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Structure of HIV Capsid Protein Reveals Potential Weakness at Inner Core of Virus

Molecular Details of a Possible New Target for AIDS Drugs

LA JOLLA, CA, October 4, 2007—Scientists at The Scripps Research Institute have published a detailed molecular model of the full-length HIV CA protein—a viral protein that forms a cone-shaped shell around the genome of HIV. This structure reveals a never-before-seen molecular interaction that may be a weakness at the core of the virus.

CA plays a crucial role in the lifecycle of HIV because it forms a protein shell inside infectious particles, providing a scaffold that organizes important components of the virus. The new CA structure, published in the October 5 issue of the journal Cell, has clinical implications and may help scientists develop new drugs for treating HIV.

"AIDS is a bona fide pandemic," says study author Mark Yeager, M.D., Ph.D. "There are several effective drugs and methods for treating and preventing HIV infections, but there is an ongoing need for new therapy due to the shear enormity of the disease and the emergence of drug resistance."

Yeager is a professor in the Department of Cell Biology at The Scripps Research Institute and Staff Cardiologist and Director of Cardiovascular Research at Scripps Clinic. He also has a joint appointment as Andrew P. Somlyo Professor and Chair of the Department of Molecular Physiology and Biological Physics at the University of Virginia. Yeager supervised the research, which was conducted by his postdoctoral fellow Barbie Ganser-Pornillos, Ph.D.

Since it was first reported more than 25 years ago, HIV has spread to every corner of the world. Globally, according to the latest figures available from the World Health Organization, some 40 million people were living with HIV in 2006. The Centers for Disease Control and Prevention (CDC) estimates that 40,000 people become infected with HIV every year in the United States.

HIV infections can be successfully managed for years with a variety of existing drugs known as antiretrovirals, which interfere with critical parts of the viral lifecycle. Interfering with some of these stages can prevent the virus from replicating, integrating its genome into the cell's DNA, or processing new infectious viral particles.

Doctors often prescribe a regimen of several antiretrovirals from different classes for people living with HIV because AIDS drugs with different mechanisms of action are more effective in combination than when taken alone. Finding new drugs with new mechanisms of action is important because HIV constantly mutates and may become resistant to existing drugs.

In general, the capsid (the protein coat that covers the core of a virion) is an attractive target because it plays a crucial role in the viral lifecycle. It packages and organizes the HIV genome, and this is necessary for the virus to transmit and replicate efficiently. If chemical compounds could target the CA protein, scientists might be able to prevent the protein's assembly into capsid shells and thereby block infectivity of HIV. Capsid inhibitors would be a novel class of drugs that would complement existing pharmaceuticals.

So Ganser-Pornillos and Yeager set out to find the complete structure of the HIV-1 CA.

But this was no easy task. Assembled capsid shells are large enough to be seen under the most powerful electron microscopes, but are too small and asymmetric to be studied in detail. For years, structural biologists attempted to solve the structure of the CA protein using other methods, but the protein is flexible, and the structure proved elusive. The problem was that CA has two rigid pieces or domains held together by a flexible linker. Think of them like two water balloons tied together with a short string. Scientists had successfully chopped the protein into pieces and solved the structures of the two domains, but despite many years of trying, nobody had visualized how the two domains fit together and how hundreds of copies of CA pack within the lattice of the capsid shell.

Ganser-Pornillos solved the problem by finding exact conditions that fixed assemblies of the full-length CA molecules into well-ordered, two-dimensional (2D) arrays. Normally, recombinant CA molecules form cylindrical shells in vitro, but a few years ago, a single mutation was identified that allowed the formation of alternative shapes—cylinders, cones, and spheres. By creating conditions in which CA formed large hollow spheres, Ganser-Pornillos was able to generate extended 2D crystalline sheets by flattening the spheres onto a thin layer of carbon. Ganser-Pornillos, assisted by Scripps Research Staff Scientist Anchi Cheng, solved the three-dimensional structure of the CA molecules in the sheets by computational analysis of images of tilted 2D crystals recorded in the electron microscope.

Even though the 2D crystals of CA were generated artificially, they were thought to recapitulate the lattice in the HIV capsid because the packing of the CA molecules had a hexagonal, honeycomb like pattern, similar to that seen in authentic viral particles. However, the hexagonal packing of the molecules in the 2D crystals was much more regular, so that a detailed structure could be determined. The clarity of the three-dimensional electron microscopy map was sufficient so that existing high-resolution structures of the two domains of CA could be "docked" into place. The resulting atomic model of the capsid lattice revealed three types of interactions that stabilize this inner core of HIV.

In particular, an interaction between the two pieces of CA had not been visualized previously. Interfering with this interaction could disrupt assembly of the capsid shell and block formation of infectious particles.

"The structure allows us to visualize the interface between the two domains of CA, which we think is the target for a set of experimental drugs," says Ganser-Pornillos. She and Yeager are now working to improve the structure. They hope to find novel compounds that bind to CA to test if they interfere with the virus's infectivity.

The article is entitled "Structure of Full-Length HIV-1 CA: A Model for the Mature Capsid Lattice," and appears in the October 5, 2007 issue of the journal Cell.

Support for this work was provided by grants from the National Institutes of Health and through a postdoctoral fellowship from the George E. Hewitt Foundation for Medical Research.

About The Scripps Research Institute

The Scripps Research Institute is one of the world's largest independent, non-profit biomedical research organizations, at the forefront of basic biomedical science that seeks to comprehend the most fundamental processes of life. Scripps Research is internationally recognized for its discoveries in immunology, molecular and cellular biology, chemistry, neurosciences, autoimmune, cardiovascular, and infectious diseases, and synthetic vaccine development. Established in its current configuration in 1961, it employs approximately 3,000 scientists, postdoctoral fellows, scientific and other technicians, doctoral degree graduate students, and administrative and technical support personnel. Scripps Research is headquartered in La Jolla, California. It also includes Scripps Florida, whose researchers focus on basic biomedical science, drug discovery, and technology development. Currently operating from temporary facilities in Jupiter, Scripps Florida will move to its permanent campus in 2009.

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