Forum for Science, Industry and Business

Sponsored by:     3M 
Search our Site:

 

Study offers clearest picture yet of how HIV defeats a cellular defender

04.03.2016

A new study offers the first atomic-scale view of an interaction between the HIV capsid - the protein coat that shepherds HIV into the nucleus of human cells - and a host protein known as cyclophilin A. This interaction is key to HIV infection, researchers say. A paper describing the research appears in the journal Nature Communications.

Cyclophilin A is found in most tissues of the human body, where it plays a role in the inflammatory response, immunity and the folding and trafficking of other proteins. When it fails to work properly or is overproduced in cells, cyclophilin A also can contribute to diseases such as rheumatoid arthritis, asthma, cancer and cardiovascular disease. It also facilitates some viral infections, including HIV.


The naked HIV capsid, left, would be quickly detected and eliminated from the cell, but a host protein, cyclophilin A, in red in the image on the right, binds to the capsid and enables it to transit through the cell undetected.

Graphic by Juan Perilla

"We have known for some time that cyclophilin A plays a role in HIV infection," said University of Illinois physics professor Klaus Schulten, who led the new study with postdoctoral researcher Juan R. Perilla and University of Pittsburgh professor Peijun Zhang and postdoctoral researcher Chuang Liu.

The HIV capsid somehow tricks this cellular protein into providing cover for it as it transits through the cell and makes its way to the nucleus, Schulten said. Once there, the capsid interacts with a nuclear pore that offers an entrance to the cell's nucleus. The virus uses the pore as a channel to inject its genetic material into the nucleus and commandeer the cell.

Studies in cell culture have found that the virus rarely makes it to the nucleus without its cyclophilin disguise. Drugs that interfere with cyclophilin also reduce HIV infections in cell culture. Such drugs cannot be used in human HIV patients because they dampen the immune response.

In the new study, the researchers used a massive computer model of the HIV capsid, which they developed in a 2013 study. Building this model meant simulating the interactions of 64 million atoms, a feat that required the use of Blue Waters, a petascale supercomputer at the National Center for Supercomputing Applications at the U. of I.

For the new study, the team used Blue Waters as well as the Titan supercomputer at Oak Ridge National Laboratory to simulate the interactions between cyclophilin A and the HIV capsid. The 3-D structure of cyclophilin A was known from previous investigations.

"We knew every atom of the underlying capsid, and then we put the cyclophilin on top of that, of which we also knew every atom," Schulten said.

The simulations revealed that cyclophilin A binds to the capsid in two ways. First, there is the "classic" binding site, one revealed decades earlier in crystallography studies. But in some places, a single cyclophilin A protein also bound the capsid at a second site, forming a bridge between two hexamers. (The HIV capsid is made up of a lattice of protein hexamers and pentamers.) Cyclophilin's bridging behavior occurred only in highly curved regions of the capsid, the researchers found.

Further research with NMR spectroscopy, which can detect unique chemical interactions, corroborated the existence of a second binding site.

By varying the amount of cyclophilin A added to the HIV capsid in their simulations, the researchers also saw that cyclophilin did not completely coat the HIV capsid. At high concentrations, individual cyclophilin molecules attached to the capsid interfered with others, disrupting their ability to bind.

Laboratory experiments also showed that having too little or too much cyclophilin A interfered with the virus's ability to infect cells.

"What we think is happening is, where there is no cyclophilin the capsid is naked, so the cell can recognize it and trigger a process that destroys the virus," Perilla said. "But if the capsid is fully occupied by cyclophilin A, it prevents recognition by the nuclear pore complex. So there is an optimal amount of cyclophilin bound to the capsid such that it allows the HIV infection to go forward."

"The HIV capsid has to show some of its surface to the nuclear pore complex so that it docks there properly and can inject its genetic material into the nucleus," Schulten said. "Now, we understand a little bit better the HIV virus' strategy for evading cellular defenses. That gives insight into battling the system."

###

Schulten is an affiliate of the Beckman Institute for Advanced Science and Technology and leader of the Theoretical and Computational Biophysics Group at Illinois.

The National Institute of General Medical Sciences at the National Institutes of Health, the National Science Foundation, the Israeli Science Foundation and the U.S. Department of Energy supported this research.

Editor's notes:

To reach Klaus Schulten, call 217-244-1604; email schulten@illinois.edu.

To reach Juan Perilla, call 217-244-7403; email jperilla@illinois.edu.

The paper "Cyclophilin a stabilizes the HIV-1 capsid through a novel non-canonical binding site" is available from the U. of I. News Bureau.

Media Contact

Diana Yates
diya@illinois.edu
217-333-5802

 @NewsAtIllinois

http://www.illinois.edu 

Diana Yates | EurekAlert!

Further reports about: HIV HIV infection cyclophilin genetic material

More articles from Life Sciences:

nachricht Bolstering fat cells offers potential new leukemia treatment
17.10.2017 | McMaster University

nachricht Ocean atmosphere rife with microbes
17.10.2017 | King Abdullah University of Science & Technology (KAUST)

All articles from Life Sciences >>>

The most recent press releases about innovation >>>

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

Im Focus: Neutron star merger directly observed for the first time

University of Maryland researchers contribute to historic detection of gravitational waves and light created by event

On August 17, 2017, at 12:41:04 UTC, scientists made the first direct observation of a merger between two neutron stars--the dense, collapsed cores that remain...

Im Focus: Breaking: the first light from two neutron stars merging

Seven new papers describe the first-ever detection of light from a gravitational wave source. The event, caused by two neutron stars colliding and merging together, was dubbed GW170817 because it sent ripples through space-time that reached Earth on 2017 August 17. Around the world, hundreds of excited astronomers mobilized quickly and were able to observe the event using numerous telescopes, providing a wealth of new data.

Previous detections of gravitational waves have all involved the merger of two black holes, a feat that won the 2017 Nobel Prize in Physics earlier this month....

Im Focus: Smart sensors for efficient processes

Material defects in end products can quickly result in failures in many areas of industry, and have a massive impact on the safe use of their products. This is why, in the field of quality assurance, intelligent, nondestructive sensor systems play a key role. They allow testing components and parts in a rapid and cost-efficient manner without destroying the actual product or changing its surface. Experts from the Fraunhofer IZFP in Saarbrücken will be presenting two exhibits at the Blechexpo in Stuttgart from 7–10 November 2017 that allow fast, reliable, and automated characterization of materials and detection of defects (Hall 5, Booth 5306).

When quality testing uses time-consuming destructive test methods, it can result in enormous costs due to damaging or destroying the products. And given that...

Im Focus: Cold molecules on collision course

Using a new cooling technique MPQ scientists succeed at observing collisions in a dense beam of cold and slow dipolar molecules.

How do chemical reactions proceed at extremely low temperatures? The answer requires the investigation of molecular samples that are cold, dense, and slow at...

Im Focus: Shrinking the proton again!

Scientists from the Max Planck Institute of Quantum Optics, using high precision laser spectroscopy of atomic hydrogen, confirm the surprisingly small value of the proton radius determined from muonic hydrogen.

It was one of the breakthroughs of the year 2010: Laser spectroscopy of muonic hydrogen resulted in a value for the proton charge radius that was significantly...

All Focus news of the innovation-report >>>

Anzeige

Anzeige

Event News

ASEAN Member States discuss the future role of renewable energy

17.10.2017 | Event News

World Health Summit 2017: International experts set the course for the future of Global Health

10.10.2017 | Event News

Climate Engineering Conference 2017 Opens in Berlin

10.10.2017 | Event News

 
Latest News

Ocean atmosphere rife with microbes

17.10.2017 | Life Sciences

Neutrons observe vitamin B6-dependent enzyme activity useful for drug development

17.10.2017 | Life Sciences

NASA finds newly formed tropical storm lan over open waters

17.10.2017 | Earth Sciences

VideoLinks
B2B-VideoLinks
More VideoLinks >>>