Getting to know retroviruses better could lead to improved drug treatments
Czech and German researchers have for the first time uncovered the detailed structure of the shell surrounding the genetic material of retroviruses, when they are still being formed - a crucial and potentially vulnerable stage in their life cycle.
A retrovirus is a ribonucleic acid (RNA) virus that is duplicated in a host cell using the reverse transcriptase enzyme to produce deoxyribonucleic acid (DNA) from its RNA genome. Then the DNA is incorporated into the host's genome by an integrase enzyme after which the virus replicates as part of the host cell's DNA. One of the most well-known retroviruses is the human immunodeficiency virus (HIV), part of the lentivirus group, a subset of the retrovirus family.
Writing in the journal Nature, researchers explain how their findings provide information on a part of the virus that could be a potential drug target in the future. The team are affiliated with the Institute of Chemical Technology and the Academy of Sciences of the Czech Republic, both situated in Prague, and the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany.
Retroviruses are made up of genetic material encased in a protein shell, which is in turn surrounded by a membrane. Where HIV is concerned, after a retrovirus enters a target cell (one of the cells in our immune system), the virus replicates, producing more copies of itself, each of which has to be assembled from a medley of viral and cellular components into an immature virus.
One of the researchers on the team, John Briggs from the EMBL, comments: 'All the necessary components are brought together within the host cell to form the immature virus, which then has to mature into a particle that's able to infect other cells. We found that when it does, the changes to the virus' shell are more dramatic than expected.'
Both the mature and immature virus shells are honeycomb-like lattices of hexagon-shaped units. By using a combination of electron microscopy and computer-based methods, the team were able to investigate which parts of the key proteins stick together to build the honeycomb of the immature shell. These turned out to be very different from the parts that build the mature shell.
The Czech-German team's findings will help scientists unravel how the immature virus is assembled in the cell and how the shell proteins rearrange themselves to go from one form to the other. This could prove crucial to those wanting to design new types of antiretroviral therapies. Although many existing antiretroviral drugs already block the enzyme that would normally separate components of the immature shell to allow it to mature, currently there are no approved drugs that act on that shell itself to prevent the enzyme from locking on.
John Briggs went on to say that although they 'still need a lot more detailed information before drug design can really be contemplated', finally being able to 'compare mature and immature structures is a step forward.'
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Document Reference: Bharat, T. A. M. et al., 'Structure of the immature retroviral capsid at 8 A resolution by cryo-electron microscopy', 2012, Nature. doi:10.1038/nature11169.
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