An antiviral leash for HIV?

[marius68]

Step by step we are building on the knowledge of this crap. An interesting new research was published today. You can read here:

http://www.the-scientist.com/blog/display/56125/


The antiviral activity of tetherin was only found last year:

http://www.nature.com/nature/journal/v451/n7177/abs/nature06553.html


An antiviral leash for HIV?
Posted by Jef Akst
[Entry posted at 29th October 2009 05:01 PM GMT]
   
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.

"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.
 

[Inchlingblue]

HIV Tamed By Designer 'Leash'

ScienceDaily (Oct. 29, 2009) — Researchers have shown how an antiviral protein produced by the immune system, dubbed tetherin, tames HIV and other viruses by literally putting them on a leash, to prevent their escape from infected cells. The insights, reported in the October 30th issue of the journal Cell, a Cell Press publication, allowed the research team to design a completely artificial protein -- one that did not resemble native tetherin in its sequence at all -- that could nonetheless put a similar stop to the virus.
 
"Tetherin is essentially a rod with anchors at either end that are critical for its function," says Paul Bieniasz of Howard Hughes Medical Institute and the Aaron Diamond AIDS Research Center at The Rockefeller University. Either one of those anchors gets incorporated into the envelope surrounding HIV or other viruses as they bud through the plasma membrane of an infected cell. "One anchor gets into the virus and the other in the cell membrane to inevitably form a tether.

"We showed we could design a completely different protein with the same configuration -- a rod with lipid anchors at either end -- and it worked very well," he continued. The finding helped to confirm that tetherin is capable of acting all on its own, he added.

They also explain tetherin's broad specificity to protect against many viruses. "It is just targeting lipids," Bieniasz said. "It's not about viral proteins." That's conceptually important, he continued, because there is no specific interaction between tetherin and any viral protein, which makes it a more difficult problem for viruses to evolve resistance. Rather than tweaking an existing protein-coding gene, "the virus has to make the more difficult adjustment of acquiring a new gene antagonist [of tetherin]."

Continued . . .

LINK:

http://www.sciencedaily.com/releases/2009/10/091029125530.htm

[J220]

Wow interesting concept. My only concern is that since this would be a "mechanical" method of action (for lack of  better word) as opposed to an immune one, that would mean that the tetherin protein will have to be present in ALL the infected cells, and have to work 100% of the time in capturing escaping virions, otherwise it will be useless because once the virus particle breaks free that's it. And so many questions:

1) Can this protein prevent infection of a cell? In other words, would it work the other way around, attaching to invading virus particle so it cannot fuse into the cell?

2) How long will this protein persist in the body? Assuming it can attach succesfully to all infected cells (and healthy ones too, I guess) how long will it be present? Weeks? Months? Years? Will this be a continous medication to be taken or a one time deal?

3) What will happen to infected cells in the long run? Will they die off quicker because of the presence of tetherin? Etc.

But....all in all an interesting concept, and it's great to see this kind of breakthrough. Cheers, J.

[veritas]

They will have to tweek this one:

"The bad news? HIV has a defense against tetherin: one of its minor proteins known as Vpu. Only AIDS viruses with defects in their Vpu, or monkey AIDS viruses that lack this component, are entangled by tetherin and end up being destroyed"

The above from an earlier article:

http://www.amfar.org/lab/article.aspx?id=6770

v

[Inchlingblue]

Here are some of the strategies being considered to get around the Vpu. It's also possible that Vpu would not have an effect against this artificial tetherin, since it is molecularly distinct from natural tetherin.

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.

These are some of the advantages of artificial versus natural tetherin:

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.

LINK:

http://www.the-scientist.com/blog/display/56125/

[Inchlingblue]

I suspected, as mentioned above, that Vpu would not have an effect on artificial tetherin, since it's made up of different molecules. The article below seems to substantiate that:

Vpu failed to inhibit the protein researchers engineered to mimic this immune system leash.

LINK:

http://newswire.rockefeller.edu/?page=engine&id=991

Bring on the clinical trials! 

[veritas]

Inch,

I like this quote from your link:

" “Tetherin presents a challenging obstacle: It cannot be evaded by just changing the sequence of the viral protein to avoid an interaction,” he says. “It is a more difficult genetic step for the virus to invent an entirely new gene product to interfere with this cellular function.”

I'm with you, bring on the clinical trials!

v