Scripps, U-Virginia researchers shed light on how outer coating of HIV forms

After a decade of studying the protein package that delivers the genetic material of HIV to human cells (called the capsid), researchers now have a complete description of the cone-shaped container. This development could aid in the development of drugs to prevent HIV infection by disrupting capsid formation

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LA JOLLA, Calif.—Scientists at the Scripps Research Institute and the University of Virginia have reached a significant milestone in human immunodeficiency virus (HIV) research: After 10 years of studying the protein package that delivers the genetic material of HIV to human cells—called the "capsid"—they now have a complete description of the cone-shaped container. This detailed description, the scientists hope, could aid in the development of drugs that can disrupt the capsid's formation, preventing HIV infection.

Publishing these findings Jan. 20 in the journal Nature, the researchers describe the last portions of the capsid to be investigated, the structure of the two ends of the cone.

"This study completes the gallery of sub-structures describing the components of the HIV-1 capsid and enables atomic level modeling of the complete capsid," the study says.

Previous research has shown that HIV binds to receptors on human cells, then delivers the capsid inside them. Once inside a cell, the capsid comes apart, releasing the virus' genetic material. HIV then makes many copies of its genes and proteins, and the genetic material is packaged into spherical immature capsids that HIV uses to escape from the infected cell.
However, if formation of the mature capsid is disrupted, the virus is no longer infectious. According to the researchers, this is the key to developing new drugs for HIV.

The study builds on a breakthrough the group made in 2007, when the group viewed the CA hexamers with a powerful electron microscope. Guided by information from that structure, in 2009 the team managed to trick the CA hexamers into forming crystals. The researchers were then able to determine the particles' structures at 2-Angstrom resolution.

In this latest study, the team used techniques similar to those they had applied to the hexamers to obtain the crystal structures of the CA pentamers. Dr. Mark Yeager, a Scripps professor and the study's senior author, and his team partitioned the HIV capsid into smaller components, then determined their respective structures.

The group first focused on the structure of the CA hexamer, the protein that makes up the HIV capsid. The new structure reveals that five CA proteins are linked at one end, called the N-terminal domain (NTD), to form a circle. The opposite ends of the CA proteins, called C-terminal domain (CTD), form a floppy belt around this central core. Then, CTD links to CTD to connect adjacent pentamers.

One amino acid in the CA protein, called arginine, with a positive charge, sits in the middle of both the hexamer and pentamer ring. The arginines in the pentamer repel each other, making the pentamer a less stable structure than the hexamer. This may explain why there are many more hexamers in the mature HIV capsid compared to pentamers, the researchers say.

Having solved the atomic structures of both CA hexamers and pentamers, Yeager and colleagues for the first time were able to build a complete atomic model of the mature HIV capsid.  

"It is remarkable that our simple modeling approach, which allowed just two types of rigid-body rotations between the building blocks, produced a fullerene model wherein essentially all the subunits displayed reasonable packing geometries," the researchers wrote. "On the basis of this analysis, we conclude that CA assembly entails flexibility at both the NTD-CTD interface and the dimer interface to generate the constantly varying lattice curvature in the HIV-1 capsid."

Next, the researchers will work to refine the model using virtual models to determine the stability of the structure in different regions and to identify possible "weak" points they can target using newly designed drugs. They will also begin studying the structure of the immature capsid to determine how this version of the capsid transitions to the mature form—a step in the virus lifecycle that has remained mysterious.
"We don't have the full story yet, but we have volume one," Yeager said in a statement released by Scripps.
The study, "Atomic level modeling of the HIV capsid," was supported by the U.S. National Institutes of Health and by P50 funding from the Center for the Structural Biology of Host Elements in Egress, Trafficking and Assembly of HIV (CHEETAH), which is based at the University of Utah.

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