HIV-1 CTL Vaccine: OH SHI-

Um, so like, you now how ‘HIV-1 doesnt evolve‘ and stuff?

Well, um, apparently its figuring out how to become invisible to an entire branch of our immune system.

Adaptation of HIV-1 to human leukocyte antigen class I

Oh shi-


Okay, there are ‘flags’ on the surface of every cell of your body– MHC Class I molecules. On these ‘flags’ are little bits of protein the cell is making, telling passing by immune cells everything is fine.

When a retrovirus infects a cell, its genome/genes are treated exactly like the host genome/genes, so bits of retrovirus proteins get put on these flags. To passing by immune cells, these flags are like a skull-and-crossbones, signaling that something has gone horribly wrong with the cell, and it needs to die.

Now, if you and I are infected with the exact same virus, our pirate flags might not look exactly the same. Depending on what MHC Class I genes we have, we present different proteins in our MHC I molecules. Your pirate flag might be red. My skull might have an eye-patch. My CTLs can see my flags, but it couldnt see yours. Your CTLs could see your pirate flags, but it couldnt see mine. Its good, but complicated, genetics and immunology.

In the case of HIV-1 infection, some peoples pirate flags REALLY piss off their CTLs. Because their CTLs get so worked up, HIV-1 infected cells are slaughtered, lowering viral loads, thus slowing progression to AIDS.

HIV-1 usually evolves around this to ‘hide’ from CTLs. Maybe it puts a sombrero on the skull so the CTLs think its a party boat. But while HIV-1 evolves ways to hide from cytotoxic T-cells, this escape comes at a fitness cost. So if the sombrero-pirate-flag-HIV is transmitted to someone with a different MHC type whos CTLs couldnt see that pirate flag in the first place, HIV-1 is going to take off the sombrero and regain fitness.

The Problem: HIV-1 is figuring out how to evade CTLs… while maintaining fitness.

Certain MHC I types are associated with better HIV/AIDS prognosis. If you have HLA-B*57, HLA-B*27, HLA-B*51, youre going to progress to AIDS slower. But this correlation is crumbling as HIV-1 evolves with us. For instance in Japan, more and more people who are B*51 negative are being infected with B*51 escape mutants. In 1983, 21%. Today, 70%.

Furthermore, HLA-B*51 does not protect against disease progression in Japanese subjects infected between 1997 and 2008, whereas HLA-B*51-positive haemophiliacs infected in 1983 had lower viraemia levels and higher CD4 counts than HLA-B*51-negative haemophiliacs…
… Moreover, the strong associations between certain HLA class molecules, such as HLA-B*57, HLA-B*27 and HLA-B*51, and slow disease progression may decline as the epidemic continues, particularly where these HLA alleles are highly prevalent, and where HIV transmission rates are high.

HIV-1 is picking our locks. If we dont shut this beast down ASAP, CTL vaccine strategies will be utterly useless.

The paper authors try to be more optimistic. Maybe a future HIV-1 vaccine will just need to be altered now and then to keep up with the virus, like influenza vaccines:

The induction of broad Gag-specific CD8+ T-cell responses may be a successful vaccine strategy, but such a vaccine will be most effective if tailored to the viral sequences prevailing, and thus may need to be modified periodically to keep pace with the evolving virus.

Ugh. This is pretty damn impressive for such a ‘pathetic’ mutator…

Comments

  1. #1 thingsbreak
    May 1, 2009

    I love your posts, but some times they scare the hell out of me.

  2. #2 Optimus Primate
    May 1, 2009

    The thoughts are kind of swirling, but let me see if I can sort of make sense out of the question that’s formulating in my head here: if this trend continues, is there any reasonable way of estimating how quickly HIV may eventually progress to AIDS?

    What I’m wondering, I guess, is this: could HIV-1 become so good at its job that it puts itself out of work? In other words, symptoms arise so quickly, and health deteriorates so rapidly, that sexual transmission becomes less likely?

    Sorry if that’s a dumb question. I’m still thinking through this one.

  3. #3 ERV
    May 1, 2009

    thingsbreak– Im a realistic optimist :D aka, Debbie Downer… :(

    Optimus– Yes, the virus could do that… but it would ultimately be less fit, and stop being transmitted. Viruses that are spread through coughing/poop have some luxuries HIV-1 doesnt– HIV-1 wants a happy medium. It wants to reproduce as much as it can (high viral loads, which kill people) but still be transmitted (requires not killing people).

    Unfortunately, to figure out that happy medium, it has to kill a lot of people, and we cant let it do that.

  4. #4 John Danley
    May 1, 2009

    So, I don’t get it, is teh Jebus “picking our locks”?

  5. #5 dreikin
    May 1, 2009

    Any info on the changes allowing HIV to do this?

  6. #6 BGT
    May 2, 2009

    I m surprised that Wee Willy Winky hasn’t spewed on this post yet. Let’s see if he can hold out for 168 hours.

  7. #7 rrt
    May 2, 2009

    Why would Wee Willy Winky wank wildly on this post?

  8. #8 William Wallace
    May 2, 2009

    OT: Abbie, quick, do a screen shot at Drudgereport, where you will see a link “WHO fears complications if HIV and H1N1 viruses combine…”. (I assume this isn’t actually possible, and that the headline is another scare tactic.)

  9. #9 William Wallace
    May 2, 2009

    And now to address the post and rrt.

    RRT, bite me.

    ERV, the post is interesting and educational, I nominate it for the best of ERV.

    Certainly, it is much better than the worst of ERV. Still no antlers on the little buggers, but sombreros are an impressive new trait. I think I am about to become an evolutionist.

  10. #10 Sascha
    May 2, 2009

    WW
    Are you referring to the following Reuters wire?
    http://www.alertnet.org/thenews/newsdesk/L2516414.htm

  11. #11 rrt
    May 2, 2009

    Wee Willy Winky:

    Oh, you are such a FLIRT! But what kind of guy do you think I am? I don’t kiss ANYTHING on the first date…

  12. #12 rrt
    May 2, 2009

    Ahem. Flirting aside, if Sascha’s article is the one, then they aren’t actually worried about HIV and H1N1 combining, WW. They’re just worried about what a true pandemic flu might do to people with compromised immune systems…hence, HIV-positive people. Bad headline writing strikes again.

    But I did mean my initial question…I just couldn’t resist the alliteration. Why would BGT expect you to attack this post? I missed something, apparently.

  13. #13 William Wallace
    May 2, 2009

    The point of the screenshot was because Drudge’s headline made it seem as though scientists were concerned that we’d end up with an HIV/flu crossbreed. I guessed he’d have corrected it by now….but it is still there. Sensationalism at its best.

  14. #14 Sascha
    May 3, 2009

    You’re making too much of a simple headline.

  15. #15 Moderately Unbalanced Squid
    May 4, 2009

    The pirate flag analogy is brilliant!

    Excellent post.

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