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Scientists Find Gene That Blocks HIV

Protein prevents monkeys from getting AIDS virus

WEDNESDAY, Feb. 25, 2004 (HealthDayNews) -- A gene that prevents Old World monkeys from getting HIV has been identified, and researchers have found that a protein the gene makes blocks the AIDS virus in human cells.

Experts say it's not known yet whether the discovery will have any clinical value in people, but it provides a potential new avenue for anti-HIV therapy.

The work appears in the Feb. 26 issue of Nature.

"It has been known for a number of years that HIV doesn't infect monkeys," says lead researcher Dr. Joseph Sodroski, a professor of pathology at Harvard Medical School and the Dana-Farber Cancer Institute in Boston.

The reason, he says, is that baboons, macaques and mangabeys from Africa and Asia carry a gene that makes a protein that blocks the virus after it enters the cell.

As HIV enters a cell, its RNA comes into contact with this protein, which prevents the virus from converting into DNA, a necessary step for the virus to replicate in the cell.

"We have identified that monkey blocking factor," Sodroski says. "It's a protein called TRIM5-alpha, which turns out to be a very potent and specific blocker of HIV."

This is the first time that the function of this gene has been understood, he adds.

Using this blocking protein, Sodroski's team showed it made human cells totally resistant to HIV. In addition, he says that when they removed TRIM5-alpha from monkey cells, HIV was able to infect them.

"So TRIM5-alpha is sufficient and necessary for blocking HIV," Sodroski says.

However, the researchers note that while the monkeys don't get HIV, they do get the monkey version of HIV, called simian immunodeficiency virus (SIV). This indicates that while TRIM5-alpha prevents HIV, it is less effective in fighting SIV.

Sodroski notes that humans also have a TRIM5-alpha gene and make TRIM5-alpha protein, which has some HIV-blocking activity, but it is not as potent in fighting HIV as monkey TRIM5-alpha.

"Finding that humans have a TRIM5-alpha gene gives us a foundation for thinking of ways to make it more potent, perhaps to stimulate our own defenses to HIV," Sodroski says.

Sodroski speculates it might be possible to use some form of gene therapy to introduce monkey TRIM5-alpha into HIV-infected patients to create HIV-resistant cells.

"The fact that the human and the monkey TRIM5-alpha proteins are 87 percent identical means that you are almost not even putting a foreign protein into humans," he says.

There may also be a way to use TRIM5-alpha to prevent HIV infection. "There might be ways of delivering the monkey protein or the monkey gene to targeted cells," Sodroski says. "There might also be ways to modify human TRIM5-alpha to become more potent against HIV."

The next step, Sodroski says, it to look at TRIM5-alpha in humans to see how it works and if its potency varies from person to person. He also would like to know if TRIM5-alpha protein blocks other types of viruses.

"We are far away from applications, but we are beginning to appreciate the potential of these kinds of genes," Sodroski says. This discovery will lay the foundation for a lot of creative thinking to find ways to manipulating this protein for prevention and treatment."

"This is a whole new vista for attempting to block new HIV infections or to control infections that have already occurred," Sodroski says. "As with all fundamental discoveries, this should be a source of optimism."

Dr. Stephen P. Goff, author of an accompanying article in the journal and a professor of biochemistry at Columbia University, says that "we don't know a lot about the TRIM family of genes and how TRIM5-alpha stops HIV infection." He adds there are probably a lot more similar genes waiting to be found.

In the long run, it would be good to develop a therapy that recreates this activity in humans, Goff says. Maybe someday doctors will create a drug that will block HIV in the same way monkey TRIM5-alpha does naturally, or a drug that will make human TRIM5-alpha do what the monkey one does, he adds.

In terms of gene therapy, Goff says that "there are a lot of potential active virus-resistant genes that could be used, if one knew how to do gene therapy really well."

"It is becoming more apparent that there are a lot of virus-resistant genes in animals, and it is going to be important to find out how they all work," he says.

More information

The National Institute of Allergy and Infectious Diseases has more information on HIV/AIDS, while the National Center for Biotechnology Information can tell you more about genes and disease.

SOURCES: Joseph Sodroski, M.D., professor, pathology, Harvard Medical School, Dana-Farber Cancer Institute, Boston; Stephen P. Goff, Ph.D., professor, biochemistry, Columbia University, New York City; Feb. 26, 2004, Nature
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