Supercomputer Simulation of HIV Capsid Finds New Avenues for Drug Research

Analysis of a supercomputer simulation of the shell that encloses the HIV-1 genetic material revealed several weaknesses that future research could exploit for ways to prevent the virus from spreading throughout a body. The simulation was conducted and analyzed by Juan R. Perilla, Ph.D., and Klaus Schulten, Ph.D., and published in Nature Communications. A video of the process that the atoms in the capsid go through during the early stages of infection provides a visual representation of the research.

Explore the inside of the HIV capsid in this VR video:

HIV spreads by inserting its own ribonucleic acid (RNA) -- its genetic material -- into an infected person's cells. The viral RNA is enclosed in a shell made of more than a thousand copies of the same protein, the capsid protein (CA). The shell itself is called a capsid. In addition to holding the RNA, the capsid helps to prevent the infected person's own sensors from triggering an immune response to the virus, and it is involved in regulating the reverse transcription of the RNA into the host cell and the pathway by which the viral material is imported into the host cell's nucleus.

The two researchers created a computer simulation of the process through which a virus-like particle -- a virus devoid of its genetic material -- enters a host cell. Because of the complexity of the process and the level of detail that the researchers wanted to capture, the simulation had to be run on a supercomputer, with the results analyzed on a second supercomputer. The entire project took two years to complete and involved a 64-million atom molecular dynamics simulation that analyzed the first 1.2 microseconds of this process.

"We are trying to understand, at a very detailed level, how the virus works and how it hijacks cells for its own benefit. We hope that this basic scientific knowledge leads to more breakthroughs in medicinal science," explained lead researcher Perilla to He and his colleague found several vulnerabilities that could be exploited by future research.

The rates of water transfer in and out of the capsid during the first few hundred nanoseconds of the process are much larger than those of other viruses, such as poliovirus. Beyond water, certain ions also move in and out of the capsid. Here, the rates at which chloride and sodium ions do so differ substantially, and the two ions also bind to different parts of the capsid. This specificity of ion translocation and binding may help move certain molecules, such as DNA nucleotides, during the process of infection. The researchers call the paths that the two ions take "ion channels." They theorize that these channels might help the capsid withstand the changes in pressure that have been observed during reverse transcription of the viral RNA into the host cell. Other experiments have shown that, without such mitigation, the changes in pressure rupture the capsid.

Positively and negatively charged ions (cations and anions) bind to genetically important portions of the capsid. The biological role that these ions may play is undetermined at this time, and some of the binding sites that were seen in the simulation have not yet been found in experiments. However, research on other viruses has shown that the distribution of electric charges on the capsid is important for the virus' ability to infect a person. Perilla thinks that this property may be a promising point of attack for countering HIV infection: "I believe that the ability to design novel drugs that alter the physical properties of the capsid opens a new avenue for the development of therapeutics, for instance, by altering the delicate electrostatic balance of the capsid."

Another potential weakness of the virus is the fact that the capsid oscillates at frequencies in the ultrasound range. These frequencies differ among capsid regions, with the highest ones at the tip and around the base of the shape. Simulating the movement of individual atoms, the researchers found that the patterns produced by such movements effectively divided the capsid into two regions: the tip and the base. The waves produced by this oscillation behave like capillary waves, a type of wave known from other membranes and fluids. Further research will be needed to elucidate the relationship between these waves and the movement of water and ions through the capsid.

The capsid's long-range collective dynamics may allow it to transfer information between sections of its structure that are (relatively) far from each other. Such communication abilities may be important when the viral RNA is imported into the nucleus of the host cell, the researchers theorize. Disrupting these communications could hinder the "uncoating" stage of the HIV life cycle.

While current HIV medications address many stages of infection, no "uncoating inhibitors" yet exist, for example. This simulation points to directions for research into new types of drugs that could halt infection in as-yet-unexplored ways.