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New Piece of the Inflammation Puzzle Uncovered; Discovery Describes How Immune Cells Die During HIV Infection

December 19, 2013

HIV Infection Triggers Pyroptosis of Lymphoid CD4 T Cells

Two separate articles published simultaneously today in Science and Nature magazines further describe our understanding of how and why a large number of CD4 cells die during HIV infection. The results from this research -- conducted by Dr. Warner Greene and other scientists at Gladstone Institutes/UCSF -- show that a chain of events through a certain pathway at the molecular level is responsible for the death of a large number of CD4 cells and progression to AIDS.

The discovery comes in two parts. The first identified a human protein called IFI16 (interferon gamma inducible protein 16) that can sense HIV genetic material found in those immune cells that are "partly" infected but don't produce more HIV. This research is covered in the article in Science magazine.

The second part showed how this sensing can trigger another human protein, caspase-1, to lure more CD4 cells to lymph tissues. This eventually will cause a process they call pyroptosis, or a highly inflammatory form of cell death. This part is covered in the article in Nature magazine.

Gladstone's ex vivo research was done by taking lymph tissue (tonsil and spleen) from HIV-positive people not on treatment and conducting a range of experiments in the lab. These results build upon previous research from 2010 of how HIV tries to productively infect immune cells but fails to do so. For example, a CD4 cell has some HIV DNA in it but doesn't produce more HIV. In an effort to protect the rest of the immune system, these "partly" infected cells go on to rupture and die, sending inflammatory signals that attract more cells. This then continues a cycle of cell death, leading to HIV disease progression.

The research team goes on to state that they've also identified an anti-inflammatory medication that interrupts the process of this heightened cell death. The drug helps prevent caspase-1 from alerting more CD4 cells to accumulate, thereby preventing pryoptosis. The drug was identified as the compound, VX-765.

"This is an exciting finding in HIV basic science from an early Phase I study," remarked Alan McCord, director of education. "However, this is not the place to start experimenting with taking anti-inflammatories in hopes that it will stop the progression of HIV disease or even that an aspirin a day is a replacement for taking HIV medications. We need to wait and see what the results from the Phase II study are before knowing what all of this means for people living with HIV."

For more information from the Gladstone Institutes, click here and here.

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