Researchers Gain Better Understanding How HIV Evades Defenses

For the first time, an atomic-scale view has shown how an HIV capsid is able to travel throughout the body undetected with the help of a cellular protein.

Cyclophilin A is found in most tissues and plays a role in the inflammatory response, immunity, and the folding and trafficking of other proteins.

It is also known to help facilitate asthma, rheumatoid arthritis, cardiovascular disease, HIV, and cancer when overproduced in cells or working incorrectly.

The HIV capsid uses cyclophilin A as protection to move through the cell and reach the nucleus. In prior studies using cell cultures, it was discovered that the virus is rarely able to make it to the nucleus without the protection of the cyclophilin.

Although there are drugs that can interfere with cyclophilin to help reduce HIV infections within the cell culture, these treatments cannot be used on HIV patients because it weakens the immune response.

During a study conducted by researchers at the University of Illinois and published in Nature Communications, a computer model of the HIV capsid was used.

The Blue Waters petascale supercomputer at the National Center for Supercomputing Applications and the Titan supercomputer at Oak Ridge National Laboratory were used to simulate the interactions between the HIV capsid and the cyclophilin A.

“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,” said leader of study Klaus Schulten.

The results of the study showed that the cyclophilin is able to bind to the HIV capsid in 2 different ways, 1 of which included the classic binding site discovered in earlier crystallography studies. The other way was that in some places, a single cyclophilin A protein would bind with the capsid at a second site, forming a bridge between 2 hexamers.

The bridging was found to only occur in highly curved regions of the capsid.

When researchers added different amounts of cyclophilin to the HIV capsid, the cyclophilin didn’t entirely coat the HIV capsid. High or low concentrations showed that when the cyclophilin attached to the capsid, it interfered and disrupted the ability to bind.

“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," said researcher Juan R. Perilla. "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 discovery may eventually lead to improved treatment of the virus.

“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 added. “Now, we understand a little bit better the HIV virus' strategy for evading cellular defenses. That gives insight into battling the system.”