Researchers have discovered an important clue to one of the fundamental mysteries of AIDS, the ability of the virus to persist in the body for years while under vigorous attack by the immune system.
An answer, say researchers at Oxford University in England, may be that the virus, by subtle mutation, actually defuses the immune system attack force that is meant to destroy virus-stricken cells.
Dr. Bruce Walker, director of AIDS research at Massachusetts General Hospital in Boston, said, "If you want to think of it with a war analogy, it's as though the soldiers are still on maneuvers, but they no longer have their weapons: When they encounter the enemy, they lose their weapons."
Ordinarily, the immune system's army of white blood cells, which includes killer T cells, can obliterate invading viruses. The T cells seek out and destroy cells that the viruses have infected. But in infections with the human immunodeficiency virus, or H.I.V., which causes AIDS, the killer cells are strangely impotent.
The Oxford researchers, Dr. Rodney Phillips, a reader in medicine and Dr. Andrew McMichael, a professor of immunology, isolated the AIDS virus from four patients. They found that the viruses had undergone a subtle mutation, or change in their genetic structure. When killer T cells approached cells infected with the mutated virus, not only did the T cells fail to kill the stricken cell, they seemed to lose their appetite for killing altogether, as if their hunter instinct had been distracted or lulled into abeyance. Now, the T cells were unable to kill even cells infected with the original, unmutated AIDS virus.
The investigators published their results in today's issue of the journal Science.
Dr. McMichael said in a telephone interview that he did not think that the newly discovered mechanism was the only way that H.I.V. evaded the immune system, but that it might be an important one. The mutations not only allow the altered strains to proliferate but also allow unaltered strains to grow with abandon. He cautioned, however, that as yet he had no way of knowing how often the virus resorted to this trickery in a real infection.
Others voiced the same reservation, but said they were nonetheless intrigued.
"This is just totally unexpected," said Dr. Dani Bolognesi, an AIDS vaccine researcher at Duke University. The discovery, Dr. Bolognesi said, means the fight against AIDS is "a whole new ball game."
Dr. Anthony Fauci, director of the National Institute of Allergy and Infectious Diseases, said the finding ran counter to the usual way a virus could evade the immune system.
"The classic way you think of a virus evading the immune system is merely by mutating, by having the immune system chase after it and never find it because the virus is constantly changing," he said.
But, Dr. Fauci added, this is more of an active role. "It's like the virus is turning around and coming back," he said, attacking the immune system rather than running from it.
Dr. Hugh McDevitt, an immunologist at Stanford University said, "they haven't proved that this is a mechanism of escape," from the immune system in a real infection. But, he added, "all the pieces are there."
The battle between H.I.V. and the immune system begins when the virus slips into a CD-4 cell, a type of white blood cell that preferentially infects. The CD-4 cell signals to killer T cells that it is infected by displaying snippets of H.I.V. proteins on its surface. This triggers the killer cells to spring into action, multiplying and seeking out infected CD-4 cells in order to pierce them open and destroy them.
In their study, Dr. Phillips and Dr. McMichael found viruses that had minor mutations that did not affect their ability to infect cells and proliferate. But they did have a profound effect on killer T cells.
The scientists were inspired to begin their study after research by others indicated that it might be possible to turn off killer T cells with particular protein fragments.
Until that work, Dr. McMichael said, researchers used to think that killer cells had an all or none response--either they would recognize and kill cells with particular protein fragments or they would ignore them. But the studies, by Dr. Paul Allen at Washington University and others, indicated that killer cells could have a sort of halfway response. they could recognize protein fragments but not kill the cells. And once they received that sort of signal, the killer cells became at least temporarily inactivated.
Dr. Bolognesi said that the Oxford discovery had "enormous implications" for vaccine research.
In testing potential AIDS vaccines, he said, researchers look to see if the vaccine has elicited the production of killer cells that can destroy H.I.V.-infected CD-4 cells in laboratory experiments. Now, he said, it becomes unclear whether such a laboratory result means that the killer cells will destroy infected cells in a patient whose viruses may be mutating to inactivate the killer cells.
But Dr. Fauci was more optimistic. "If you prevent infection with a vaccine, the virus isn't going to be able to do these little tricks," he said.
Dr. Fauci added that, to him, the discovery was more important for understanding how the AIDS virus infection becomes chronic.
Dr. McDevitt agreed. It is still a puzzle, he noted, to explain how the virus can elicit a strong immune response yet remain unscathed.
"This could be one mechanism," he said
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