A team of computational and experimental researchers headed by Prof Klaus Schulten from the University of Illinois at Urbana-Champaign has constructed an atomic model of the immature retroviral lattice of a virus called Rous sarcoma virus.
An atomic model of the immature retroviral lattice of RSV. Image credit: Boon Chong Goh / University of Illinois.
Retroviruses are a large and diverse family of human and animal viruses, including the medically significant Human Immunodeficiency Virus (HIV).
These viruses are tricky to treat. They go through a multistage process to produce infectious particles.
The viruses that are released from infected cells are initially in an immature state and are composed of an RNA genome surrounded by a coat of protein.
Upon their release, the viruses undergo a maturation process that rearranges the viral proteins and activates the conversion of the RNA genome into DNA through a process called reverse transcription.
The viral DNA then invades the host cell’s genome. The infected cell is programmed to release multiple copies of the immature virus into the host’s bloodstream. These newly released viruses must in turn mature before they can infect other cells.
Not only do retroviruses cause life-long infections, but also in the complex process of reverse-transcribing RNA into DNA, many mutations can occur, making the retrovirus even more difficult to target.
One strategy for preventing the spread of a retrovirus is to lock the viral particles in their immature, non-infectious state.
Unfortunately, the complexity and size of the viral particle – an irregular and incomplete hexagonal shell of close to 100 nm in size – have prevented the experimental determination of the atomic-level structure of the particle.
A number of studies have examined the structure of the Rous sarcoma virus (RSV), which affects birds and provides a good model for other retroviruses, but none have been able to provide a high-resolution look at the immature stage of the virus.
With the help of supercomputers, Prof Schulten and co-authors were the first to provide the atomic-level structural model of the immature retroviral lattice of RSV.
“We have had a pretty good understanding of the mature infectious particle at a level where we can make specific predictions about the local chemical interactions between the protein subunits in the virus,” said Prof Rebecca Craven of Penn State University, a co-author on the study published in the journal Structure.
“But the field was really lacking similar high-resolution knowledge about the immature virus. This new model is the first to give us an atomic-level look at the immature state. With that knowledge we can try to understand the precise molecular mechanisms of virus maturation and help to elucidate how drugs can be designed to interfere with that.”
A six-helix bundle domain located on the inside surface of the immature protein shell could be a key to understanding and blocking the virus.
“Recent advances in cryo-electron tomography allow us to model the majority of the immature retroviral lattice, except the six-helix bundle domain. Experimentalists do not have a clear view of that domain because of its high flexibility. And that’s where we come in. Using advanced computational techniques and supercomputers, we modeled and refined an all-atom model of the six-helix bundle,” said lead author Boon Chong Goh from the University of Illinois at Urbana-Champaign.
The scientists believe that the six-helix bundle is amphipathic, a chemical property that possesses an affinity for both water and fat, and that it is enclosed by a ring of salt bridges, contributing to the stability of the bundle.
“HIV is a close relative to RSV, and HIV is also known to have this domain, which has been a drug target for years. A drug named Bevirimat (BVM) was developed to target the six-helix bundle of immature HIV, but it did not pass the clinical trials,” Goh said.
“The experience with Bevirimat did show that inhibitors that target the six helix bundle domain can be very powerful HIV anti-retroviral drugs by preventing virus maturation,” Prof Craven added.
“The main idea is that you have two forms of the virus: the immature and the mature. The immature is not infectious, so the idea is that ultimately you want to prevent it from becoming the mature form,” said co-author Dr Juan Perilla, also from the University of Illinois at Urbana-Champaign.
“The problem is that Bevirimat targets the six-helix bundle domain, but no one really knows the structure of the immature lattice in HIV. There are a few models, but they are not high resolution, so we decided to work in this direction and we picked RSV because it’s a good model to study the virus. Our next step is to go to HIV.”
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Boon Chong Goh et al. 2015. Atomic Modeling of an Immature Retroviral Lattice Using Molecular Dynamics and Mutagenesis. Structure, vol. 23, no.8, pp. 1414-1425; doi: 10.1016/j.str.2015.05.017
