How HIV "Exhausts" Killer T Cells

American and South African scientists working at the epicenter of the AIDS epidemic in South Africa have discovered how the human immunodeficiency virus (HIV) "exhausts" killer T cells that would otherwise attack the virus. The researchers found that HIV can simply "turn off" fully functional T cells by flipping a molecular switch on the cells. In test tube studies, however, the scientists showed that they could reinvigorate the killer T cells by blocking that inhibitory switch, which is called programmed death-1 (PD-1).

The study's senior author, Bruce Walker, a Howard Hughes Medical Institute researcher at Massachusetts General Hospital, said that clinical testing of drugs that block the PD-1 switch could begin very soon, since such drugs exist already. However, he cautioned that these kinds of drugs could cause serious side effects, including autoimmune reactions that trigger the immune system to attack the body. Walker added that the researchers' findings will also likely have application in understanding other chronic viral diseases.

The findings by Walker and his colleagues were published in an advance online publication on August 20, 2006, by the journal Nature. Walker is also at the Partners AIDS Research Center and Harvard Medical School.

Other co-authors were from the University of KwaZulu Natal in South Africa, Oxford University, Dana-Farber Cancer Institute of Harvard Medical School, Emory University School of Medicine, and The Wistar Institute.

"It's long been known that people with HIV infection have a lot of HIV-specific immune cells that one would think would be actively combating the virus," said Walker. "But a major puzzle has been that even in late-stage illness, when one can still measure great numbers of these immune cells, they don't seem to be controlling the virus at all."

An important clue to why killer T cells stop functioning after infection came from earlier studies in mice, which were published by co-author Rafi Ahmed of Emory. Ahmed found that chronic viral infection actively inhibits T cells by switching on the cells' inhibitory PD-1 pathway. He also found that blocking the PD-1 pathway in the mice restored T cell function and reduced the amount of virus in the animals' blood, which is known as viral load. Ahmed's studies showed that blocking PD-1 rejuvenated killer T cells, which directly attack viruses, but did not investigate helper T cells, which mobilize the immune system against infection.

Ahmed's findings prompted Walker and his colleagues to explore the role of the PD-1 pathway in a large population of HIV-infected patients in the KwaZulu-Natal province of South Africa. The province is at the epicenter of the HIV epidemic in sub-Saharan Africa; a third of pregnant women there are infected with HIV. The researchers conducted much of their work at the Doris Duke Medical Research Institute in Durban. Durban is the largest city in KwaZulu-Natal, and HIV prevalence among pregnant women in the city exceeds 50 percent.