Researchers at the University of Pennsylvania School of Medicine discovered that an HIV-1 accessory protein called Vpr destroys the host cell’s ability to survive by binding to a host receptor. This, in turn, keeps an important enzyme from activating the cell’s immune system. These findings refine an earlier understanding of Vpr HIV pathogenesis and imply new approaches to treating AIDS, inflammatory diseases such as rheumatoid arthritis, and possibly sepsis. This research appears in the February print issue of Nature Cell Biology.
Over a decade ago, Penn’s David Weiner, PhD, Associate Professor of Pathology and Laboratory Medicine, and colleagues reported that Vpr corrupted the glucocorticoid receptor (GR) pathway of the host cell. Vpr helps to usurp host-cell function by regulating cell differentiation, cell death, and suppressing host-cell immune response proteins. Weiner’s group found that Vpr binds to the glucocorticoid receptor, but it remained unclear whether the GR pathway was required for Vpr to commandeer the host cell’s machinery.
"We started to realize a few years ago that no one had asked the real question: Is the glucocorticoid receptor necessary for Vpr’s effects on the host cell?" recalls Weiner. To answer this question, the researchers used an siRNA, a short sequence of RNA used to silence gene expression, to completely destroy expression of the glucocorticoid receptor protein.
When the researchers kept the glucocorticoid receptor protein from being made, Vpr did not kill host cells. "This indicated that glucocorticoid receptor function is not what’s really necessary for Vpr activity," says Weiner. "The glucocorticoid receptor-Vpr complex must be interacting with something else."
The team, led by first author Muthumani Karuppiah, PhD, Senior Research Investigator, looked for molecules with which the glucocorticoid receptor-Vpr complex would bind and identified PARP-1, another protein that controls the action of NF-kB, a major immune regulator in the host cell. To verify their idea, the researchers used a mouse model in which PARP-1 was knocked out and found that their cells were immune to sepsis (pathogens and their toxins in the blood), because the NF-kB molecules did not go into overdrive, kicking up inflammatory molecules called cytokines. This data demonstrate that Vpr attacks PARP-1 activity, so the mice are immune to toxins created by pathogens – one indication that their immune surveillance has been compromised.
Using biochemistry tests, the researchers were able to show that Vpr does interact with PARP-1 through the glucocorticoid receptor. Vpr hitches a ride on the glucocorticoid receptor, driving glucocorticoid to bind to PARP-1– which, in turn, inactivates it. "Ultimately, glucocorticoid is really an intermediary between Vpr and PARP-1," explains Weiner.
Weiner cites several potential clinical implications of this basic research. These findings show an immune function that had not been previously attributed to the glucocorticoid receptor. "With additional study this research may provide approaches for designing new drugs to fight AIDS, as well as for inflammatory disorders," suggests Weiner. "This research also gives us a new way to think about the relationship between immune activation and sepsis, and it may have implications ultimately for our understanding of novel approaches to prevent sepsis."
Karen Kreeger | EurekAlert!
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