Unmasking HIV's "Master Manipulator"


It's made up of just a few genes wrapped in a protein-sugar coat. But the virus that causes AIDS has proved to be diabolically clever. Not only has it managed to stay a step ahead of the best drugs scientists can devise but it also has evolved to thwart one of nature's most remarkable and complex accomplishments, the human immune system. While most invading microbes quickly succumb to the mighty assault of antibodies and killer cells unleashed by the immune system, HIV just seems to shrug it all off.

Slowly, however, researchers are figuring out how HIV performs this extraordinary feat. And the results are pointing the way toward new ways of attacking this deadly scourge.

"DOOMED PATHWAY." In laboratories at the University of Geneva in Switzerland, a team led by Didier Trono has been studying one particular HIV gene, dubbed "nef." After HIV infects a cell, nef is the first gene turned on, producing the nef protein. This protein, in turn, plays a major role in protecting the virus from the onslaught of the immune system. Nef "is a master manipulator of the cell," explains Trono. Once it appears, "it sends the cell down a doomed pathway."

Trono has uncovered the detailed biochemical mechanism by which the nef protein accomplishes two major tasks. First, it hides the infected cell from the immune system's sentinels and soldiers, enabling the virus to make a huge number of copies of itself undisturbed. And once the new viruses have been made, nef clears the way for them to escape from the cell.

To understand how all this works, consider a bit of basic immunology. When a microbe infects a cell, the cell calls for help. It does this by taking pieces of the invader and displaying them on the cell's surface. In essence, it's waving a flag that says to the immune system: Help! I've been infected. Come destroy me!

In order to display this signal on its surface, the cell uses a molecule called MHC-1. Think of MCH-1 as the flagpole on the cell surface. The cell runs bits of the microbial attacker up the flagpole to signal that it has been conquered.

"WINDOW OF OPPORTUNITY." But HIV has evolved a way to block this signal. The MCH-1 flagpole actually has a little tail that sticks into the cell itself. Like a saboteur, nef attaches to this tail. And in a bit of molecular trickery, it mimics a natural cell protein that tells the cell to take down the flagpole. In response, the cell membrane reaches up on each side of the MCH-1 molecule, pulling it inside the cell. Suddenly, the cell no longer is able to call for help from the immune system. Explains Trono: "Nef gives the virus the window of opportunity" it needs to evade the immune system long enough to start churning out copies of itself.

But to break out of the cell, HIV employs another devilish trick. Protruding from the surface of the blood cells HIV likes to infect are additional molecules called CD4. Imagine them as fence posts all over the cell. Only these posts have the ability to bind to things floating around in the blood.

Unfortunately for AIDS patients, one of the things CD4 binds to very well is the AIDS virus. Indeed, HIV has evolved a region of its protein envelope that unerringly homes in on and attaches to CD4. That's the first step in the infection process.

SPREADING INFECTION. Once HIV invades and copies itself over and over, the new viruses inside the cell have a problem. They need to break out of the cell to spread the infection to other cells. But if they did, they wouldn't get far. Instead, they'd be attracted to all the CD4 "posts" on the cell's surface -- and get stuck there. "The viral particles will get glued to the cells," says Trono.

So, after it gets into a cell, the virus' nef leaps into action. Like the MHC-1 flagpoles, the CD4 posts also have a little tail poking into the cell. Nef attaches to that as well, triggering a process in which the cell engulfs and destroys its own CD4 molecules. Hence, the virus runs free outside the cell.

The elegant work by Trono and his colleagues helps explain one of the original mysteries of the AIDS epidemic. Early on, doctors discovered that some people who were infected with HIV were able to control it without any help from drugs. These people, it turned out, had been infected with a strain of the virus with a defective or missing nef gene. With the new knowledge, it's clear that without nef, the immune system is capable of beating back the invader.

"OUT OF THE CLOSET." The new study also suggests that drugs designed to block nef could be potent weapons against HIV. Preventing nef from taking down the MHC-1 distress signal, for instance, "would force the virus to come out of the closet and be recognized by the immune system," explains Trono. And keeping HIV from destroying the CD4 molecules could leave the new viruses helplessly glued to the cells' surfaces.

Trono cautions that developing such drugs may be difficult. But at the very least, the new scientific knowledge offers hope of opening up a new front in the war on this crafty foe. By John Carey at the AIDS conference in Chicago


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