August 25, 2006

Molecular switch may turn off immune cells that target HIV

A primary mystery of the AIDS epidemic — why the immune system does not control HIV infection — may have been solved by a team led by MGH researchers. They report how a molecular pathway involved in the immune cell "exhaustion" seen in some chronic viral infections plays a similar role in HIV infection and that blocking the pathway restores some function to HIV-specific T cells. The paper from researchers at the Partners AIDS Research Center (PARC) at MGH, the University of KwaZulu-Natal (UKZN) in South Africa and other institutions received early online publication in Nature.

"Back in 1987, we confirmed the existence of HIV-specific CD8 cells, which should destroy virus-infected cells," says Bruce Walker, MD, director of PARC and principal investigator of the Nature study. "But it didn't make sense that these cells were found in high numbers but were not doing their job. These new findings finally explain those early discoveries: the immune cells are there, but they have been turned off in persons with high viral loads."

Recent animal studies showed that a molecular pathway involving a receptor called PD-1 inhibits the immune system in viral infections not controlled by the immune system. To find whether a similar process takes place in HIV infection, the researchers studied immune cells from African HIV patients who had not yet received antiviral treatment. They found that HIV-specific CD8 cells from those patients did express high levels of PD-1 and the molecule's levels were associated with impaired CD8 cell function, higher viral levels and lower levels of CD4 T helper cells.

Experimentally blocking the PD-1 pathway appeared to improve the ability of CD8 cells to respond to HIV and increased the proliferation of CD4 cells. "Our finding that defects in exhausted T cells can be reversed demonstrates that active inhibitory mechanisms may play a major role in blocking T cell function. In other words, the cells may be turned off but not permanently disabled," explains Daniel Kaufmann, MD, of PARC-MGH, a co-first author of the Nature paper.

Co-first author Cheryl L. Day, PhD, of PARC-MGH and UKZN adds, "One of the next questions we need to answer is whether we can turn the immune system back on for HIV-infected patients in a way that will benefit them without incurring serious side effects." Other PARC-MGH co-authors are Elizabeth Mackey, Quentin Eichbaum, MD, PhD; Marcus Altfeld, MD, PhD; and Philip Goulder, MD, PhD.