News: An antiviral leash for HIV?

Posted by Jef Akst

 

A structurally-distinct immune protein prevents the release of HIV and other viruses from infected cells by literally tying them to the cell membrane, according to a study published online today (October 29) in Cell. This antiviral leash -- known as tetherin -- could be co-opted as a new type of antiviral therapy, the authors say.

Scanning EM image of HIV particles (yellow) trapped on the surface of a cell (green) by tetherin Image: Devon Gregory and Marc Johnson

"It's a key step forward," said molecular virologist John Guatelli of the University of California, San Diego, who did not participate in the research. "There's a potential window of opportunity there to make [this natural antiviral system] work better or to block the viral proteins that counteract it" to help control viral spread.

Tetherin is a membrane protein produced by the immune system that blocks the release of HIV and other viruses enclosed in a lipid membrane. Originally identified in the mid-1990s, its antiviral activity wasn't discovered until last year. It has a very distinct structure, including two lipid-based membrane domains -- one on either end of the molecule -- and a rod-like structure that connects the two. Based on the molecule's physical features, scientists guessed that it may act as a natural and nonspecific antiviral -- tethering viral particles to the cell by embedding one lipid end in the viral envelope as it buds off while leaving the other in the cell membrane as an anchor. The tethered virus would then be stuck to the cell surface and unable to infect distant cells in the host.

To nail down the protein's mechanism, virologist and Howard Hughes Medical Institute investigator Paul Bieniasz of the Aaron Diamond AIDS Research Center at The Rockefeller University and his colleagues manipulated various parts of the tetherin protein and tested how well the altered proteins prevented virus release. Both lipid ends, they found, were required to keep the virus attached to the host cell, supporting the idea that tetherin was acting to physically connect the viral and cell membranes. If one end was deleted, the protein was still expressed in the cell membrane and incorporated into the viral membrane, but because there was nothing to hold it to the cell's surface, the virion -- with tetherin in tow -- escaped the cell's grasp.

"The way that tetherin works -- essentially by infiltrating lipid bilayers -- conceptually explains why it's so effective in the sense that it inhibits a wide range of viruses," said Bieniasz. Indeed, tetherin restricts the release of all retroviruses tested so far. This is because "the mechanism doesn't evoke any specific interactions between tetherin and viral proteins," Bieniasz explained.

Because this innate immune response can target a wide range of viruses, it may be difficult for viruses to evolve resistance to it, Bieniasz added. Normally, viruses can avoid host immune responses by simply making slight alterations to the sequences of existing proteins such that the host protein can no longer recognize it, he explained. But in this case, the viruses "have to make the much more difficult evolutionary step of acquiring an antagonist to neutralize tetherin function."

That's exactly what the viruses have done. HIV-1, for example, produces a molecule called Vpu that prevents tetherin from inhibiting virion release. That molecule, however, can only block the activity of specific tetherins; Vpu from HIV-1, for example, does not affect tetherin's hold on viruses infecting macaques, or vice versa. One option for antiviral therapies would be to target Vpu directly. Alternatively, researchers may be able to introduce non-native tetherin molecules that would be unrecognizable to Vpu into HIV-infected cells to prevent the release of the virus.

To investigate this possibility, Bieniasz and his colleagues tried replacing parts of the molecule with pieces of other proteins that were structurally similar but varied significantly in amino acid sequence. Unlike the simple deletions that had impaired tetherin's function, substituting various segments of the molecule did not affect its antiviral function, suggesting that tethrin's structure, and not its sequence, allows it to prevent the release of budding viruses.

"All it needs to work are these key structural features," Guatelli said. "This is remarkable because it indicates that the specific protein sequence itself is not important, just how it interacts with membranes and, possibly, with itself."

Because of this unique property, the researchers were able to construct an artificial tetherin from a hodgepodge of other protein elements that successfully inhibited the release of both HIV-1 and the Ebola VP40 viruses in cell cultures. The viral protein Vpu was unable to inhibit the artificial protein.

Such artificial tetherins may provide a novel angle for antiviral therapies by preventing viruses from spreading throughout the host, said University of Southern California virologist Paula Cannon, who was not involved in the research. First, these artificial molecules -- like natural tetherin -- "could have a broader antiviral effect than just against HIV-1," she said. But unlike natural tetherin, which has other roles in the cell, these artificial tetherins "could be a much safer way to reduce virus release [without] the side effects" that may be associated with altering native tetherin activity