HIV-1 Vaccine: Again, OH SHI-

Your immune system is like an onion ogre parfait.

Its has lots and lots of layers.

You have intrensic immunity– Abilities every single one of your cells has to defend itself from viruses. VpuTetherin would be a good example of this, as would APOBEC and Trim5a. Pick a cell in your body– it can make these proteins. Doesnt have to be a special immune cell.

Then you have innate immunity– Certain immune cells are not specific for any particular pathogen, but they can identify patterns that are ‘wrong’. They see things your body knows aint right, like double-stranded RNA (your body doesnt make that!) or unmethylated bits of DNA made up of mostly Cs and Gs (your body doesnt have that!), or bacterial proteins like flagellin (mammals dont have flagella that look like bacterial flagella!). These cells dont care what virus is making the double-stranded RNA (HIV-1, rotavirus, respiratory syncytial virus), it just knows that double-stranded RNA is wrong, and that happens to be a step in these viruses life-cycle. Only immune cells can see pathogens this way, and respond accordingly.

And then theres adaptive immunity– This is the one you all are probably most familiar with. These immune cells evolve in the face of infection to be specific for that pathogen. Very generally, Cytotoxic T-cells evolve to specifically target and kill host cells infected with the pathogen, and B-cells evolve to make antibodies specific for the pathogen, to neutralize them or make them easier for your immune system to see–>kill.

All this specific immune response takes time to evolve (couple weeks). Viral vaccines use weak/dead viruses to prime your adaptive immune response. Thus when you are exposed to a real, harmful virus ‘in the wild’, your body has a cheat-sheet for how to get rid of the virus. Your response is stranger and faster than if you had never gotten the vaccine.

To bring this back to HIV-1, we might be screwed when it comes to making a CTL vaccine (or, if we dont do it quick we are screwed). HIV-1 is figuring out how to pick our locks at a population level.

Okay, well, what about antibodies, then? What about a vaccine that revs up B-cells instead of T-cells?

Well, a series of papers have been coming out of a lab in the Netherlands that makes me think we might be screwed on that front too.

And once again, its all evolutions fault.

Escape from autologous humoral immunity of HIV-1 is not associated with a decrease in replicative capacity.


Rapid escape from preserved cross-reactive neutralizing humoral immunity without loss of viral fitness in HIV-1-infected progressors and long-term non-progressors.

So heres The Problem: Lots of people who are infected with HIV-1 make nice cross-reactive neutralizing antibodies (their antibodies dont just work against the subtype of HIV-1 they are infected with, but other subtypes as well).

These antibodies are not enough.

Everyone still progresses to AIDS after infection. Slowly, quickly, everyone eventually gets AIDS.

So, either these neutralizing antibodies fade with time, or HIV-1 is evolving to get away from the antibodies.

Its not the former– all the patients used in these studies have great cross-reactive neutralizing antibody responses.

Its the latter. HIV-1 evolves to escape these antibodies… and your body cant catch up. It keeps making the old antibodies, making antibodies to viruses that were in your body months… years ago… When those viruses are long gone. HIV-1 evolved away from them.

Now, theoretically this would be A Good Thing. HIV-1 can escape CTL responses. It comes at a fitness cost. HIV-1 can escape drugs. It comes at a fitness cost. So HIV-1 escaping from antibodies should come at a fitness cost…

Except it doesnt (I would argue that these papers dont measure ‘fitness’. they technically measure replicative capacity. unless there are gross deficiencies in any of their isolates, they wont be able to see small fitness differences, but I digress).

What this means, is, the absolute opposite of everything and anything you have heard a Creationist tell you about how proteins evolve. They say that you make a mutation here, you make a mutation there, and suddenly, things dont work anymore! Wow, isnt that protein PERFECTLY DESIGNED!

In the case of HIV-1 Envelope, not only is there massive genomic and protein sequence variability, but this variability translates into functional plasticity. Envelope can change a lot, and still work fine and dandy. Envelope can change a lot and these changes do not come at a fitness cost.

HOW THE HELL CAN IT DO THAT?????

*sigh*

This all just means that making an HIV-1 vaccine to elicit antibodies is going to be a tough road… *sigh* Deeeeebie Downer…..

Comments

  1. #1 Shirakawasna
    March 3, 2010

    Erm, Vpu -> tetherin instead?

    (also, pssssst, quasispecies general fitness woo)

  2. #2 ERV
    March 3, 2010

    Oops! Thanks, its hard to look at things from the host perspective :P

    … quasispecies general fitness woo…
    ??

  3. #3 Kevin
    March 3, 2010

    Viruses are too smart – I should have been a virologist instead of an immunologist. Oh well…

    One small quibble though: non-immune cells still have innate immunity. Most epithelial and endothethelial cells express and RLR’s (which detect “wrong” RNA and DNA inside the cell) and a subset of TLR’s (which detect bugs outside the cell), and make various inflammatory cytokines – not nearly as much as a macrophage or dendritic cell, but still.

  4. #4 Shirakawasna
    March 3, 2010

    What, you don’t like my vague non-sequiturs?

    I’m just appreciating the coolness of the ‘breadth’ of quasispecies’ fitness, where relatively high fitness can be spread out over a lot of genotypic space. It’s cool… and also lets HIV escape our immune system (as you know). >_<

  5. #5 Optimus Primate
    March 3, 2010

    Your response is stranger and faster than if you had never gotten
    the vaccine.

    This may be my favorite typo of the week. Because, honestly, the more I learn
    about immunology, the weirder and messier and more fascinating it gets.

    (Also, as someone who very much relies on your links as a memory refresher,
    I’m curious about what “making a CTL vaccine” was supposed to link to. It just
    leads back to this post.)

    (Also also, Shirakawasna, I think maybe Abbie read “woo” as
    woo, not Woo! If that
    makes sense.)

  6. #6 ImagingGeek
    March 3, 2010

    I’m quite surprised that people are still following up on this line of research. I haven’t done any HIV research in a few years, but at least when I left the field it was generally felt (amongst us silly immunologists anyways) that HIV was relatively insensitive to antibodies, largely due to the fact that HIV appears to be able to spread quite well via cell-cell contact (the whole DC-thing), thus avoiding exposure to extracellular antibodies.

    Sure, antibodies may get at the HIV in the blood, but given most HIV replication appears to be in the gut, where most transmission seem to be cell-to-cell, one has to wonder why people are still looking at antibodies.

  7. #7 W. Kevin Vicklund
    March 3, 2010

    I linked to this in another thread, but it’s kind of buried in my comment. Thought it was cool enough to bear repeating.

    Why Anti-HIV Antibodies Are Ineffective At Blocking Infection

    Basically, the spikes that stud HIVs surface are too far apart for efficient double-binding by antibodies. Double-binding is orders of magnitude more effective than single-binding. Ergo, antibodies suck at binding HIV. And then HIV evolves.

  8. #8 Sili
    March 3, 2010

    Parfait? Parfait shouldn’t have layers.

    Are you thinking of millefeuille or baklava?

  9. #9 Dr. Duke
    March 3, 2010

    You wrote “…Everyone still progresses to AIDS after infection. Slowly, quickly, everyone eventually gets AIDS. …”

    Should probably say “almost everyone”. There are in fact a small percentage of infected people who have not yet progressed to AIDS, and perhaps never will in a normal lifespan. You should also specify “if left untreated”, because with the currently available highly active antiretroviral treatments a very large percentage of people are expected to lead a normal lifespan without developing AIDS. A small percentage of treated people will die from other complications of infection (such as Leukemia) or side effects of the drugs, but still most will live far longer than if they had been untreated.

    See for example:
    Successful HIV treatment: lessons learned.
    Cohen CJ.
    J Manag Care Pharm. 2006 Sep;12(7 Suppl B):S6-11.
    PMID: 16984222

  10. #10 HouseOfNumbers
    March 3, 2010

    View the new documentary “House of Numbers” to see why questions about this must be raised and deeper issues about HIV and AIDS need to be discussed. Lives are at risk, and this is the first documentary with the worlds foremost authorities highlights the scientific problems with HIV testing, science, statistics, and why there is no cure. If sheds new light on a misunderstood phenomena. GO to http://bit.ly/bGwuST to see the trailer.

    Truth about AIDS as told by Dr. Luc Montagnier. AIDS can be reversed. Nutrition is the answer. http://bit.ly/bGwuST

  11. #11 Richard Hendricks
    March 3, 2010

    Perhaps HIV’s outer proteins have a chameleon coat that they can change without affecting how well the rest of the protein behaves? Like masks on a killer, changing and mutating constantly to tie up the immune system with fighting last week’s variant, while the active sites lie buried within.

  12. #12 W. Kevin Vicklund
    March 3, 2010

    Richard Hendricks @10:

    That’s pretty much what is happening! Except what’s really happening is that the changes to the inner workings generally result in lots of ‘dead’ viruses, so it’s mostly changes to the outer coating are propagated. AIUI, at least.

  13. #13 Optimus Primate
    March 3, 2010

    Wait. Never mind about the link. I must be losing my mind.

  14. #14 Stephen Wells
    March 3, 2010

    @9: a valid point. A successful treatment is, famously, something which lets the patient live long enough to die of something else :)

    I guess that German bone-marrow guy is currently the only “cured” patient, properly speaking.

  15. #15 Jon H
    March 3, 2010

    I’ll also note that the BUAV report includes a photo captioned “Brain damaged Marmoset at Cambridge University ©BUAV”.

    The animal picture is indistinguishable from a “Marmoset recovering from lifesaving tumor removal surgery”. It’s just “ooh, look, cute monkey with sutures! BAD” Furthermore, you can’t tell from a picture how well the animal is being cared for, how often the vets check on it, what level of painkillers are in its system, whether it’s actually in pain, or really anything relevant.

    Post-op pictures, human or animal, look nasty, eliciting an emotional response that may not be justified.

    I’ve seen other animal rights writings which exaggerate things completely out of proportion. One described a monkey in a vision study as having a tube ‘attached to its mouth’. The tubes aren’t ‘attached’ to the monkey, they’re placed there, like when your dentist hangs a suction tube over your lip to suck up the saliva. Only less painful because the suction tube sometimes gloms onto your tongue, which hurts, while the reward tube provides apple juice.

  16. #16 Jon H
    March 3, 2010

    Crap, nevermind, wrong blog.

  17. #17 ERV
    March 3, 2010

    Its funnier on this blog.

    ROFL!!!

    I think this particular comment thread has firmly established we all need to go to bed early tonight. hehehehehehe!!!

  18. #18 Optimus Primate
    March 3, 2010

    Says you. I just need a drink. And some reading glasses, apparently.

  19. #19 ERV
    March 3, 2010

    Hey, want me to release the ‘House of Numbers’ comment for this post?

    Its just spam, but its fun to see how clueless the HIV Deniers are :D

  20. #20 Optimus Primate
    March 3, 2010

    Release it!

    Also, in case you didn’t know, if you Google House of Numbers +HIV, your post about it is on the first page of results. :)

  21. #21 ERV
    March 3, 2010

    Its #10. hehehe.

  22. #22 Optimus Primate
    March 3, 2010

    Holy shit biscuits! All we need to do to avoid AIDS is wash our junk and eat our Wheaties? Silly AIDS patients. It’s so easy!

    I’m reminded of the whackjob Mannatech (glyconutrient) peddler who told me, after my mom died, “Oh, that’s so sad, because cancer is 100% preventable with the right supplements.”

    No, I didn’t punch her.

    Yes, I wanted to.

  23. #23 Mr. Hopey Changey
    March 3, 2010

    Use Oleander extract in herbal supplement form. One herbal oleander based supplement was 100% effective in a clinical trial of raising white blood cell counts in HIV/AIDS patients with extremely compromised immune systems.

    Also recommend Colloidal Silver 25 ppm minimum while taking whey protein to keep muscle tissue strong. If AIDS really is caused by a virus ( man made virus I might add) then we should be able to kill it somehow.

  24. #24 Mr. Hopey Changey
    March 3, 2010

    “Oh, that’s so sad, because cancer is 100% preventable with the right supplements.”

    That’s not true of course, but Vitamin D3 in the right doses could significantly affect the number of breast cancer cases. It could cut breast cancer by 75 %, yet the FDA (Fascist Dumb Asses) refuses to adhere to anything that works.

  25. #25 NM
    March 3, 2010

    Try googling the quote “Truth about AIDS as told by Dr. Luc Montagnier. AIDS can be reversed. Nutrition is the answer.” to see how much spamming he’s been doing. Most of it under dsinla, which I think is one of the producers, David Syner. Meanwhile another of the HIV infected denialists in the film, Kim Bannon, is dying:

    http://www.facebook.com/group.php?v=wall&ref=share&gid=152423602146

  26. #26 Mr. Hopey Changey
    March 3, 2010

    OOOH Someone changed my name. Wow. I’m impressed. NOT!

    Anyway, HIV is largely, but not entirely a gayism disease. Of course people who have never had sex at all have contracted the disease, but homo males are the largest percentage of HIV patients. Gayism has its consequences. You would think people would learn.

  27. #27 R2
    March 3, 2010

    This is all very, very interesting (I love virology), but /please/ share some good news from the world of retroviral research!

    I know they are nanogods of cool, but we must be doing something right somewhere?

    The hopes for a therapeutic vaccine in 5 years fades with every post. My respect for the retroviruses grows, however.

    (BTW, this post is not meant as criticism of your blog, just life!)

  28. #28 Dawn
    March 4, 2010

    Gee, Mr. Hopey Changey. Ya think maybe all those women in Africa with AIDS, and all their children, are gay? WOW. I never would have guessed. And all the hetero males and females who got it from unprotected sex. And all those babies who got it from their mothers. Oh…and how do you explain gay women, who have the lowest rate of HIV (and STDs in general) if HIV is a “gayism” disease?

    Nowadays, “homo males” as you call them, are not the largest percentage of NEW HIV patients. They may be the largest part of the population but I doubt it now. (PS…”Gayism”? Oh really now. Can’t you be an adult and call it by its proper name? Your phrasing makes it sound like you are about 5 years old.)

  29. #29 Orakio
    March 4, 2010

    Clearly, some rogue has trained HIV in the arts of ninjutsu. Countertactics are clearly required. Too bad we can’t feed them highly murderous false targets.

  30. #30 Jason
    March 4, 2010

    Dawn,

    MHC is using a Sarah Palin sound bite as a moniker. And not only that, but a REALLY REALLY stupid sound bite. Why would you expect him to communicate and not sound like he’s 5?

  31. #31 dNorrisM
    March 4, 2010

    18. I could use a drink too:

    “Your immune system is like an onion ogre parfait Pousse Cafe.”

  32. #32 Prometheus
    March 4, 2010

    #31 dNorrisM

    “Pousse Cafe”

    Does anyone ever actually order these for reasons other than to exact revenge on a bartender?

    #8 Sili

    “Parfait? Parfait shouldn’t have layers.”

    True only of the inferior French parfait.

    Superior American parfait have layers.

    Erv should have specified “Your immune system is like a [Dairy Queen Peanut Buster Parfait or Jello Gelatin pretzel parfait].

  33. #33 Dawn
    March 4, 2010

    @Jason: Oh. Well, I never listened to Sarah Palin; my nervous system couldn’t stand her, so I didn’t know that was one of her sound bites. Thanks for the explanation.

    Maybe Sarah’s problem is that, with 5 kids, she is stuck in “baby talk” mode. I might have used that phrasing with my infant, but not once they were verbal.

    Still haven’t figured out what MHC’s problem is. Maybe infantilism?

  34. #34 Paul
    March 4, 2010

    #30 I was doing work today with Madagascar Hissing Cockroaches, which we call MHC for short. This thread’s MHC gives my MHC’s a bad name.

  35. #35 Proud Kuffar
    March 5, 2010

    Denialism=A clear and present danger to us all.
    We are so screwed!

  36. #36 TotallyUncool
    March 5, 2010

    Now I’m trying to imagine an onion ogre parfait — no matter how I put those ingredients together in my mind, it just doesn’t sound appetizing.

    Raw bermuda onions and stinky, dirt-encrusted ogres kind of go together, but it’s hard to see how either of them would really work well in a parfait.

    But then again, nobody ever said that your immune system had to taste good…

  37. #37 Sascha
    March 20, 2010

    @31

    Note that the original pousse-café is nothing more than a coffee with a jigger of the strong stuff mixed in. Don’t expect a Parisian waiter to even contemplate adding panache to your order.

    Just couldn’t resist.

  38. #38 Scrabcake
    March 23, 2010

    Hey hopeychangey whatever. I know this is a bit late, but I’m reading And The Band Played On, and I NEED to kick your lame ass.
    It’s attitudes like yours that caused our late highly-overrated president Reagan to chronically underfund the CDC for AIDS, all the while lying through his teeth about the amount the government was spending on it. (Give you a hint–it was more in the hundreds of thousands than the millions and this is AFTER there were 500 known cases)
    It’s that kind of attitude that caused the media to largely ignore the disease even when haemophiliacs and needle-sharers were getting it too. Eh. It’s just teh gheys. Whatev.
    It’s attitudes like yours that fiddled while rome burned and 20,000 people in the united states got infected because local municipalities wouldn’t set up AIDS clinics and education, because it was a gay disease (even though it wasn’t).
    It’s attitudes like yours that caused the blood banks to transfuse HIV laden blood into thousands of people: grandmothers, babies, little children, over a span of years because they refused to believe the CDC’s insistence that AIDS could be spread via transfusion.
    Did you know that the people funding the first research in the early years of the epidemic were the Gay community? THEY didn’t seem to mind that their money was going to benefit haemophiliacs and grandmas who’d gotten hip replacements.

    Do you think there was a supplement or combination of supplements that weren’t tried by the gay community during the early years of the epidemic when researchers, local officials and the Reagan admin took turns not giving a shit?
    And. None. Of. Them. Worked.

    So, Sit and Spin, you immoral bastard.

  39. #39 Travis
    March 23, 2010

    Scrabcake,

    It’s attitudes like yours that caused the blood banks to transfuse HIV laden blood into thousands of people: grandmothers, babies, little children, over a span of years because they refused to believe the CDC’s insistence that AIDS could be spread via transfusion.

    This quote hits a bit close to home. There was a tainted blood scandal in Canada where thousands of people were infected with HIV and Hep C due to tainted blood in the late 1970s and early 1980s. As someone who was born premature and received blood transfusions during the time in question I had to get tested for these diseases. The only good point was that I was fairly young and did not really understand why I was being tested until later. Now the reasons for this disaster were different, more incompetent, but tainted blood should be treated seriously.

  40. #40 scrabcake
    March 23, 2010

    Damn, Travis,
    That is scary. I was too young to know what was going on at the time, and I’m glad you are ok. Reading this book, I just want to bang so many heads together on both the right and the left. The blood banks wouldn’t do a thing about blood supply contamination except for a disclosure sheet that people had to fill out before donating — they refused to screen the blood because of the price and balked at asking anything but lightweight questions of donors for fear of offending the gay groups.
    They’d only ban you from donating if you had lesions for Kaposi’s Sarcoma. The incubation period for AIDS is so long that by the time donors showed any symptoms they’d donated ages ago, but the blood banks, especially the nonprofits refused to pull blood until the CDC could document a person who had developed AIDS symptoms from a transfusion donated by a person showing AIDS symptoms WHEN they donated, and even when the CDC gave them THAT, they backpedaled for months.
    And the Band Played On does not have too many “proud to be an American” moments in it. It’s pretty much a documentation of a 10 way trainwreck with a space shuttle plummeting into the middle for good measure.

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