took a live SIV--HIV's simian cousin--and genetically altered it so that gp120 would lose a few of its sugars. He made several variations of this live-virus vaccine, injected these into monkeys, then analyzed their antibodies. This simple strategy "dramatically increased the neutralizing antibodies," he says. Indeed, some of his altered viruses induced antibodies that were 100 times more potent than those induced by the natural, unaltered virus.
But those antibodies are active even against the completely sugared, wild-type virus. Desrosiers, one of the field's most energetic and influential researchers, says no vaccine he's tested has provoked such a vigorous antibody response. In short, just stripping off gp120's sugars seems to allow the immune system to create potent antibodies.
Of course, there are caveats. For one thing, most scientists consider a live-HIV vaccine too dangerous. So Desrosiers plans to test his approach in a much safer killed-virus vaccine. It should also be possible to synthesize just the sugarless gp120 protein, without the rest of the virus, and see if that stimulates the body's defenses.
But the biggest caveat is this: While Desrosiers has induced better antibodies than he's ever seen, "will they be good enough to protect against infection?" wonders Duke University's David Montefiori, a leading expert in the field. And even if they protect against one viral strain, will they protect against all the various strains that the highly mutable AIDS virus can produce? Montefiori cautions, "There's probably still a long way to go."
Undoubtedly. But Desrosiers has helped pioneer a huge territory for further study. And having the new, ultraprecise picture of gp120 can only help, because it will allow researchers to make sure that the core keeps its all-important shape as they remove various sugars. "Equally important" is how John Moore, a top vaccine researcher at New York's Aaron Diamond AIDS Research Center, describes the two studies. They "go hand-in-hand," agrees Mark Lewis, a vaccine researcher with the U.S. Army. But while it will take some time to translate gp120's picture into vaccines that can be tested, "Ron's study is more immediately applicable," says Margaret Johnston, scientific director of the International AIDS Vaccine Initiative. Noting that Desrosiers tested his vaccine in living animals, she says, "Someone could go in right away and make a gp120 [vaccine for humans] with certain sugars deleted."
So what's the toughest problem? Companies, afraid the road is too long for quick profit, have largely backed out of vaccine research. So, Johnston wonders, "Is anyone going to take this information and make it into a vaccine?"
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