The chain of molecular events that drives the death of most of the immune system's CD4 T cells as an HIV infection leads to AIDS has been identified by researchers.
Further, scientists at the Gladstone Institutes have identified an existing anti-inflammatory drug that in laboratory tests blocks the death of these cells- and now 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.
The two separate articles published in two journals detail the research from the laboratory of Warner C. Greene, MD, PhD, who directs virology and immunology research at Gladstone, an independent biomedical-research nonprofit.
His lab's Science paper reveals 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.
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 paper further describes 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," Robert F. Siliciano, MD, PhD, a professor of medicine at Johns Hopkins University, and a Howard Hughes Medical Institute investigator, said.
"This one-two punch of discoveries underscores the critical value of basic science-by uncovering the major cause of CD4 T cell depletion in AIDS, Dr. Greene's lab has been able to identify a potential new therapy for blocking the disease's progression and improving on current antiretroviral medications," Siliciano added.
The study was simultaneously published in two separate journals, Nature and Science.