The blow-by-blow cellular story of those rare people whose immune systems control AIDS on their own has been unknown to scientists — until now.

Researchers have uncovered the mechanisms used by a type of white blood cell to destroy HIV-infected cells. If a vaccine could program cells to do this, it could protect people from AIDS.

"The cells are massively loaded with killer molecules. They were able, in our assay, to kill almost all the HIV-infected cells," said Mark Connors, an AIDS specialist at the National Institute of Allergy and Infectious Disease. "The killing was very efficient and very rapid."

It's still too soon to extrapolate from the observations to a fully effective vaccine against AIDS — something that scientists have pursued for years, only to be repeatedly disappointed.

But despite the failures of vaccines and other treatments, glimmers of hope are seen in what are known as long-term non-progressors: people whose immune systems naturally and inexplicably control a virus that causes two million deaths every year. Approximately one person in 5,000 possesses this protection, and researchers have identified many genes and proteins that appear to play a role in this defense.

The latest findings, published today in Immunity, suggest a specific approach for a vaccine.

"It tells us what we want to build," said James Riley, a University of Pennsylvania AIDS researcher who was not involved in the study.

Connors' team studied CD8+, or cytotoxic, T cells — the immune system's first responders, responsible for destroying virus-infected cells before the virus can replicate and spread.

Once cytotoxic cells taken from long-term non-progressors were primed by an initial exposure to HIV, they loaded themselves with grains containing two weapons: proteins that can dissolve cell walls, and toxic molecules called granzyme B.

When armed, the cells attacked HIV-infected cells by drilling holes in their walls and pumping them full of granzyme B. Connors compared the cells to a gun loaded with bullets.

In contrast, cytotoxic cells taken from people with typical

HIV vulnerability "didn't load with enough bullets to be capable killers."

In addition to vaccines, Riley said the mechanism could also inspire cell-based therapies. "We don't know, from a vaccine point of view, how to induce these types of cells," he said.

Connors next hopes to identify the mechanisms that instruct cytotoxic cells to take up arms.

"There's something that's going on in these people," said Connors, "and we're amassing the tools to try and take that apart."

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Lytic Granule Loading of CD8+ T Cells Is Required for HIV-Infected Cell

Elimination Associated with Immune Control [Immunity] (not yet online)*

*Image: A cytotoxic cell attacks a tumor cell / National Institute for Medical Research

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