U.S. Department of Health and Human Services; National Institutes of Health NIH News, National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS) http://www.niams.nih.gov - Tuesday, February 10, 2009
CONTACT: Marcia Vital, NIAMS, 301-496-8190 e-mail:vitalm@mail.nih.gov

For the first time, scientists can see an elusive protein that forms part of the shell of a retrovirus -- a finding that may help in the development of therapies to disrupt the functioning of retroviruses, which include the HIV/AIDS virus. The study, led by scientists at the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), part of the National Institutes of Health, appears in the current issue of the journal "Nature."

The target of the research was a retrovirus capsid pentamer protein -- a protein composed of five subunits that forms part of the capsid, the shell containing the nuclear material of a retrovirus. To date, scientists have only been able to visualize capsid hexamer proteins, which are composed of six subunits. Since structure often impacts function on the molecular scale, these findings may further our understanding of capsid assembly in retroviral replication and may lead to interventions to disrupt it.

The NIAMS scientists, led by Alasdair Steven, Ph.D., a senior investigator in the Laboratory of Skin Biology of the NIAMS ' Intramural Research Program, and in collaboration with scientists from The Pennsylvania State University College of Medicine in Hershey, studied a retrovirus called Rous sarcoma virus (RSV), a cancer-causing virus found in chickens. However, since many retroviruses have similar proteins in the capsid, the scientists' work has implications for many retroviruses, including other cancer-causing viruses and human immunodeficiency virus (HIV).

Retroviruses vary in the shape and size of their capsids. HIV has a capsid in the shape of an ice cream cone. RSV's capsid has an icosahedron shape, with 20 sides and 12 points. Despite the fact that scientists have only been able to visualize hexamer proteins in two-dimensional sheets or tubes, they knew mathematically that pentamers had to exist in order to create the various capsid shapes seen in retroviruses.

The scientists used a technique called cryo-electron microscopic analysis of in vitro-assembled capsids from RSV to visualize the capsid proteins in three dimensions. In short, they froze the capsid proteins, made a cast of their shapes, and then used electron microscopy to simulate a three-dimensional model of the shapes. They discovered the subunits that make up the hexamer and pentamer proteins are practically identical in shape and chemical make-up, and are also practically identical to the subunits found in HIV capsid proteins. The scientists investigated further to see how these subunits interacted to create such diverse capsid protein shapes and sizes.

The answer had to do with tops and bottoms. Each protein subunit is like a balled-up string with two ends. The top end is called the N-terminal domain (NTD) and the bottom end is called the C-terminal domain (CTD). Each subunit is connected to its neighboring two subunits through the connection of the ends of the strings. This provides for three types of binding: top to top (NTD-NTD), top to bottom (NTD-CTD), and bottom to bottom (CTD-CTD). These different interactions determine the shapes and sizes of the various capsid proteins. And, it is the combination of these capsid proteins that determines the shapes and sizes of the capsids themselves.

These findings contribute to our understanding of the structure, function, and creation of retroviral capsids. Currently, research is investigating the potential to disrupt capsid assembly during viral replication. Discoveries in this area could lead to treatments to prevent or halt the progression of a retroviral infection.

The mission of the National Institute of Arthritis and Musculoskeletal and Skin Diseases, a part of the Department of Health and Human Services' National Institutes of Health, is to support research into the causes, treatment and prevention of arthritis and musculoskeletal and skin diseases; the training of basic and clinical scientists to carry out this research; and the dissemination of information on research progress in these diseases. For more information about NIAMS, call the information clearinghouse at (301) 495-4484 or (877) 22-NIAMS (free call) or visit the NIAMS Web site at <http://www.niams.nih.gov>.

The National Institutes of Health (NIH) -- The Nation's Medical Research Agency -- includes 27 Institutes and Centers and is a component of the U.S. Department of Health and Human Services. It is the primary federal agency for conducting and supporting basic, clinical and translational medical research, and it investigates the causes, treatments, and cures for both common and rare diseases. For more information about NIH and its programs, visit <www.nih.gov>.

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Reference: Giovanni C, Purdy JG, Cheng N, Craven RC, Steven AC. "Visualization of a missing link in retrovirus capsid assembly. " Nature. 2009 Feb 5;457(7230):694-8. DOI:10.1038/nature07724.

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