London: A new study from Heidelberg University Hospital has analysed the involvement of particular components of the infected cell in virion release, and discovered that the enzyme VPS4A plays a more active role in the process than was previously thought.
The team showed that complexes containing about a dozen VPS4A molecules form at points in the membrane at which newly assembled virions later emerge.
“We can now demonstrate in detail, for the first time, how host proteins interact with components of HIV, to enable them to bud from infected cells. Our ultimate goal is to elucidate the entire life cycle of the virus,” said Professor Don C. Lamb.
“With the methods we have at our disposal, we can also study the effects of drugs on infected cells, which may allow us to improve their efficacy or even lead to the development of new classes of active compounds.”
Viruses smuggle their own genetic material into a host cell and reprogram the cell to produce new virus particles.
For release of the newly synthesized viruses, HIV exploits cellular proteins involved in the loading, sorting and budding of cellular vesicles known as ESCRT proteins.
During budding, HIV makes use of ESCRT to cut the last connection between the virion coat and the cell surface, allowing it to exit the cell. The enzyme VPS4A forms part of the ESCRT machinery and is known to be necessary for the disassembly of the complex after use, allowing its components to be recycled.
The results showed that VPS4A also acts at an earlier stage in the budding process.
“In this case, we were able to count how many enzyme molecules assembled at the HIV budding site during its interaction with the nascent virion,” said Dr. Barbara Muller.
“Our current methodology allows us to monitor the assembly of individual virions, and we are working on further refinements that will allow us to follow the complete life cycle of HIV,” said Lamb.
“We can already visualize some steps of the life cycle at the level of a single virus, observe interactions and determine the kinetics of different processes. Of course, this means that we can also label therapeutic agents and observe what effects they have in infected cells. This can help us to optimize the currently available drugs and even allow us to develop new ones.”
The study appears in Nature Cell Biology online on 10 March 2011.