HIV, Tomato, Tomahto

This is, quite possibly, one of the weirdest examples of convergent evolution I have ever seen.

I dont want to get ahead of myself, but HIV-1 transactivator protein (Tat) and Tomato Bushy Stunt Virus P19 are totally interchangeable. HIV and TBSV arent related, like, at all… yet two of their parts are interchangeable…

This is so weird.

Let me elaborate.

Plants dont have immune systems like you and I (dir), but they have evolved their own ways of dealing with viral infections. Because most plant viruses have RNA genomes (RNA genomes can slide from cell to cell via plasmodesmata, berry berry sneaky), a really effective antiviral for plants is RNA interference.

Awesome animation that explains RNAi better than I could.***

So RNAi is great for regulating the expression of cellular genes at the RNA level (gene regulation isnt just at the DNA level!), and for destroying RNA viruses.

WIN!

Except viruses have evolved ways of interfering with RNA interference. *blink* Evolution is an arms race, man.

RNA silencing suppression (RSS) is kinda a common thing in plant viruses, considering their main adversary in plant hosts is RNA silencing machinery. One was found in influenza, and another in Ebola. But whether HIV-1 has some sort of RSS has been controversial– some labs say yes, some say no, some just look at their data and shrug.

This lab figured it out:

HIV-1 Tat RNA silencing suppressor activity is conserved across kingdoms and counteracts translational repression of HIV-1


There are lots and lots and lots of different kinds of retroviruses. The ‘basic’ ones have three genes (gag, pol, and env) and promoters, and thats it. HIV-1 is a lentivirus– that is a ‘complex’ retrovirus that has the basic genes, plus accessories.

One of those accessories is ‘transactivator‘, Tat. If you knock out Tat in HIV-1, you dont get very many infectious particles. We figured that was because of Tats main function as a transcription factor that acts on the nascent proviral RNA (wut?!? it encourages transcription of the HIV genome, but it doesnt bind to DNA, it binds to the HIV RNA). Well this clever lab noticed that Tat also had some features in common with plant viral proteins involved with RSS. They ran some experiments and got data that freaked me out.

1– If you put HIV-1 Tat or Tomato Bushy Stunt Virus P19 in plant cells, the viral proteins interfere with RNAi.

HIV-1 Tat interferes with RNA silencing machinery in plants.

2– If you put HIV-1 Tat or TBSV P19 in animal cells, the viral proteins interfere with RNAi.

A plant virus protein has RSS activity in mammalian cells. Whoa!

3– If you mutate HIV-1 Tat in the putative RSS active sites, you dont get much viral production.
Suppressing RNAi is necessary for optimal HIV-1 production.

4– If you knock out HIV-1 Tat, and supplement with TBSV P19, you get normal HIV-1 production again.
So the decrease in particle production isnt due to Tat having some assembly functions, and that was getting knocked out. Tat has RSS activity, and if you knock it out, it can be compensated for by a plant virus RSS protein.

HIV-1 Tat and Tomato Bushy Stunt Virus P19 are totally interchangeable. Its as if this lab clipped off a birds wings, replaced it with dragonfly wings, and the bird could fly and navigate just fine.

Freaky!!!

*** As if this wasnt weird enough, RNAi doesnt work on these viruses through chopping up their RNA. The machinery just sorta snuggles up to the RNA… getting in the way, so ribosomes cant get on the RNA to make protein– Its called translational repression, but I dont know enough about how this works to blag on it… I dunno if the field even totally gets how translational repression works… A post for another day, but I wanted you all to know Im not telling you all about all the coolness in this superfriggencool paper :P

Comments

  1. #1 andy
    January 23, 2009

    I’d always wondered about what the plant equivalent of an immune system was. (Ditto for fungi). But I followed the path of physics, and got too afraid to ask…

  2. #2 ERV
    January 23, 2009

    RNAi doesnt cover everything– its just one component! But its a very useful component for getting rid of viruses :)

  3. #3 Tommy V.
    January 23, 2009

    I wonder can plant viruses become endogenous in the plant genome?

  4. #4 The Science Pundit
    January 23, 2009

    I would imagine that translational repression isn’t as efficient as cleavage. Presumably the RNAi’s that use cleavage can move on to other RNA’s after having completed their deed, while those that use translational repression remain bounded.

  5. #5 Rogue Epidemiologist
    January 23, 2009

    @andy
    I (a cell bio student) once asked my friend (a plant bio student) the same question.

    She put it thusly, “When a plant cell gets infected, it puts out a distress signal. Then the cells around it help out by killing it.”

    Sucks for the cell, great for the plant.

    As for that video clip of the RNAi in action, that was one of the best animations of DNA txn/tln I have ever seen. Gorgeous!

  6. #6 mo
    January 23, 2009

    Wow!

    I’m a biologystudent and I’m also doing Virology. I was told that Tat acts as a transcriptional activator by jumping on the starting HIV transcript and hyperphosphorylating RNAPII CTD. From the first look on the introduction this seems also true. So maybe Tat does two cool things. Or is it?

  7. #7 Anon
    January 23, 2009

    A woodworking book I read (an excellent book) reminded us that wood is meant for the tree, not for the woodworker…. it also spoke of the difference between animals and plants, when it came to injury: Animals heal–Plants compartmentalize.

  8. #8 Jared
    January 24, 2009

    I read something about translational repression not long ago on PLoS, something about the miRNAs not binding correctly with the target sequence and RISC therefor not being able to attract Dicer, or something like that, so it’s just stuck bound to this dsRNA, I might blog on it next, after my post on Asperger Spectrum and the many possible causes.

  9. #9 chezjake
    January 24, 2009

    I thought that since the election we didn’t have to worry about Bushy Stunts anymore. =)

  10. #10 Sili
    January 24, 2009

    Oh, that Designer. :shakes head: No imagination.

    Do you take viral/vaccinatory requests?

  11. #11 Volt
    January 24, 2009

    This is incredible interesting.Thanks for the post. This blog is one of the most interesting science blogs out there. Kudos.

    http://microbialmicrocosm.blogspot.com/

  12. #12 Jonathan
    January 24, 2009

    Abs –
    Yes, I still follow your blog, and yes, it is definitely getting more awesome with time! This is one of the best entries I’ve read in a long time. Keep it up!

  13. #13 Chris Noble
    January 25, 2009

    HIV-1 Tat RNA silencing suppressor activity is conserved across kingdoms and counteracts translational repression of HIV-1

    Anyone want to place a bet on how soon somebody will argue that this paper is evidence that:

    a) HIV doesn’t exist.
    b) Evolution is wrong.
    c) Both a and b.

  14. #14 amphiox
    January 25, 2009

    Is there any sequence homology between HIV tat and TBSV P19 that might suggests a lateral gene transfer event at some point in the past?

  15. #15 Vorn
    January 25, 2009

    “Tomato Bushy Stunt Virus” sounds like the name of an anime or something.

  16. #16 ERV
    January 26, 2009

    amphiox– Nononono, Tat and P19 are totally unrelated. You get Tat from alternative splicing of the HIV-1 mRNA (doubly spliced). P19 is the result of ‘leaky’ ribosome scanning on a subgenomic RNA (this virus is never in the nucleus, no splicing)– the ribosome misses the start codon for P22, and hits the start codon for P19 instead.

    Gene wise, they couldnt be much more different. Except, they both evolved an arginine-rich region that can bind to double-stranded RNA (for this RSS activity)– convergent evolution!

  17. #17 JustaTech
    January 26, 2009

    So, does this mean that if I feed my mice tomatoes they will finally have an immune response to HIV-1 tat?

    Didn’t think so. *sigh*

  18. #18 Rrr
    January 26, 2009

    Can your mice do bushy tail stunts? :-)

  19. #19 Brian Foley
    January 26, 2009

    The Qian et al paper is not the first on this activity of the HIV-1 Tat protein. Others had previously published that the K51A mutation eliminated the anti-RNAi activity of Tat:

    Bennasser Y, Le SY, Benkirane M, Jeang KT (2005) Evidence that HIV-1 encodes an siRNA and a suppressor of RNA silencing.
    Immunity 22:607–619.

    Triboulet R, et al. (2007) Suppression of microRNA-silencing pathway by HIV-1 during virus replication.
    Science 315:1579–1582.

    Huang J, et al. (2007) Cellular microRNAs contribute to HIV-1 latency in resting primary CD4+ T lymphocytes.
    Nat Med 13:1241–1247.

    And yes, the Tat protein has other functions besides this one, both in promoting transcription and in preventing premature termination of transcription.

  20. #20 Jared
    January 26, 2009

    Oh, the reason Tat inhibits RNAi; Tat binds Dicer, which is necessary to kick off RNAi, it does this by binding to TAR and when Dicer comes along, it hugs it really tightly… You can even get the two to co-immunoprecipitate in [what is probably] this structure.

  21. #21 Jared
    January 27, 2009

    It would be interesting to see of Tat also plays a role in “priming” CD4+ lymphocytes for infection, I know it has the ability to kill some of them, but it would be neat to compare the infection rates of Tat mutant which lacks the protein transduction domain.

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