The immune tricks that keep HIV in check in long term non-progressors (LTNPs) -- people who carry the virus but don't get AIDS -- have been a mystery for decades. It turns out that T cells in LTNPs destroy the virus by punching holes in infected cells and injecting a strong dose of apoptotic proteins, according to a study to be published in the December 19th issue of Immunity.

"This study brings us closer to a potential vaccine or cure for AIDS," Guido Silvestri of the University of Pennsylvania School of Medicine, who was not involved in the study, told The Scientist in an email.

The researchers, led by Mark Connors at the National Institute of Allergy and Infectious Diseases, began with a finding their group reported back in 2002: LNTPs have 20 times more CD8+ T cells than progressors. To examine what that CD8+ cell surplus is doing in LTNPs, the researchers looked at genes upregulated by the cells. They found that CD8+ cells upregulate the production of two killer proteins -- perforin, which creates pores on the surface of cells, and granzyme B, a cytotoxin that initiates cell death -- at nearly twice the rate of progressors. These findings suggest that CD8+ cells destroy HIV-infected cells in LTNPs by lysing infected cell membranes and injecting a strong dose of killer proteins.

"Upregulation of perforin is necessary to kill HIV-infected cells," Connors told The Scientist. "The fact that progressors' cells don't is the problem with their cells. This is the only thing we've found that completely distinguishes non-progressors from progressors."

The team went on to treat cultured progressor CD8+ cells with a cocktail of mitogens, which activate signal transduction pathways. With the chemical boost, the cells started destroying infected HIV cells close to the rate of LTNPs. "I think that's an important proof of concept, showing that [immune] cells from progressors may be non-functional," Joel Blankson from the Johns Hopkins School of Medicine, who did not participate in the research, told The Scientist.

Although such mitogens could never be given to patients, Blankson added, "it shows that the cells' capacity to kill is there, but something inherently in the cell needs to be woken."

Connors said his team is already investigating what is inhibiting the killing pathway in progressor T cells. In addition, new vaccines could be developed to trigger the innate killing ability of these cells -- current vaccines have failed at priming the immune system through classical adaptive immunity since the surface proteins on the HIV virus are so mutable. "Studies like this one may lead to the development of new, immune based interventions, either preventative or therapeutic, that may harness the human immune system in ways that will result in complete control, or even eradication, of HIV," Silvestri wrote. "Of course we have a long way to go (I'd say 10-20 years at least), but this is a step in the right direction."



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