Structure of HIV Capsid protein in its native state revealed

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The human immunodeficiency virus (HIV) is a deadly virus that causes acquired immunodeficiency syndrome (AIDS) which affects 2 million people annually. HIV virus has a unique ability to constantly adapt and mutate which makes it challenging to develop effective drugs against it.

A clearer idea of proteins involved in the HIV lifecycle could help scientists design drugs to combat the virus. A key protein located in the inner shell of HIV–the capsid protein forms protective lattices around viral RNA molecules. However, the precise molecular detail of how individual, full-length capsid proteins assemble to shield the viral genome are not well understood.

“The capsid shell acts as an ‘invisibility cloak’ that hides the virus’ genetic information, the genome, while it is being copied in a hostile environment for the virus. Fine-tuned capsid stability is critical for successful infection: too stable a capsid shell and the cargo is never delivered properly; not stable enough and the contents are detected by our immune defenses, triggering an antiviral response. Capsid stability is a key to the puzzle, and you have to understand its structure to solve it”, says Stefan Sarafianos, the lead researcher.

In their new work published in Science, Sarafianos and his team from University of Missouri School of Medicine have been successful in capturing the most complete model of an HIV capsid protein. The research team used a technique called X-ray crystallography to unravel the protein’s structure.

The protein building block of HIV capsid (top left) can assemble to form a hexamer (top middle). Crystals grown using this building block (bottom left and middle) contain an array or lattice of hexamers (right). | Image by Karen Kirby and Anna Gres
The protein building block of HIV capsid (top left) can assemble to form a hexamer (top middle). Crystals grown using this building block (bottom left and middle) contain an array or lattice of hexamers (right). | Image by Karen Kirby and Anna Gres

The model of the capsid protein, surprisingly revealed “ordered” water molecules at areas between the viral proteins. “We thought, ‘How could some simple water molecules really be of consequence?'” Sarafianos said. “But when we looked carefully, we realized there are thousands of waters that help stabilize the complex capsid scaffold. We hypothesized that this is an essential part of the stability of the whole capsid assembly.” The water molecules help the capsid shell to be flexible and assume different forms, which is critical for the life cycle of the virus, Sarafianos said.

The National Institutes of Health recently awarded this team a grant of $2.28 million over five years to continue their study on developing antiviral drugs that target the capsid protein.

The original paper can be accessed here.