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Scientists may have found how HIV becomes AIDS

PHILADELPHIA — PHILADELPHIA -- One of the great mysteries about AIDS is how people can live for years with the human immunodeficiency virus and still feel healthy. Then, for unknown reasons, they begin getting sick and die.

What causes this devastating downturn?

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University of Pennsylvania scientists announced Monday that they may have discovered how the virus moves out of its "latent" stage to begin its aggressive and lethal attack on the body's immune system.

The culprit may be a protein, unique to people with acquired immune deficiency syndrome, that appears to tell infected cells when to make more virus.

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The finding could point the way to new treatment strategies that might allow infected people to hold the virus at bay indefinitely.

Although these people would still carry HIV, they might not get sick and die, scientists said.

The protein "gives us another avenue for developing therapies and drugs that might inhibit this virus," said David Weiner, an assistant professor of pathology and laboratory medicine who headed the study.

The study, published yesterday in the Proceedings of the National Academy of Sciences, focused on a protein assembled by an HIV gene known as "vpr," one of nine known genes in the AIDS virus.

The protein appears to be required for infected human cells to produce new, infectious viral particles that go on to infect other cells.

Shortly after it enters a person's body, HIV is taken up by the lymph system -- such as the lymph nodes, spleen and tonsils -- where it infects a large number of cells but does not cause symptoms of illness.

After five years or longer, this latent or silent infection ends. A large amount of virus bursts out of the lymph system and into a person's bloodstream, where it begins its progressive and deadly destruction of key white blood cells. It is at this point that infected people start to get sick.

In laboratory tests, Mr. Weiner's research team found that the amount of "Vpr" protein in the blood serum of infected people correlated with the stage of their disease.

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People in the early stages of infection had low levels of "Vpr." By contrast, people with fully developed AIDS had high levels of "Vpr."

In addition, the scientists found that by exposing cells to "Vpr" protein in the laboratory, they could turn latent infection into active infection. They had the same results with fresh blood samples taken from HIV-infected people.

In each case, "Vpr" proved to have a powerful effect on HIV-infected cells, causing them to begin reproducing new virus within 24 hours. At the same time, the scientists discovered they could block the production of new virus by exposing the cells to antibodies to "Vpr."

Mr. Weiner said the findings point to the "Vpr" protein as a possible new target for drug development.

He said new drugs might be designed to cripple the "Vpr" protein. Or, antibodies to the "Vpr" could be used to hold the virus in check. These could be made synthetically or by stimulating the body's immune system through a genetic vaccine.

Mr. Weiner said he is developing such a vaccine that would create antibodies to "Vpr" by injecting people with the "vpr" gene. The work -- part of a larger study of DNA vaccination -- is being conducted on small animals.

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Mr. Weiner said his findings suggest the existence of a "regulatory loop" involving "Vpr" and antibodies to "Vpr."

In the lymph system, where many cells are infected, "Vpr" antibody levels may not be high enough to block growth of the virus. But elsewhere in the body, where smaller numbers of cells are initially infected, there may be enough "Vpr" antibody to keep the virus in its latent stage, Mr. Weiner suggested.

He hypothesized that as HIV disease progresses, the balance shifts in favor of the "Vpr" protein, which eventually causes cells far away from the lymph system to begin reproducing virus.

Mr. Weiner said his research also pointed to another intriguing possibility -- that "Vpr" protein in the blood of people with HIV may cause such AIDS-related illnesses as dementia and the "wasting syndrome" in which AIDS patients lose weight and muscle mass.


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