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

Diana Yates, Illinois News Bureau
3/4/2016 12:00 AM

U. of I. physics professor Klaus Schulten, right, postdoctoral researcher Juan Perilla and their colleagues used experimental data and computer simulations to determine how a human protein that aids HIV infection binds to the HIV capsid.


Photo by L. Brian Stauffer
U. of I. physics professor Klaus Schulten, right, postdoctoral researcher Juan Perilla and their colleagues used experimental data and computer simulations to determine how a human protein that aids HIV infection binds to the HIV capsid. Photo by L. Brian Stauffer
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.

"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, University of Pittsburgh professor Peijun Zhang and U. of P. 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.


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. 
Image courtesy of Juan Perilla, University of Illinois at Urbana-Champaign
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. Image courtesy of Juan Perilla, University of Illinois at Urbana-Champaign
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.

Recent News

  • Accolades
  • Alumni News

Congratulations to Physics Illinois alumnus M. George Craford on being presented today with the IEEE Edison Medal of the Institute of Electrical and Electronics Engineers. The medal is awarded annually in recognition of a career of meritorious achievement in electrical science, electrical engineering, or the electrical arts. The citation reads, “for a lifetime of pioneering contributions to the development and commercialization of visible LED materials and devices.”

 

Craford is best known for his invention of the first yellow light emitting diode (LED). During his career, he developed and commercialized the technologies yielding the highest-brightness yellow, amber, and red LEDs as well as world-class blue LEDs. He is a pioneer whose contributions to his field are lasting.

  • Research

While heritable genetic mutations can alter phenotypic traits and enable populations to adapt to their environment, adaptation is frequently limited by trade-offs: a mutation advantageous to one trait might be detrimental to another.

Because of the interplay between the selection pressures present in complex environments and the trade-offs constraining phenotypes, predicting evolutionary dynamics is difficult.

Researchers at the University of Illinois at Urbana-Champaign have shown how evolutionary dynamics proceed when selection acts on two traits governed by a trade-off. The results move the life sciences a step closer to understanding the full complexity of evolution at the cellular level.

  • Research
  • Condensed Matter Physics

Since the discovery two decades ago of the unconventional topological superconductor Sr2RuO4, scientists have extensively investigated its properties at temperatures below its 1 K critical temperature (Tc), at which a phase transition from a metal to a superconducting state occurs. Now experiments done at the University of Illinois at Urbana-Champaign in the Madhavan and Abbamonte laboratories, in collaboration with researchers at six institutions in the U.S., Canada, United Kingdom, and Japan, have shed new light on the electronic properties of this material at temperatures 4 K above Tc. The team’s findings may elucidate yet-unresolved questions about Sr2RuO4’s emergent properties in the superconducting state.

  • Research
  • AMO/Quantum Physics

Using an atomic quantum simulator, scientists at the University of Illinois at Urbana-Champaign have achieved the first-ever direct observation of chiral currents in the model topological insulator, the 2-D integer quantum Hall system.

Topological Insulators (TIs) are arguably the most promising class of materials discovered in recent years, with many potential applications theorized. That’s because TIs exhibit a special quality: the surface of the material conducts electricity, while the bulk acts as an insulator. Over the last decade, scientists have extensively probed the microscopic properties of TIs, to better understand the fundamental physics that govern their peculiar behavior.

Atomic quantum simulation has proven an important tool for probing the characteristics of TIs, because it allows researchers greater control and greater possibilities for exploring regimes not currently accessible in real materials. Finely tuned laser beams are used to trap ultracold rubidium atoms (about a billion times colder than room temperature) in a lattice structure that precisely simulates the structure of ideal materials.