How HIV Disables a Smart Bomb?

BETHESDA, MARYLAND--Nobel laureate David Baltimore has challenged a basic tenet of AIDS research: that a type of immune cell is routinely able to seek out and destroy HIV-infected cells. Speaking here yesterday at the Ninth Annual Conference on Advances in AIDS Vaccine Development, Baltimore, a virologist at the Massachusetts Institute of Technology (MIT) and head of a National Institutes of Health AIDS-vaccine advisory panel, proposed that HIV actually disarms the immune cells, white blood cells called cytotoxic T lymphocytes (CTLs). The findings may shed light on why some experimental vaccines work in monkeys.

A critical problem in AIDS-vaccine work is determining which immune responses a vaccine must stimulate. Many researchers have focused on antibodies, which glom onto viruses in the bloodstream and prevent them from mounting a successful infection. Much attention also has been given to CTLs that can, like smart bombs, target and destroy cells that HIV already has infected. But Baltimore's lab has now cast doubt on whether CTLs can do the job on their own.

Baltimore and Kathleen Collins at MIT, along with CTL guru Bruce Walker of Massachusetts General Hospital, began with two deceptively simple questions: Can CTLs actually kill HIV-infected cells? Or do the target cells, like those infected with cytomegalovirus and some other pathogens, produce a factor that protects them from CTLs? To answer these questions, the researchers devised an assay to probe whether HIV interferes with CTL production. For the immune system to manufacture CTLs against specific pathogens, an infected cell must hold pieces of the pathogen on its surface, broadcasting what the enemy looks like. Baltimore's team found, however, that an HIV protein called nef prevents infected cells from displaying HIV fragments to the CTL-making part of the immune system, essentially blindfolding it.

"It looks very interesting," says Anthony Fauci, head of the National Institute of Allergy and Infectious Diseases, the meeting's sponsor. "We need to take it a little further and see how far you can push this." Baltimore stresses that it's impossible to extrapolate from the test-tube findings to people. But he says the study may help explain why monkeys and humans infected with HIV strains that lack the nef gene appear to be unharmed by the virus: Maybe the infected cells stimulate the production of anti-HIV CTLs, which throttle an infection from the beginning.

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