Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

HIV accessory protein disables host immunity via receptor-protein intermediary

31.03.2006
Findings point to possible novel ways to fight AIDS, immune disorders, sepsis

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!
Further information:
http://www.uphs.upenn.edu

More articles from Life Sciences:

nachricht During HIV infection, antibody can block B cells from fighting pathogens
14.08.2018 | NIH/National Institute of Allergy and Infectious Diseases

nachricht First study on physical properties of giant cancer cells may inform new treatments
14.08.2018 | Brown University

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

Die letzten 5 Focus-News des innovations-reports im Überblick:

Im Focus: New interactive machine learning tool makes car designs more aerodynamic

Scientists develop first tool to use machine learning methods to compute flow around interactively designable 3D objects. Tool will be presented at this year’s prestigious SIGGRAPH conference.

When engineers or designers want to test the aerodynamic properties of the newly designed shape of a car, airplane, or other object, they would normally model...

Im Focus: Robots as 'pump attendants': TU Graz develops robot-controlled rapid charging system for e-vehicles

Researchers from TU Graz and their industry partners have unveiled a world first: the prototype of a robot-controlled, high-speed combined charging system (CCS) for electric vehicles that enables series charging of cars in various parking positions.

Global demand for electric vehicles is forecast to rise sharply: by 2025, the number of new vehicle registrations is expected to reach 25 million per year....

Im Focus: The “TRiC” to folding actin

Proteins must be folded correctly to fulfill their molecular functions in cells. Molecular assistants called chaperones help proteins exploit their inbuilt folding potential and reach the correct three-dimensional structure. Researchers at the Max Planck Institute of Biochemistry (MPIB) have demonstrated that actin, the most abundant protein in higher developed cells, does not have the inbuilt potential to fold and instead requires special assistance to fold into its active state. The chaperone TRiC uses a previously undescribed mechanism to perform actin folding. The study was recently published in the journal Cell.

Actin is the most abundant protein in highly developed cells and has diverse functions in processes like cell stabilization, cell division and muscle...

Im Focus: Lining up surprising behaviors of superconductor with one of the world's strongest magnets

Scientists have discovered that the electrical resistance of a copper-oxide compound depends on the magnetic field in a very unusual way -- a finding that could help direct the search for materials that can perfectly conduct electricity at room temperatur

What happens when really powerful magnets--capable of producing magnetic fields nearly two million times stronger than Earth's--are applied to materials that...

Im Focus: World record: Fastest 3-D tomographic images at BESSY II

The quality of materials often depends on the manufacturing process. In casting and welding, for example, the rate at which melts solidify and the resulting microstructure of the alloy is important. With metallic foams as well, it depends on exactly how the foaming process takes place. To understand these processes fully requires fast sensing capability. The fastest 3D tomographic images to date have now been achieved at the BESSY II X-ray source operated by the Helmholtz-Zentrum Berlin.

Dr. Francisco Garcia-Moreno and his team have designed a turntable that rotates ultra-stably about its axis at a constant rotational speed. This really depends...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

VideoLinks
Industry & Economy
Event News

Within reach of the Universe

08.08.2018 | Event News

A journey through the history of microscopy – new exhibition opens at the MDC

27.07.2018 | Event News

2018 Work Research Conference

25.07.2018 | Event News

 
Latest News

'Building up' stretchable electronics to be as multipurpose as your smartphone

14.08.2018 | Information Technology

During HIV infection, antibody can block B cells from fighting pathogens

14.08.2018 | Life Sciences

First study on physical properties of giant cancer cells may inform new treatments

14.08.2018 | Life Sciences

VideoLinks
Science & Research
Overview of more VideoLinks >>>