Elite Suppressors

There are two questions I get over and over and over again from friends, family members, readers, etc about HIV-1:
1. Will we ever get a vaccine?
2. How come some people who are infected with HIV-1 never get AIDS, and some people succumb very quickly?

Ive already touched on Q1 a couple of times, I think it is about time I posted on Q2.

From my sterile perspective as a researcher, we categorize patients by how fast they progress to AIDS. Usually people are just ‘progressors’, they get infected and slowly progress to AIDS over the course of a decade or so. However, there is a gradient of how quickly patients progress, from ‘rapid progressors’ to ‘long-term non-progressors.’ Rapid progressors never really recover from their acute HIV-1 infection, and die very quickly (many of the infants I study died within a year after infection). On the other end of the spectrum, I study infants who are long-term non-progressors– they are infected with HIV-1, they are on no drugs, and their CD4+ T-cell numbers are relatively stable.

Then there is a group we really, really want to learn more about– the Elite Suppressors. These folks have anti-HIV-1 antibodies, are on no anti-retrovirals, but they have very little virus floating around their blood. Less than 50 viruses per milliliter (‘normal’ HIV-1 patient? 10^7 copies per ml). Its also really hard to find infected T-cells in these people too. This is what we ‘want’ HIV-1 infection to be if we cant figure out how to make a vaccine! Yeah, youre infected, it sucks, but its not going to kill you (at least, for a very long time– there are Elite Suppressors that have been infected for +25 years and are still fine), drug costs arent going to bankrupt you (Elites are on no drugs), and its harder to pass on the virus to other people (if your viral load is extremely low, the odds are lower you will pass one on to someone else).

So the question is: How do they do it, and how can we make sure everyone who is infected with HIV-1 can react the same way?

It could be the virus.
The reason why an individual is a rapid progressor or an elite suppressor might be because of the virus they were infected with in the first place. Some HIV-1 variants are ‘meaner’ than others– For an easy example, HIV-2 isnt as ‘bad’ as HIV-1. Theyre related, but there are enough differences between them (LIKE VPU LOL!) to make one more pathogenic than the other.

There was also an interesting case in Australia, where a group of individuals were infected (through a blood transfusion) with HIV-1 viruses that had a deletion in an accessory gene, nef. These folks held up pretty well… but vaccine efforts centering around deleting nef (or other accessory genes) making a live attenuated vaccine didnt work.

It could be the person.
There are so many variables within one human, you guys. So many…

It could have something to do with the receptors HIV-1 needs to infect your cells. Maybe my CCR5 binds super tight to HIV-1, and yours dont bind HIV-1 very well. Maybe yours cant bind HIV-1 at all, like the ‘Delta 32s‘. People with a mutation in their CCR5 gene cant be infected with certain kinds of HIV-1 because they just dont have the receptor it needs to infect you. Along those same lines, maybe you express a lot of CCL3L1 (the natural ligand for CCR5), and HIV-1 never gets a chance to bind to CCR5 because they are never available– theyre always bound to CCL3L1.

Your genes also come into the equation when it comes to your HLA type. Remember this from the MHC-Mate fiasco?

MHC Class I molecules are on the surface of all of your cells. Proteins that your cells make eventually get degraded, and MHC molecules present little bits of these proteins at the cell surface. Its a signal to cytotoxic T-cells that everything is fine.

When your cells are infected with a virus, or have become cancerous, its MHCs start presenting proteins that arent ‘normal’– they become a signal to CTLs that something is wrong, and the cell needs to be killed.

I might present a set of bits of HIV-1 proteins in my MHC, but you might have a different HLA type, so you present different bits of the same proteins. Maybe your cytotoxic T-cells get into a murderous rage over your bits and kill infected cells very effectively, and my CTLs dont even notice anything is wrong. There are HLA types that seem to have a protective effect against HIV-1 when you look at a population, but when it comes down to individual cases, just because you have a ‘protective’ HLA type, doesnt mean you will be an elite suppressor.

It might have something to do with intracellular, ‘natural’ anti-retrovirals, like APOBEC and tetherin. Maybe the elite suppressors have a tetherin on steroids.

It could have something to do with variations in your immune cells– B cells, T cells, macrophages, dendritic cells, etc.

We dont think it has much to do with antibodies and B cells anymore. Everyone infected with HIV-1 makes ‘neutralizing antibodies’ (antibodies that prevent HIV-1 from binding and infecting cells). The problem is The Red Queen. Your antibodies are always a step behind the virus. And, there doesnt seem to be any difference between the antibodies of a rapid progressor vs a non-progressor. Its probably not antibodies that make an elite suppressor.

It might have something to do with those cytotoxic T-cells. As your activated CTL numbers go up, HIV-1 viral load goes down… but we all know the mantra: Correlation does not equal causation. People are still looking into this.

Dendritic cells have ‘toll like receptors‘ that recognize patterns, like bacterial walls or viral genomes, and release ‘warning’ signals to recruit other immune cells. Maybe my receptors are better than yours. Maybe your cells release more of the warning signal than mine.

……

There are many, many more variables.

Theoretically, if this were a different disease, what we would do experiments on mice. We have inbred mouse strains, which means that the mice are all clones of one another. If you leave one of those clones alone, and create a different line of mice that is 100% identical to the clone, but doesnt have, say, T regulatory cells, its becomes easier to tease out the contribution of each potential variable.

But we cant infect mice with HIV-1.

The best animal model we have are macaques, and they sure arent clones of one another.

And you sure cant knock out an elite suppressors T regulatory cells ‘just to see what happens’…

So, long story short, while we have lots of ideas for why one person might progress to AIDS more slowly than another person… we dont know why.

Comments

  1. #1 keely
    September 12, 2008

    great explanation, thanks.

  2. #2 IR
    September 12, 2008

    Fantastic post.

    Another fine example of science working on a problem it doesn’t have an answer to (and admitting it as well) instead of just saying ‘goddidit’.

  3. #3 Michael the G
    September 12, 2008

    Long time reader first time poster blah blah.

    Nice lay-speak explanation of the difficulties in ferreting out “Slow-Progressors”

    You mention trials with mice and why they are not quite as suitable due to their inability to contract HIV-1. I direct your attention to one J. Victor Garcia http://www.eurekalert.org/multimedia/pub/2224.php

    and more importantly his rather fantastic mice
    http://www.eurekalert.org/pub_releases/2006-10/usmc-nlm102006.php

    Neat stuff eh?

  4. #4 Savely Savva
    September 12, 2008

    Unfortunately, the current biomedical science ignores the Biofield (EPIGENETIC) control system of the organism. The latter is the cause of different reactions of organisms to the same agents.
    Please see http://www.misaha.com and my introductory article in the book promoted there.

    Best wishes,
    Savva

  5. #5 ERV
    September 12, 2008

    Retarded spammer– I DO epigenetic research. *points to profile* OMG TEH BIO ESTABLISHMUT IZ IGNORZING IT AAAAAAH!

    Ive done experiments with a particular epigenetic modification and HIV-1 infection and I got negative results. HIV-1 insertion points are so random, I didnt even necessarily predict epigenetics would play a role with this particular virus.

    Thanks for the spam, though. I was needing some more protein today.

  6. #6 Sili
    September 12, 2008

    Stupid, stupid request, but …

    I. Did. Not. Pay attention in biochem. Young and foolish … well … just foolish, actually.

    Would it be too rude of me to ask if you could perhaps go through some basics of the immunesystem at some point? Just what are antibodies, T-cells, B-cells, whatchamacallems … and how do they tie together?

    I know, I know – it really is much too lazy of me to ask to be spoonfed like this, but …

  7. #7 Kendall
    September 12, 2008

    So a friend of mine is working on an AIDS vaccine at Harvard. I shouldn’t say friend. I should say brother of a friend who is really cute, and I really think was trying to hit on me while I was in Boston (which would have been awesome, but I was only there for like 3 days). Anyway, he said he thought they could plausibly have a vaccine in the next 3 years. Sound crazy? Maybe … I was trying to talk to him about what the real issues with the vaccine were, but I think he thought I wasn’t serious and was just trying to flirt with him (which, I was…but I did want to know!). So thanks for the older posts. I’ll read up so I’ll be ready for him for the next time I visit Boston ;-)

  8. #8 Becca
    September 12, 2008

    Does you know people working on the TLR variation X HIV suceptibility story?
    (I’m not being totally lazy- my “TLR variations HIV” only gave me a single pubmed hit, I figured it was worth checking with you for more)

  9. #9 Jared
    September 12, 2008

    ok, Sili, here’s a quick version:
    antibodies- also known as immunoglobulins come in a variety of types: IgA, IgD, IgE, IgG, and IgM, some of them have multiple flavors
    They are produced by B cells which also come in a variety of types: Plasma cells, Memory cells, and garden variety B cells each of which producing a different mixture immunoglobulin types.
    T-cells come in a few flavors also, NKT, Memory, Suppressor, CD8+, and CD4+; CD8+ are also known as cytotoxic T cells (Tk), while CD4+ cells are also known as T (helper) cells (Th). Tk cells kill infected cells while Th cells activate other cells. NKT cells can perform functions of T cells as well as functions of NK cells. Memory and Suppressor seem self-explanatory.
    NK cells kill other cells infected by a virus or tumors (usually). They do this via responses to stress chemicals released by a cell upon infection as well as a few other mechanisms.
    A good start for you would be to click
    http://en.wikipedia.org/wiki/Immune_system
    and read it all including the links.
    P.S. Immunobiology isn’t really covered in biochem.

  10. #10 Jason
    September 12, 2008

    Hey Abbie,

    Interesting post!

    Though, I was talking to a buddy of mine who’s an Infectious Disease prof up here and we talked about what it really means to be a long-term nonprogressor. Seems he doesn’t think it’s a good title; he’s of the mind that perhaps there is no such thing as non-progression, just different degrees of slow. Thoughts?

    As for the Elites, I wonder if anyone has done a massive sequencing project (can you tell I do genomics) for all of the Elites and compared it to the pool of others out there.

    Interesting stuff here!

  11. #11 Jared
    September 12, 2008

    Oh, Abbie, I wanted to add, how about disemvoweling the spammer?

  12. #12 Sili
    September 12, 2008

    Thank you, Jared. Something for me to look at in the morning.

    I know. I think the course was called “Protein chemistry” – it was a bit of everything, using a coupla chapters of Stryer. As I said, I didn’t pay attention – it was a mandatory course for everyone doing science, and I hate being told what to do.

    The only thing I do remember is something to do with Y-shaped thingummabobs with … five or seven varying parts. I think those were the antigens.

    As I said … I put in an effort not to learn back then …

  13. #13 Jared
    September 12, 2008

    On second thought, Abbie, how about a good post on why Savely Savva is full of shit?

  14. #14 Bayesian Bouffant, FCD
    September 12, 2008

    Elitist.

  15. #15 The Chemist
    September 12, 2008

    the Elite Suppressors

    Is it wrong that I think this sounds like a character class from Halo?

    Freakin’ interesting. I had no idea people could naturally survive HIV.

  16. #16 philos
    September 13, 2008

    Give it up ERV and get a real job.

    http://www.harpers.org/archive/2006/03/0080961

    Or go read Science Fictions

  17. #17 William Wallace
    September 13, 2008

    I have had two relatives die from HIV, and many friends. I have other friends who are still living with the disease.

    It is a tragic disease, and in one case, one of my friends was a hemophiliac, who caught it during a blood transfusion.

    In every other case, the disease was caught through either promiscuous sexual relations, or illicit drug use while sharing needles.

    In this context, what do you think about recommending abstinence, monogamy, and avoidance of certain types of drug use?

  18. #18 Alan Kellogg
    September 13, 2008

    For an example of an extremely fast progressor look into the case of Ryan Boell, aka “Angelsboi”

    Ryan was a young homosexual in his early twenties. Had a weak immune system to begin with, and got the virus through oral sex and an abscessed tooth. Had trouble with the first cocktail, later lost access temporarily to his medication thanks to a mix up in paper work. Was subsequently in and out of hospital until his final visit, when he died of AIDS related complications.

    Ryan is a good example of what can happen when everything goes wrong. Weak immune system, delay in getting effective medicaton, temporary loss of medication; with the last two leading to damage from opportunistic infections plus the virus itself that made survival problematic at the best. Ryan is an extreme case, but still an instructive one.

    BTW, he got the nom d’web “Angelsboi” for his crush on the character of Angel from Buffy the Vampire Slayer and Angel. Even sent the actor a mash note or two. :)

  19. #19 Jared
    September 13, 2008

    Dear Mr. WW
    Are you not familiar with HIV being capable of infecting children while the mother during pregnancy or breast feeding?
    Should we blame the child for something the mother did? Are you also not familiar with the fact that some individuals are INTENTIONALLY infected with HIV by someone that dislikes them? Are you also not familiar that organ transplants can also account for HIV infection?

    If you educate people about ways to avoid transmission of diseases, they can still have sex (they will anyway) and not die from it. No matter how much you try to scare the sex drive out of people, you will fail, it is a primal drive.

  20. #20 Stacy S.
    September 13, 2008

    1. Great post

    2. Thanks for answering Sili’s question Jared.
    (BTW – thanks for asking Sili)

  21. #21 sadunkal
    September 13, 2008

    “Then there is a group we really, really want to learn more about– the Elite Suppressors”

    Here’s your chance, Watch the Video 2 for some hard to find info about the “Elite Suppressors”:
    http://www.garynull.com/aidsinfopage.php?vid=2

    You’re welcome. :)

  22. #22 dubiquiabs
    September 13, 2008

    Do you think it a viable Hx that elite suppressors may over-express telomerase?

    HIV progresses to AIDS when the replicative capacity of cytotoxic T-cells is exhausted. Effros, Dagarag et al. at UCLA apparently were able to extend telomeres of CD8 T cells by inducing telomerase in vitro and rodents (see eg: Exp Gerontol. 2007 May;42(5):416-420). I don’t know of any human trials though.

  23. #23 natefoo
    September 13, 2008

    WiWa,

    Abstinence-only education has been proven to be worse than comprehensive sex-ed. Repeatedly. Under your suggestion of promoting abstinence, transferrance of STDs and cases of teen pregnancy would rise.

    Abstinence is great until kids finally give in… when they do (and the stats say that most of them will), do they have any idea how to protect themselves?

  24. #24 The Chemist
    September 13, 2008

    WW,

    You only need to have sex with someone once to get HIV. How does this count as “promiscuity”?

    I went to a school where kids were given the standard abstinence line.

    *Newsflash*- Sex is an instinct that does not need to be taught. For a place where no sexual advice was given, there was still a lot of sex. Fortunately the message about condoms was passed around by word of mouth, though I knew more than a few people who relied on “pulling out”.

    By your standards I guess this is an improvement.

  25. #25 clinteas
    September 14, 2008

    You know WW,you are lucky you get to play with the big boys at all,because where you crawled from,posts like yours would be banned,its just that people around here are actually tolerant to a certain degree to your insanity…

    //In this context, what do you think about recommending abstinence, monogamy, and avoidance of certain types of drug use?//

    Lets tell the Africans about abstinence,shall we…

  26. #26 Oldfart
    September 14, 2008

    No one answered Philos and the Harper’s article. Googling that article does not return much in the way of debunking articles that contradict the claims made in the article. In fact, I found only one site that contradicted the article (by simply stating that Harper’s had been hornswaggled). For all I know that article has been debunked long ago (since it was published in 2004). If so, I’d appreciate some links.

  27. #27 LisaJ
    September 14, 2008

    Great post ERV. Thanks for the education! I am also a biomedical researcher who studies epigenetic mechanisms of gene regulation (in my case in regulation of neural stem cells and cancer). It’s a fascinating subject and one that, from my perspective, seems to really be on the rise. So yeah, nice try Savva.

  28. #28 Chris Noble
    September 14, 2008

    No one answered Philos and the Harper’s article.

    Errors in Celia Farber’s March 2006 Article in Harper’s Magazine

  29. #29 Rrr
    September 15, 2008

    Chris, yo linky no worky, but GIYF. Simply googling the blue streak gave over 1500 hits. Seems there is plenty of rebut about…

  30. #30 minimalist
    September 15, 2008

    You know WW,you are lucky you get to play with the big boys at all,

    Wally got exactly what he wanted, which is to have a whole bunch of people responding to his inane crap. I think by now he’s just trolling for hits for his sad little wingnut blog.

  31. #31 Chris (Fabulously in the City)
    September 15, 2008

    Wow, thank you posting this. This is very, very valuable information to know.

  32. #32 Lab Rat
    September 16, 2008

    heh, I first thought this article was going to be about politics, where the word ‘elite’ has been banded about depressingly for a while.

    Brillient post, thanks for the information :) And the information in response to silis question.

    “Wally got exactly what he wanted, which is to have a whole bunch of people responding to his inane crap. I think by now he’s just trolling for hits for his sad little wingnut blog.”

    *blinks* dude! get a grip. He had an opinion that was different to yours and couched it in fairly polite terms. That response is kindof … scary.

  33. #33 Reginald
    September 16, 2008

    Wally’s still around? I thought we’d heard the last of him ages ago. Good to see that he still clings to his insanity I guess!

  34. #34 Temaharay
    September 16, 2008

    “Elite suppressors” that could be a movie title.

  35. #35 Temaharay
    September 16, 2008

    But on a serious note, it’s very interesting that there are people who have a natural resistance to the progression of this virus.

    It makes me wonder if this quirk can also effect someone’s chances of acquiring this disease itself.

  36. #36 biopunk
    September 16, 2008

    Lab Rat @ 32,

    No matter how “polite” his terms, W.W. has an agenda not based on evidence.

    You called yourself a scientist, so please understand that outside your lab, and all over the world, persons like W.W. have beliefs that no amount of evidence will sway.

    That’s the scary part.

    But what do I know? I’m probably just a pawn of the homosexual agenda or something…

  37. #37 Richard Hendricks
    September 16, 2008

    Abbie,
    How fragile is the AIDS virus? I recall that it cannot survive for long outside our bodies, and I was wondering what it would take to make our bodies inhospitable to the virus. Maybe changing temperature or pH or some other levels within our bodies might cause an effect. Maybe those Elite Supressors are low in some kind of salt or something crazy and that prevents AIDS from proliferating.

  38. #38 Lab Rat
    September 17, 2008

    biopunk @ #36

    Oh yes, I do understand that there are the scary people around, with beliefs based on no amount of evidence. And I will admit that I’ve had a fairly sheltered academic life, so don’t often come into contact with such people (and therefore possibly am not as annoyed at them as you). Also I didn’t realise that WW had been a regular poster (probably a lot more regular than me).

    I was just ever so slightly phased by what I saw as a sort of unmitigated blast attack. It is becoming slightly more understandable with more information about the context.

    =D

  39. #39 Lab Rat
    September 17, 2008

    akk “and therefore possibly am not as annoyed at them as you” should have read “and therefore possibly am not as annoyed at them as others” sorry!

  40. #40 minimalist
    September 17, 2008

    Wally has been banned at pretty much every blog he’s ever posted at, so that should tell you something. I think Abbie keeps him around for the same reason Arnie has a chew toy.

  41. #41 Calli Arcale
    September 17, 2008

    On the abstinence/refrain from drug use/etc question…

    My two cents is that kids should get comprehensive sex ed, but for people diagnosed with HIV (which is what WW may have been getting at), doctors should be advising them of the importance of abstinence if possible, safe sex if not, limiting sex partners, and avoiding risky drug use practices to avoid passing the disease on. Doctors should also give similar advice when a patient is diagnosed with other STDs, such as herpes. What the patient does with the information is their own business, but I think the doctor owes it to the patient to give them a chance to understand the seriousness of their situation. I think it is probably a fairly small subset of the population who is willing to knowingly infect other people (sex addicts and psychopaths); the rest will appreciate knowing what they can do to protect their partners.

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