A UNSW study has shown for the first time how HIV hijacks a host molecule to strengthen its protective shell and shield itself from attack. The findings have implications for potential new drug developments.
Scientists from UNSW Sydney and the UK have discovered that the human immunodeficiency virus (HIV) hijacks a small molecule from the host cell to protect itself from being destroyed by the host’s immune system.
The finding, as well as details of the new strategy that enabled it, are published as back-to-back papers in eLife. They identify a new target for antiviral therapy against HIV and provide a method for testing and measuring new drugs designed to target the capsid.
UNSW PhD student Chantal Márquez is involved in both studies and is the first author of the paper describing the new method.
Using a new single-molecule microscopy technique – developed at UNSW’s Single Molecule Science in the Faculty of Medicine – the research teams found that HIV specifically incorporates a small molecule from the host cell – inositol hexakisphosphate – to strengthen its capsid. The host inadvertently provides the key for the virus infecting it to lock down the protective shell, keeping the genetic cargo safe until it is released into the nucleus.
“The HIV capsid falls apart within minutes once it’s isolated from the virus,” said Associate Professor Till Böcking, who led the UNSW team involved in both studies.
“Our strategy lets us study exactly how a native capsid breaks apart in real-time without taking it out of the viral membrane.”
“We can now see the effect of different molecules on the capsid, and pinpoint precisely when it cracks open and begins to collapse,” says Associate Professor Böcking.
“Capsids need to be much more stable inside a cell because the infection process takes hours, not minutes – so we wanted to find out what keeps it stable inside a cell,” says Dr David Jacques of Single Molecule Science, who is an author of both studies.
“It’s like a switch. When you bind this molecule, you stabilize the capsid, and release the molecule to open it up,” explains Associate Professor Böcking.
“The HIV capsid has been intensively studied, but the question of how it can simultaneously be both stable and poised to ‘uncoat’ has been one of the great unanswered questions in HIV biology,” says Dr Leo James, leader of the research team at the Medical Research Council Laboratory of Molecular Biology in Cambridge, UK.
Most of the currently approved HIV therapies target enzymes needed at different stages of the virus’ life cycle, but none of them are directed at the HIV capsid. New drug alternatives could improve the treatment of HIV with reduced toxic effects.
Source : UNSW