Hey, do you all remember Michael Behe?

Dude was for real ‘famous’ a while back (not just ‘Christian famous’). He went on talk shows and news programs (including the Colbert Report) to talk about his personal brand of Creationism, Intelligent Design.

Unfortunately, things ‘didnt go as planned’ with Intelligent Design. The courts didnt buy ID, in no small part thanks to the asshatty defense of it given by Michael Behe.

Even The Arguments Regarding Design ‘think tank’, the Discovery Institute, has abandoned ID in favor of pushing ‘academic freedom’ bills in state legislatures.

Behe also helped IDs death along with his last book, ‘The Edge of Evolution’. He said some bafflingly stupid things about HIV-1 evolution (like, ‘its-called-’Google’-what-is-the-matter-with-you?’ stupid). Ive had fun over the years covering the Scientific process discovering more and more about that little protein Behe ignored, Vpu, and covering what Vpu has taught us about our own evolution.

Its a neat little bugger.

But its not the only one.

HIV-1 and HIV-2 are not the same thing. HIV-1 we got from chimpanzees, HIV-2 from sooty mangabeys. Their epidemiology is different. Their disease course/pathology is different. Their protein functions are different. Their genomes are different.

One of those genomic differences is in the form of the accessory proteins. HIV-1 has Vpu. And HIV-2 has Vpx. We know (or, are in the process of knowing) Vpus story– whats up with Vpx?

Much like its cousin Vpu, studying Vpx has taught us not only more about how retroviruses work, but has enabled the discovery of new human proteins and new anti-viral systems our body is equipped with. By studying Vpu, scientists discovered a previously puzzling protein, tetherin. We learned that unless tetherin is tamed, budding retroviruses (and some other kinds of viruses) are trapped on the host cell surface. They cant run off to infect new host cells. Scientists studying Vpx have discovered another one– SAMHD1:

How SAMHD1 changes our view of viral restriction.

Evolutionary and Functional Analyses of the Interaction between the Myeloid Restriction Factor SAMHD1 and the Lentiviral Vpx Protein.

The Ability of Primate Lentiviruses to Degrade the Monocyte Restriction Factor SAMHD1 Preceded the Birth of the Viral Accessory Protein Vpx.

‘Discovered’ isnt the right word… we knew about SAMHD1 before, as if someone has a mutation in that gene, they get Aicardi-Gouti√®re syndrome (lethal autoimmune disease). But discovering its association with HIV-2 Vpx has helped us elucidate what it is doing under normal circumstances.

Under normal circumstances, SAMHD1 is sitting around in differentiated, non-cycling cells– good examples of this are HIV targets, dendritic cells and macrophages. Because these cells arent replicating their genomes and dividing (like, say, skin cells) SAMHD1 is sucking up all the wayward free nucleotides (A, T, C, G).

When HIV infects a DC or Macrophage, it needs those wayward ATCGs to reverse transcribe its RNA genome into DNA, so it can integrate into the host cells genome. But if there is a lot of SAMHD1 around, then there is little ATCG around, which means the environment is not conducive to successful HIV infection.

So how does HIV deal with this hurdle?

HIV-2 experienced a gene duplication or recombination event, resulting in the Vpr-like gene, Vpx. Either the ancestor Vpr or the new Vpx had the ability to interfere with SAMHD1 function– either Vpr got the ‘freedom’ to drop that particular function to explore other sequence space, or Vpx gained the function on its own, but in either case, the Vpx protein performs the function now.

HIV-1, on the other hand, cant deal with SAMHD1. It cant. It has no accessory protein that interacts with SAMHD1 at all… so how does HIV-1 still replicate in human cells?

Apparently, SAMHD1 can make reverse transcription and successful integration more difficult, but not impossible. HIV-1 does okay as a pathogen on its own, even in the presence of SAMHD1. Vpxs ability to interact with SAMHD1 is kinda like lentiviral ‘bling’. Its not absolutely necessary for replication, its just kinda nice.

And this actually kinda makes sense. SAMHD1 has been in the human–>primate genome for a very long time. It didnt evolve in response to HIV or SIV. It probably evolved as one of the many ways your genome keeps endogenous retroviruses and other kinds of pirate DNA in check, and even then, it is part of a network of proteins that are supposed to work together to accomplish this task. SAMHD1 is not ‘supposed’ to be able to restrict HIV-1, entirely, specifically, all on its own.

But maybe if we figure out *exactly* how SAMHD1 is exerting its anti-HIV pressure, we can capitalize on it. Maybe figure out how to boost its expression in all cells as an anti-HIV therapy. Or maybe a general therapy for any virus that has a DNA step in its replication cycle!

But even if there is literally nothing practical we can do with this information, its always fun to discover something new… something our mindless viral friends have known about for millions of years…

Comments

  1. #1 starskeptic
    February 14, 2012

    Great stuff, Abbie…

  2. #2 charles soper
    February 14, 2012

    Thanks Abigail, interesting post.
    ‘SAMHD1 restriction activity toward HIV-1 is evolutionarily maintained, [but] antagonism of SAMHD1 by Vpx is species-specific’….hmmm, sounds rather plastic and post hoc.

  3. #3 Justicar
    February 14, 2012

    something our mindless viral friends have known about for millions of years…

    Behe’s not that old, Abbie. Play knife – don’t fork him over like that.

  4. #4 Rob
    February 15, 2012

    Abbie,

    How is SAMHD1 regulated in cells that need to undergo cell division? How is it “turned off?” Is there any similarity to normal cellular control of SAMHD1 activity and the mechanism by which Vpx works?

  5. #5 fnxtr
    February 23, 2012

    Once again highlighting the difference between ID armchair quarterbacks and actual, real life scientists. Thanks again, ERV.

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