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Study Describes how HIV Beats Body's DefensesVirus moves in as T-cells drop protein shieldsSabin Russell, The San Francisco Chronicle, April 14, 2005 |
Volume 4 Issue 41April 2005 |
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Scientists in San Francisco have apparently cracked a 20-year-old mystery surrounding the complex relationship between the AIDS virus and the immune system. In a paper released Wednesday in the online edition of the British journal Nature, UCSF researchers at the Gladstone Institute of Virology and Immunology have explained how certain blood cells are able to fend off the AIDS virus naturally but then drop their defensive shields at a crucial moment -- letting the virus in. Their findings open up exciting new possibilities for drug development. |
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Since the earliest days of the AIDS epidemic, scientists have known that infection-fighting white blood cells known as T-cells play a central role in the course of the disease. HIV, the virus that causes AIDS, seems to feast on these foot soldiers of the immune system, and when the number of T-cells circulating in the blood falls below a certain threshold (a T-cell count of 200 or less), the body is prone to a wide variety of lethal infections. For more than two decades, AIDS researchers have been puzzled by a paradox: The AIDS virus is devastating to T-cells, but most of the time, it cannot infect them. Roughly 95 percent of T-cells that circulate in the blood are in what is called a "resting state." As long as these immune cells are quiet, the AIDS virus leaves them alone. It is only when they become activated -- rapidly multiplying to kill invading microorganisms -- that HIV slips in. The virus infects the activated T-cells, hijacking their genetic machinery to make copies of itself, and eventually kills them. One of the first hurdles facing AIDS researchers in the early understanding of the disease was that they could not grow the virus in a dish of T-cells until they learned to put in chemicals that activated those cells. The latest research, conducted by Dr. Warner Greene and colleagues at the Gladstone institute, provides a plausible reason why HIV can only infect T- cells when they are active. Greene said most scientists had assumed that resting T-cells were missing some crucial element that HIV needed to get inside them. Instead, his laboratory discovered that resting T-cells have a powerful anti-viral defense wired into their genes. "Resting T-cells deploy an anti-viral shield that is amazingly effective against HIV,'' Greene explained in an interview. "Unfortunately, the shield 'goes down' when the T-cell is activated.'' Once the mechanics of this "shields up-shields down" response are fully understood, researchers may be able to design drugs to keep the natural defenses deployed, or turn on similar shields in other cells vulnerable to HIV. The shield is a naturally occurring protein known as APOBEC3G. A team of scientists led by Michael Malim at the University of Pennsylvania first reported the existence of the protein in a landmark paper in July 2002. It set off a rush of research into APOBEC, an enzyme that may have evolved eons ago in mammals as a defense against viruses. Unfortunately, HIV uniquely has a protein that appears to neutralize APOBEC, and much of the research since Malim's discovery has focused on how this molecular countermeasure -- called VIF -- might disarm a cell's defenses by destroying APOBEC. Greene's team has taken a different tack and discovered surprisingly that APOBEC exists in two forms: a lightweight version found in resting T-cells, and a heavyweight version found in activated cells. The lightweight APOBEC is lethal to HIV, while the heavyweight version is readily destroyed by VIF. In fact, Greene's researchers found that when T- cells become active, the free-floating lightweight proteins are scooped up into the heavyweight "complexes," like anti-aircraft missiles returned to their bunkers. In the imagery of Star Trek, the "shields are down.'' HIV then destroys them in their bunkers. The key experiment in Greene's study, conducted by lead author Ya-Lin Chiu, was the use of a specially designed "gene-silencer" that knocked out the lightweight version of APOBEC in resting T-cells. Without that enzyme, the resting T-cells were infected just as easily by HIV as activated T-cells. Just why T-cells would abandon such an effective natural defense against HIV when they become active is a new, unanswered and vitally important question. It is possible, Greene said, that cells deactivate lightweight APOBEC when they are about to divide, because the same chemical that kills viruses might damage the cell's own genes during the cell-division process. That raises the specter that any possible treatment to keep the anti-viral shield up could cause cancer in the cells it is trying to protect. Nevertheless, in the rarified air of HIV molecular biology, Greene's findings are generating excitement. "I think Warner's paper is very interesting and provocative,'' Malim said in an e-mail from Kings College Medical School in London, where he now works. "It is a beautifully executed study and raises all sorts of critical questions about the wider functions of APOBEC proteins.'' Greene said his laboratory is already conducting automated screens to spot chemical compounds that might block the "shields down" order, or otherwise mimic the antiviral properties of lightweight APOBEC. Dr. Roger Pomerantz, director of infectious diseases at Thomas Jefferson University in Philadelphia, said the research is further evidence that "there are things in the body that inhibit HIV.'' Because AIDS has proved such a devastating and intractable disease, there has been a tendency to see HIV as a totally new pathogen that humankind has no defense against, Pomerantz said. "But it did not parachute in from Mars," he said. "It's no different from many other diseases.'' The study of the body's natural defenses against retroviruses and other AIDS-like pathogens is opening up a valuable vein of new research, Pomerantz said: "This is a very hot area.'' ©2005 San Francisco Chronicle |
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