Researchers are planning a Phase 2 clinical trial to determine if this drug or a similar drug can prevent HIV-infected people from developing AIDS and related conditions.
Scientists at the Gladstone Institutes identified the precise chain of molecular events in the human body that drives the death of most of the immune system’s CD4 T cells as an HIV infection leads to AIDS.
Two separate journal articles, published simultaneously in Nature and Science, detailed the research from the laboratory of Warner C Greene, who directs virology and immunology research at Gladstone, an independent biomedical-research nonprofit based in San Francisco.
His lab’s Science paper revealed how, during an HIV infection, a protein known as IFI16 senses fragments of HIV DNA in abortively infected immune cells.
This triggers the activation of the human enzyme caspase-1 and leads to pyroptosis, a fiery and highly inflammatory form of cell death.
As revealed in the Nature paper, this repetitive cycle of abortive infection, cell death, inflammation and recruitment of additional CD4 T cells to the infection “hot zone” ultimately destroys the immune system and causes AIDS.
The Nature paper further described laboratory tests in which an existing anti-inflammatory inhibits caspase-1, thereby preventing pyroptosis and breaking the cycle of cell death and inflammation.
“Gladstone has made two important discoveries, first by showing how the body’s own immune response to HIV causes CD4 T cell death via a pathway triggering inflammation, and secondly by identifying the host DNA sensor that detects the viral DNA and triggers this death response,” said Robert F Siliciano, a professor of medicine at Johns Hopkins University, and a Howard Hughes Medical Institute investigator.
Once the scientists discovered how CD4 T cells die they began to investigate how the body senses the fragments of HIV’s DNA in the first place, before alerting the enzyme caspase-1 to launch an immune response in the CD4 T cells.
They also identified that reducing the activity of a protein known as IFI16 inhibited pyroptosis.
“This identified IFI16 as the DNA sensor, which then sends signals to caspase-1 and triggers pyroptosis,” said Kathryn M Monroe, the Science paper’s other lead author, who completed the research while a postdoctoral fellow at Gladstone.