Sept. 5, 2006
Molecular switch may turn off
HIV-targeting immune cells
One of the primary mysteries of the AIDS epidemic—why the immune system is unable to control HIV infection—may have been solved by an international research collaborative.
In an upcoming issue of Nature
, researchers from Emory and other institutions report how a molecular pathway involved in the immune cell “exhaustion” that characterizes several other chronic viral infections plays a similar role in HIV infection. They also found that blocking the pathway restores some function to HIV-specific CD8 and CD4 T cells.
Recent studies by Rafi Ahmed, director of the Emory Vaccine Center at Yerkes National Primate Center and a Georgia Research Alliance Eminent Scholar, and Gordon Freeman of Dana Farber Cancer Institute, have shown that a molecular pathway involving a receptor called Programmed Death-1 (PD-1) inhibits the immune system in chronic viral infection—those in which the immune system does not completely clear the virus.
CD8 cells initially respond to viral infection by dramatically reproducing and producing cytokines that help destroy the virus, but in chronic infection high levels of virus appear to overwhelm and exhaust CD8 cells. Ahmed’s studies indicated that PD-1 is over-expressed on these exhausted CD8 cells and may act as a molecular switch to turn off their activity.
In the current study, designed to find whether a similar process takes place in HIV infection, the U.S.-based researchers, led by Bruce Walker at Massachusetts General Hospital, worked closely with collaborators at the University of KwaZulu-Natal in Durban, South Africa, an area where more than 30 percent of the population is HIV infected.
The researchers first examined HIV-specific CD8 cells from 71 infected individuals who had not yet begun antiviral therapy and found that PD-1 expression was indeed higher on HIV-specific cells than on cells targeted against better controlled viruses or on CD8 cells from uninfected individuals. HIV-specific cells with high PD-1 expression also were less able to divide and expand in response to HIV proteins.
To examine whether antiviral therapy might change the expression of PD-1, the researchers examined blood samples taken from four HIV-positive participants before and after they began therapy. Along with the expected drop in viral load in response to treatment, there was also a significant decrease in PD-1 expression on HIV-specific CD8 cells, suggesting that elevated receptor expression may be a response to the high viral loads of untreated individuals.
Using antibodies to block PD-1 in blood cells from infected individuals significantly increased the ability of HIV-specific CD8 cells to proliferate in response to viral antigens and also increased the cells’ production of cytokine, indicating improved function. Blocking PD-1 also increased the proliferation of HIV-specific CD4 cells.
“We are pleased that our collaborative research has helped lead to an increased understanding of the HIV virus and how it eludes the immune system,” Ahmed said. “Blocking this critical pathway may provide a preventive therapy for HIV-infected people.”