Researchers Uncover Shell Structure of HIV-like Retrovirus

Tanmay Bharat from the European Molecular Biology Laboratory in Heidelberg and colleagues have shed more light on how the Gag polyprotein in retroviruses such as HIV changes as the virus matures. These findings, reported in the June 3, 2012, advance online edition of Nature, offer clues about new targets for antiretroviral therapies.

Below is an edited excerpt from an EMBL press release describing the study and its findings in more detail.

Shape-shifting Shell

Structure of a retrovirus at a potentially vulnerable stage

Heidelberg -- June 3, 2012 -- Scientists at the European Molecular Biology Laboratory (EMBL) in Heidelberg, Germany, have for the first time uncovered the detailed structure of the shell that surrounds the genetic material of retroviruses, such as HIV, at a crucial and potentially vulnerable stage in their life cycle: when they are still being formed. The study, published online today in Nature, provides information on a part of the virus that may be a potential future drug target.

Retroviruses essentially consist of genetic material encased in a protein shell, which is in turn surrounded by a membrane. After entering a target cell -- in the case of HIV, 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.

"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," says John Briggs, who led the research at EMBL. "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. Using a combination of electron microscopy and computer-based methods, Briggs and colleagues investigated 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. This knowledge will help scientists to 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.

Findings such as these may one day prove valuable to those wanting to design new types of antiretroviral therapies. Many antiretroviral drugs already block the enzyme that would normally separate components of the immature shell to allow it to mature. But there are currently no approved drugs that act on that shell itself and prevent the enzyme from locking on.

Although the virus shells imaged in this study were derived from the Mason-Pfizer monkey virus and made artificially in the laboratory, they closely resemble those of both this virus and HIV -- which are very similar -- in their natural forms.

"We still need a lot more detailed information before drug design can really be contemplated," Briggs concludes, "but finally being able to compare mature and immature structures is a step forwards."

The work was done in collaboration with the group of Tomas Ruml at the Institute of Chemical Technology in Prague, Czech Republic.

6/5/12

Reference

TAM Bharat, NE Davey, P Ulbrich, et al. Structure of the immature retroviral capsid at 8Å resolution by cryo-electron microscopy. Nature. June 3, 2012 (Epub ahead of print).

Other Source

European Molecular Biology Laboratory. Shape-shifting Shell. Press release. June 3, 2012.