Kinda sorta not really therapeutic HIV-1 vaccine (but its still a step in a positive direction)

Posted by ERV on January 7, 2013
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Everyone has been wanting to know about this news item:

This is the actual paper:

A Dendritic Cell–Based Vaccine Elicits T Cell Responses Associated with Control of HIV-1 Replication

They did something super cool–

  1. Took viruses out of HIV+ patients.
  2. Grew up a bunch of virus.
  3. Heat inactivated the virus (killed it).
  4. Took dendritic cells out of the same HIV+ patients.
  5. Fed the DCs the dead virus.
  6. Put the DCs back into the patients (virus + cells from the same patients– autologous).

The obvious questions, are, of course:

  1. WAT???
  2. WHY WOULD YOU DO THAT????
  3. WHAT IS WRONG WITH YOU PEOPLE?????

I swear, it actually makes sense.  Dendritic cells are professional antigen presenting cells. The idea goes– The DCs chewed up the dead virus, showed it to other cells in the HIV+ patients immune system, and were like “HERE. YOU GUYS DO SOMETHING ABOUT THIS.”

The DCs were doing this naturally, but not good enough. In the body, they have to be in the right place at the right time with the right kind of HIV (there is some argument over whether DCs take up live HIV and pass it off to target CD4+ T-cells, if they arent infected themselves). With this approach, the scientists got a bunch of different kinds of HIV already present in the patient (NOT a laboratory strain of virus! The viruses that are actually in the patient!), killed it, and got it in the same place as a bunch of DCs.

Once the DCs were primed with the HIV, they were injected back into the patents.

Result?

Their immune systems DID do something about HIV!

… For a while.

For a little while, some of the patients (12 of 22) saw a big drop in their viral load. Not as much virus floating around is usually the goal of antiretrovirals, and here is a non-antiretroviral that could do the same trick!

… For a while.

Eventually, all of the patients viral loads rebounded (and not in like, 10 years. they rebounded in a few months). And, the therapy didnt have a beneficial effect on CD4+ T-cell counts.

So, no, the cure for HIV/AIDS is not ‘around the corner’.  This study did not ultimately work for the same reason everything we have tried (vaccines and antiretrovirals) havent worked: diversity within the HIV-1 quasispecies.

You throw something at HIV, there is something already present in the population resistant. It might take it a day, it might take it a few months, it might take years, but HIV figures out how to deal with whatever you threw at it, while maintaining viral fitness.

It wasnt very hard for these patients quasispecies to figure out how to deal with the DC therapeutic vaccine.

BUT, like I was saying the other day– We dont need a 100% WIN the first time we do something with HIV.  We just need little wins, little steps in the right direction that can be refined and hopefully, maybe, someday, turned into a BIG WIN.

We know now we can do that crazy procedure I numbered up above.  We can do it, it doesnt hurt the patients, and it has a brief therapeutic effect.  We have to figure out how to do it better.  Or make a different approach work first.

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Comments

  1. #1 Mu
    January 7, 2013

    Can you enlighten us pot-and-kettle scientists how involved this technique would be in a real world application? Is that something you could automate from a blood sample taken, or does it need a biopsy and 6 weeks of manual labor for each patient?

  2. #2 Orakio
    January 7, 2013

    That’s… pretty damn cool. I always refer to Vaccines as training regimens for my immune system, and I guess it doesn’t really matter all that much if it happens inside or outside of the body. Looks like it’s always going to require some level of individual attention, unfortunately, but it is a start.

  3. #3 IGetRashes
    Mediocrity, USA
    January 7, 2013

    What other troublesome viruses could be attacked with greater success using this method?

  4. #4 ERV
    January 7, 2013

    Mu– Its not *that* bad, but its not trivial, either. The two main protocols are:
    1– Isolating/culturing/purifying virus. They dont give all the specifics for their particular protocol (its a Science paper *rollseyes*), but this shouldnt take more than a few days. Maybe a week. Mostly just set-it-and-forget-it labor wise. The thing you would have to worry about here is contamination of your cultures (see: XMRV). If you are doing this for 2 patients, 20 patients, 200 patients, things could get messy. So you have to not only do the protocol, but do some QC to make sure you didnt contaminate the viral cultures.

    2– Isolating and feeding the DCs. Pretty damn simple, really. Draw some blood, put it in a flask, anything that sticks to the plate is a ‘DC’ (not really, but good enough). They didnt do any complex purification procedure. Grow the DCs for 5 days in the right media, feed them the virus, and immediately inject them back into the patients.

    Not something that is so simple you could readily automate it, but not *that* bad for an extremely personalized therapy.

    Orakio– This procedure is very much like a vaccine! Killed HIV, just like the killed influenza in the seasonal flu vaccine. But youre right– outside of the body instead of inside to increase our odds of getting the response we want.

    IGetRashes– Well, lots of other troublesome viruses can be addressed with normal vaccines. No crazy protocols needed :) And troublesome viruses that we dont have good vaccine options for (common cold)– you would be better all on your own before all the pieces were put together for this approach. You would be sick for a day or two, optimistically it would take a week to get the DCs ready, well, youd be getting better from that cold by then all on your own. But I bet the hepatitis people will be interested!

  5. #5 Bryan
    January 7, 2013

    Mu,

    One vaccine like this already exists, for prostate cancer. It is not an easy method to use, as you need to take blood from each patient, grow DCs out of that blood, “feed” the HIV to those DC’s, and then re-inject the DCs back into the same patient you took the cells from originally.

    Unfortunately, you cannot just use any DC – the HLA’s have to be matched between DC and patient (the chance of a perfect match with the general public is almost nil).

    That said, the procedure can be somewhat automated. we perform similar experiments in my lab (growing cells out of blood and pulsing with antigens), and the methodologies are simple enough that they could be partially automated.

    Expense will be an issue though – even with automation, these sorts of procedures are bound to be expensive.

    Bryan

  6. #6 rehana
    January 8, 2013

    The obvious question to me is what happens if you do it again with the same patient? Are the surviving viruses better at dealing with vaccines, or are they just the ones that are least like the vaccine you used?

  7. #7 Orakio
    January 8, 2013

    Rehana – It’s possible that the therapy would be able to be repeated for the new quasispecies of virus. Maybe.

    Part of the problem is that the responses that the DCs evolve in response to the killed viruses don’t work on every virus in the patient, for a variety of reasons: Maybe they’re not capable of expressing a proper antigen in the generations available to them, maybe the killed viruses don’t adequately represent the live quasispecies in the patient, maybe maybe maybe. HIV presents a boggling array of variations, and the DCs can only be expected to go so far.

    My next thought though, would be: What other cells can be isolated from the body and given a similar training regimen? While I suspect that filtering out a large sample of the quasispecies, killing, and returning to the body to stimulate the immune system would mostly just present the remaining HIV with lots of tasty CD4 cells, there’s got to be other parts of the system we can send on a training trip.

  8. #8 SimonG
    UK
    January 8, 2013

    Would cross-contamination of the viral cultures really matter? Wouldn’t that just lead to some immunity against HIV they haven’t got (yet)?

  9. #9 OWE
    January 8, 2013

    @ Bryan, ERV

    There is something about HIV-1 infection and vaccination that I do not understand. Perhaps you can help me?

    HIV-1 originates from chimpanzees. It forms a quasispecies in the infected individual and this is believed (as I understand it) to be the main obstacle in producing a vaccine. It also seems to explain the immune deficiency because the immune system cannot cope with an ever changing virus and eventually is overwhelmed.

    However, chimpanzees and monkeys have all sorts of SIVs! Do these SIVs in (natural or artificial) hosts also form quasispecies as HIV does in humans? And does HIV-1 in an artificially infected monkey also form a quasispecies like in humans? And do these monkeys also get sick because their immune systems cannot cope with these changing viruses? I am not very familiar with the SIV literature but I have the impression that many monkey species have adapted to their SIVs in the wild and live well together.

    Therefore, could it be that HIV-1 inhibits an important (so far unidentified) factor that the human immune system needs to work properly? Monkeys would then still make this (monkey) factor despite SIV infection and do not get sick, despite quasispecies and contrary to HIV-1 infected humans (that fail to make the human analogue).

    I do not know the current HIV and SIV literature very well, so apologies if this is a stupid question!

    OWE

  10. #10 Orakio
    January 8, 2013

    OWE: SIVcpz is confirmed to cause an analogue to AIDS in Chimpanzees: http://www.nytimes.com/2009/07/23/science/23chimp.html?ref=science&_r=0

    The only real difference is that chimpanzees have had about 1,500 generations of evolution in the face of the pressure of the disease, while we’ve had a handful in the communities that eat bushmeat, and 1-2 generations, largely unexposed, in the developed world.

  11. #11 David Edwards
    UK
    January 17, 2013

    There’s another recent development that, coupled with the above development Abbie’s just covered, might bring us a step nearer to the “big win”. Sadly the paper’s behind a paywall, but this hopefully won’t affect Abbie’s ability to access and comment upon it :)

    Paper can be found here:

    http://online.liebertpub.com/doi/abs/10.1089/hum.2012.176?prevSearch=harrich&searchHistoryKey=