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As AIDS spreads worldwide, research suggests a new approach to combating the HIV virus

Last Friday the UN held World AIDS Day, but there was little to celebrate. The worldwide death toll since the AIDS outbreak began in 1981 has now reached 21.8 million. Three million people died of AIDS this year alone, and a staggering 36.1 million others are infected with the HIV virus. Most will also die of AIDS.

We are a long way from home free in this country. An estimated 850,000 Americans are infected with HIV. For the last three years new AIDS cases have held steady at 40,000 per year, and annual AIDS deaths at 12,000.

As AIDS spreads worldwide, researchers continue to seek a cure. Work has proceeded along two fronts:

Preventing infection. Initial efforts focused on developing a vaccine directed against the HIV virus. However, conventional vaccines have not proven successful -- HIV alters its genes so often that vaccines directed against one HIV strain don't work against others.

Treating the infected. Recently-developed combinations of rather expensive drugs have been successful in halting the progress of HIV infections, as long as patients keep taking the drugs, but do not eliminate the virus. The drug regime is difficult to follow, and has unpleasant side effects, but must be continued to keep the virus in check.

Not very encouraging. However, in their search for an AIDS cure researchers are learning a great deal about the HIV virus. Now some of this new knowledge seems to be paying off. Two weeks ago, research was reported in the Proceeding of the National Academy of Sciences that suggests a possible new approach to treating AIDS.

Three different laboratories have been independently studying how the HIV virus exits from cells it has infected. They may have uncovered a key vulnerability that can be exploited to prevent the virus from spreading.

Researchers studying HIV had already gained a pretty good idea of how the virus multiplies within infected cells. First, HIV directs the cell to manufacture HIV genes and proteins, which are then assembled into thousands of new virus particles.

One of the virus proteins, called Gag, plays a key role in allowing the new virus to get out of the cell so it can go about infecting other cells. Gag covers the surface of the virus like a coat. This coat interacts with the cell's membrane, setting in motion a chain of events that ejects the virus particle from the cell.

First, there is a bulging out of the membrane, like a thumb pushing out from a balloon. Then the base of the protrusion pinches inward, producing a lollipop-shaped structure containing the virus. Finally, the membrane-encased virus pinches off and is released to infect other cells, protected from our immune system by its human membrane coat.

A tantalizing clue led these researchers to focus on the pinching-off process. Sometimes the membrane sac that is pinched off contains something unexpected -- not only the HIV virus, but also a protein from the infected cell. This protein, called ubiquitin ("you-bee-quit-in"), shouldn't be there. It has nothing to do with being a virus.

Or does it? One of the roles of ubiquitin in cells is to trigger endocytosis, a kind of budding into the cell. Seen in this light, the occasional presence of ubiquitin in HIV particles seems like an enormous hint: do HIV viruses use ubiquitin to bring about their budding from the cell?

Looking carefully, the researchers found that sometimes ubiquitin is physically attached to the HIV, tied to Gag like an anchor. This is what you would expect if ubiquitin was being used by HIV as a tool to trigger budding.

This suggests a simple experiment: remove ubiquitin from the cell, and see if this stops HIV budding.

Researchers used a clever trick to get rid of ubiquitinin within cells. They treated HIV-infected cells with chemical inhibitors that blocked cell protein recycling. One of the other jobs ubiquitin has in the cell is to attach to damaged proteins, labelling them for recycling. By stopping this recycling from happening, the researchers locked up all the cell's ubiquitin. Stuck onto damaged proteins, the ubiquitin molecules were not free to bind Gag.

What happened when ubiquitin levels were reduced in this way? HIV budding was inhibited three fold!

The hint was right on. Ubiquitin must attach to Gag for budding to occur. This attachment is carried out by a special enzyme, called ubiquitin ligase. After attachment is complete, the ubiquitin-virus complex attaches to the membrane and triggers budding.

This suggests an exciting possibility. If we can find a drug that inhibits ubiquitin ligase, it may prove to be a potent AIDS defense. By stopping HIV budding, such a drug might well prevent the virus from spreading from one cell to the next, forcing the infection to a halt.

We don't have the required inhibitor drug yet, and we don't know what side effects it might have. But AIDS gives us so few targets of opportunity that the discovery of a new avenue of attack, however unproven, is exciting. There's no telling if this will work out. I'm crossing my fingers.

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