(Philadelphia, PA) - 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
“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 Karuppiah Muthumani, 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,”
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.”
Study co-authors are Andrew Y. Choo (now at Harvard Medical School),
Wei-Xing Zong (now at the State University New York, Stony Brook),
Muniswamy Madesh, Daniel S. Hwang , Khanh P. Thieu, Joann Emmanuel,
Sanjeev Kumar, and Craig Thompson, all from Penn, as well as Arumugam
Prmkumar from Memorial Sloan-Kettering Cancer Center, New York.
The research was funded by the National Institutes of Health.
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