Sunday, March 14, 2010

Restriction Factor-Tetherin: Not so fast you little virion

It is time to move on from all things TRIM related and I am going to take things in a different direction. Rather than talking about viruses getting in, I am going to be talking about getting out. BST2/Tetherin has a cool story to tell.

Although, scientists talk a lot of game with our technical jargon we do like to keep things simple (because even simple hardly ever works). For example when you want to know what a gene/protein is doing, the easiest way to figure it out is to get rid of it. When scientists deleted the Vpu gene of HIV-1 they saw something weird. First their cells made less virus. Naturally, they wanted to know what part of the viral life cycle was disrupted. It turns out the virus could do everything it needed to, except new viruses could not detach from the cell surface (see picture bellow from Neil et al., 2008). The conclusion was that Vpu was required for proper budding. The funny thing was that if you put SIVs into some human cells a similar thing happens. No one could figure out why but the story stopped there. Surly some grad students and postdocs got burned on this one.


The answer was only recently revealed. Vpu was not actively involved in the budding process at all, instead it was actively opposing a restriction factor that prevented budding. This factor makes a protein string preventing the new virus from leaving the cell. Previously named BST2 the factor was renamed Tetherin because it could “tether” a virus to the cell surface. The ability of a virus to get around this block is species and virus specific. HIV-like viruses, primate lentiviruses (PLVs) that make a niche in one species have a protein to take care of that specie’s Tetherin. If you put the virus in another species it has trouble getting around it.

If viruses had brains this is the sort of thing that would drive them crazy. Look at it from the virus’ point of view. It flies around an organism till it finds the right receptor. It dodges TRIM, it finds a nice spot to integrate into the genome, it makes all the proteins it needs before the cell kills itself or goes into lockdown mode, and now at the very last step the cell gets the last laugh and says…. gotcha bitch. Tetherin is basically a bungee chord preventing the virus from blasting of from the cell. The cell can then reel the virus back in and destroy it.

Insights Gained from the discovery

When one aligns Tetherin sequences from a few species you notice something very quickly, there is a lot of diversity. This is because this protein has been locked in an arms race against viruses, emphasis on viruseS. This protein is not only active against HIV when it is missing its Vpu, but if it were not counteracted it would work against HIV-2, SIVmac, SIVcpz, many other SIVs, Ebola, Marburg, at least one Arena viruses and KSHV. It is beginning to appear that Tetherin is active against just about any virus with a membrane, which begs the question how do other virus get around it?

The most stunning evidence of this arms race comes from how viruses have adapted to counteract Tetherin. I mentioned before that the effects of Tetherin are only observed either when a virus loses a gene to that takes care of Tetherin, or the virus finds itself in a cell that has a different type of Tetherin. The primate lentiviruses have jumped from species to species and they have utilized many proteins to counteract Tetherin. The Vpu of HIV-1 counteracts human Tetherin, but remember that virus came from a chimp virus SIVcpz. In a chimp the virus uses its Nef protein to do the same job. SIVmac in macaques also uses its Nef protein, while some types of the closely related HIV-2 use their envelope protein. This underscores a fundamental property of the PLVs, they are vey plastic, when presented with a challenge they will find a way to evolve around it. Arguably, solving the same problem independently with multiple solutions is one strong case against intelligent design.

Chimps and Humans are quite similar and the PLVs infecting them only diverged in an evolutionary blink of an eye. So why does one type of virus use Vpu while the other uses Nef? Again the answer is evolution. At some point after the two species diverged the human protein lost 5 amino acids in its tail. The amazing thing is that these amino acids are in the exact spot that some SIV Nef proteins recognize Tetherin. Nef basically grabs the tail of Tetherin, pulls it off the cell surface and marka it for destruction. The missing 5 amino acids protect human tetherin from Nef. Sadly, HIV evolves so quickly that it just switched to Vpu in humans to do the same task. The missing amino acids are common to all humans. The obvious question to ask is what virus selected for this? Was it the same virus that selected for only one version of Trim5 in humans? These are all interesting questions that make me want to build a time machine and find out.

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