The Amazing HIV virus

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Discussion by: Roedy

I have had HIV since 1985. Every few years my personal strain of HIV develops an immunity to the drugs that I am taking, and I have to flip to a new cocktail of 3 or so drugs.  The  theory is it should be much harder for my personal strain of HIV to simultaneously evolve resistance to three drugs than to one. But they do it!  Doctors refer to the drugs as "chemotherapy". The drugs tend to have nasty side effects such as nausea, diarrhea, low energy, neuropathy, nightmares and death (abacavir allergy).  So it is quite a trick to find a combination that I can tolerate. The process is not always successful).

Genetic sequencing has greatly improved the process of finding a good combo.  Everyone in BC with HIV has had their personal strain of HIV repeatedly genetically sequenced and all its mutations mapped. The mutation map is a nucleotide number followed by a letter for the freak nucleoside.  From this map, they know which mutations give resitance to what degree to all the various drugs.  So they can tell which drugs will fail even if I have never tried them.  There are roughly half a dozen families of drugs.  If your personal strain evolves immunity to one drug in a family, it will likely already be resistant (or soon will be resistant) to the others in the family. There must be thousands and thousands of mutations for my strain to fluke out and find a way around almost the entire HIV pharmacopia. (Can anyone enlighten me on the math about the rate of mutation?)

I am in an awkward position in that there is no suitable drug cocktail left.  I am awaiting the release of a new drug (doltutegravir) to fill in the third drug of the cocktail.  In the meantime I am not taking any drugs, least I aid the HIV to develop immunity to the drugs in an incomplete cocktail.

Danes have been working on an HIV cure, where they trick the HIV to come out of hiding deep in cells. Then it can be completely eradicated by the patient's immune system.  I have to hang in there until that works out.

I want to whack creationists over the head with an umbrella when they assure me animals of any sort never evolve.  Tell that to my amizingly capable personal strain of HIV evolutionists!  I have to admire their computing power, even if they are "trying" to kill me.

 

24 COMMENTS

  1. I am astounded at the ability of my personal crop of HIV, without the aid of computers, help from other HIV populations, or PhD s, to outwit almost the entire pharmacopoeia of HIV drugs. HIV has has a very high mutation rate. It pulled off this computation feat by brute force, randomly trying mutations.

    This lead me to wonder if a new class of HIV drugs could be developed to help HIV reproduce its DNA(RNA?) more accurately. Other creatures have better mechanisms to correct errors. Perhaps those mechanism could be grafted onto or provided for HIV. If it would sit still, it would be scarcely a problem.

    I have passed the idea onto Dr. Julio Montaner. We will see what he thinks.

  2. They’ll just point out that “they’re still viruses”, because they argue evolution never produces “new kinds” (kinds not being a thing, mind, just an idea about Noah’s ark). The response to the “no new kinds” argument is as follows: Taxa are usually defined$ to include their descendants, but not necessarily ancestors, so new ones are created within old ones, e.g. humans are a taxon that has formed inside primates. ($ In particular, a taxon defined this way is called a clade.) Our evidence for this sort of evolution, i.e. for common descent, is as follows. If common descent is true, multiple methods will reconstruct the family tree; when we use them for this, they agree on that tree in minute detail, despite their being millions of known species. If there was no common ancestry, this kind of concordance would simply not happen.

    • In reply to #2 by Jos Gibbons:

      They’ll just point out that “they’re still viruses”, because they argue evolution never produces “new kinds” (

      I would argue that if you discovered some rats that were immune to every known rat poison, that these were not rats but superrats, clearly a new “kind” of beast. It is not as though individual rats acquired this power by being bitten by radioactive spiders. The process by which the superrats formed was tracked molecule by molecule, and it happened in exactly the way Darwin said it would, though he knew nothing of DNA or RNA. But strangely Jehovah seems to have forgotten that he created viruses and bacteria too, just as he forgot all the details of celestial mechanics when he finally got round to writing the bible.

    • In reply to #2 by Jos Gibbons:

      They’ll just point out that “they’re still viruses”,

      do they accept germ theory then??!!!! no one trying to teach the controversy? oh to be a creationist and just pick and choose the bits of science that suit me

  3. Roedy,
    Here is an article entitled “Retrovirus mutation rates and their role in genetic variation”

    http://vir.sgmjournals.org/content/79/6/1337.full.pdf

    I know it is archaic (being from 1998)….. but it has some of the info you might be looking for and perhaps the references cited could help you track down some useful info.

    Because HIV is a retrovirus, it has RNA at it’s core and employs reverse transcriptase to make a copy of it’s RNA back into DNA which then causes the infection. Reverse transcriptase has no proofreading ability (unlike polymerases which proofread). The error rate of a polymerase is about 1 in 10,000 without proofreading and it jumps to 1 in 10,000,000 with the proofreading characteristic. This is what is missing from the sloppy reverse transcriptase.

    In this paper:
    Science 25 November 1988:
    Vol. 242 no. 4882 pp. 1171-1173
    DOI: 10.1126/science.2460925
    The accuracy of reverse transcriptase from HIV-1

    The authors describe the error rate of the reverse transcriptase as 1 in 1,700!!!! Holy crap that’s high! They go on to talk about certain mutational hotspots within the HIV genome that are prone to error at a rate of 1 in 70.

    On the Protein Data Bank site, from 2002, the error rate is said to be about 1 in 2000. Even commercially available engineered reverse transcriptase has a high error rate (1 in 17,000)…

    Since the HIV genome is 9749 nucleotides, the error rates indicate that almost every HIV particle generated in an active infection harbors mutation. Every one is different. The genome drifts. I do not know if this is the kind of info you were looking into, but I hope this provides a little help in finding what you need.
    crooked.

      • I have poked around a bit to try to formulate a coherent answer to your question. It has been frustrating, to say the least. There does not seem to be consensus (for that matter there doesn’t seem to be a lot of research going on)… Most of the sources I have seen are textbooks rather than journal articles. Also frustrating is that there is not a whole lot of human telomerase literature.

        Anyway, at the risk of being wrong, I found a couple references that suggest that the telomerase is just as sloppy as the reverse transcriptase. The difference being that the telomere is a repeating motif whereas the HIV genome is more or less a long string of “random” A,T,G,C nucleotides. They are not random because they are informational, however, they are not a triplet repeat like the telomere.

        So, it seems that the telomerase makes mistakes at around the same rate as the RT. And neither can proofread.
        crooked.

        BTW, GREAT question! It has been driving me nuts for days.

        In reply to #12 by Neodarwinian:

        In reply to #3 by crookedshoes:

        Roedy,

        Here is an article entitled “Retrovirus mutation rates and their role in genetic variation”

        http://vir.sgmjournals.org/content/79/6/1337.full.pdf

        I know it is archaic (being from 1998)….. but it has some of the info you might be looking for and perhaps t…

        • In reply to #17 by crookedshoes:

          I have poked around a bit to try to formulate a coherent answer to your question. It has been frustrating, to say the least. There does not seem to be consensus (for that matter there doesn’t seem to be a lot of research going on)… Most of the sources I have seen are textbooks rather than journ…

          One would assume, regardless of what would be copied, that a reverse transcriptase enzyme would have a large error rate. Still, I can’t find the exact number either!!!

  4. Re comment 3. At least you’ll be able to explain to creationists “why it is so”, though they’ll probably just drag up “mysterious ways”. You won’t win the debate in their eyes of course, but you will feel good about your argument.

  5. Doctors tell HIV patients that is it extremely important never to miss a dose of HIV medications, but they don’t explain why. Here is my Darwinian explanation:

    1. Let us say there is zero HIV drug X in your body. Some of your HIV might spontaneously develop an immunity to it, but they have no advantage. There is probably a slight disadvantage to the mutation. So the strain quickly dies out.

    2. Let’s say you have a therapeutic dose of X in your body. If some of your HIV develop 25% immunity to it, they are killed off anyway, and the strain quickly dies out.

    3. Let’s say you have skipped a dose of X, and you have only a 10% dose in your body, if some of your HIV evolve 25% immunity to it, many of them will thrive, and perhaps later develop 50% and 100% immunity. In this case you have produced an efficient gradient favouring HIV with immunity. This means drug X will soon lose its effectiveness.

    • Roedy,
      I know some stuff about the virus’ molecular genetics; not much about it’s treatment or course of infection (other people’s specialty, not mine)… Anyway, I think your explanation is excellent but I’d also include the idea of the viral load in the bloodstream. If the medicine can keep the viral load free in the bloodstream at zero, then the intracellular virus is effectively kept “bottled up” and new WBC’s are not infected. This minimizes the replication events and slows the evolution of the virus within the patient.

      I am a little out of my area here, and would love to be corrected or affirmed, but it seems to me that high copy number is the real advantage of the speed and sloppiness of the replication of the virus.

      In reply to #6 by Roedy:

      Doctors tell HIV patients that is it extremely important never to miss a dose of HIV medications, but they don’t explain why. Here is my Darwinian explanation:

      Let us say there is zero HIV drug X in your body. Some of your HIV might spontaneously develop an immunity to it, but they have no advanta…

    • In reply to #6 by Roedy:

      Doctors tell HIV patients that is it extremely important never to miss a dose of HIV medications, but they don’t explain why.

      Roedy, thanks for the fascinating and personal discussion. In addition to keeping mutation and viral release at bay, I think another reason it is important to not miss doses is that there is a threshold of missed doses (which varies by drug) below which, if you start again, you get back to therapeutic drug levels quickly with little rise in viral load. If one misses more doses than this threshold, even with perfect adherence thereafter it can take a long time to catch up Link. So you don’t want to miss doses and then give the virus a chance to select for faster multiplication in the presence of the incomplete combo. I guess this is why it is judged better to stop completely and pick up later with a better combo that the virus is naive to.

  6. Hopefully we’re only a decade or so away from being able to transplant some nice cloned bone marrow which has the rare but identified immunity to HIV. Apparently about 1% of Europeans carry the immunity and a bone marrow transplant from one of them (for an unrelated condition) recently cured the recipient of his HIV infection.

  7. Be well Roedy! I hope you continue to live a long life.

    Danes have been working on an HIV cure, where they trick the HIV to come out of hiding deep in cells. Then it can be completely eradicated by the patient’s immune system. I have to hang in there until that works out.

    This would be great not only for HIV but a slew of other viruses.

    The interesting thing about the 1% of Europeans that have immunity to HIV is that their ancestors were immune to the Bubonic Plague. Why would this be? What is common?

    • In reply to #10 by QuestioningKat:

      …The interesting thing about the 1% of Europeans that have immunity to HIV is that their ancestors were immune to the Bubonic Plague. Why would this be? What is common?

      There was a suggested correlation between areas of high plague incidence in Europe and current-day CCR5-delta 32 phenotype (which confers resistance to HIV entering cells by it being more difficult for HIV to bind on to it) where presumably those that survived the plague did so due to the CCR5 mutation.

      However, as this article (QJM Link) suggests, it may have been overstated and even mistaken; that in fact the opposite is true and that the worst areas of Bubonic Plague e.g. the Mediterranean, have the lowest mutant CCR5 carriage (also CCR5 doesn’t appear to be involved in Y. pestis infection anyway). They suggest (and cite others’ research) that some of what were called ‘plagues’ in Northern Europe were other infectious diseases that sprang up periodically, that may or may not have anything to do with CCR5. The CCR5 mutation may have already been around before this and has clustered for other reasons (e.g they mention its presence follows prevalence of lactose tolerance so may be nothing to do with a selection pressure involving disease).

  8. Hi Roedy, hope all goes well during your wait for the new drug.

    I admire your self-restraint concerning creationists – in your shoes I think I’d feel a tad angrier – noting their constant anti-science, pro-superstition lobbying. How many researchers use Biblical biology as the basis for new drug development? Probably the same number of oil companies that refuse to use microfossil data and evolutionary timescale estimates when prospecting for new fields…

    …none.

    • First of all, best wishes to you and yours, Roedy.

      In reply to #13 by This Is Not A Meme:

      I was recently studying HIV and there was information above my understanding, and I hope someone here can explain it. Is HIV evolving to be “less virulent”, meaning it’s becoming less harmful due to a new survival strategy?

      http://www.ncbi.nlm.nih.gov/pubmed/17203103

      If it doesn’t kill the host, it’ll spread better because it’ll have more time to spread. Thus it will be in hosts more frequently. It doesn’t need to do literal battle with the other variants, firing proteins at each other or something. Evolution doesn’t work as imagined in “After Earth” or as with Giger’s biomechanoid (or, pardon my Godwin, by the Nazis), creating nastier and nastier things. Those are just projections of the evolved human instincts of fear of the unknown and disgust, which have no structure in common with the process of evolution that I can see.

  9. Hi, I’ve only justb read this and just wanted to add that I’m at the launch site for Dolutgravir and we just had a successful Pre Approval Inspection from the FDA. We’re all hoping that it’s on the market absolutely ASAP. The trouble is that “Evolution is cleverer than think” so even that won’t run forever.
    Best Wishes M

  10. We domesticate (artificially select) all manner of plants and animals. Why not microorganisms and disease organisms and parasites?

    Why pray tell? You might for example create a perfected parasite that causes no harm, and locks up the niche more virulent forms would use.

    You might create a version of HIV that is better than wild HIV at colonising, however it has a built it suicide pill. When it has taken over you trigger the suicide pill.

    Botox and snake venom in small amounts is used therapeutically. Perhaps tamed microorganisms could be similarly exploited for their poisons.

    You might be able to alter them so they go after a different host, one you don’t like.

    • In reply to #20 by Roedy:

      We domesticate (artificially select) all manner of plants and animals. Why not microorganisms and disease organisms and parasites?

      Why pray tell? You might for example create a perfected parasite that causes no harm, and locks up the niche more virulent forms would use.

      You might create a version…

      That is a neat idea indeed, I wonder if it was ever tested. Anyways, even if it works, approving something like that for therapeutics could be a nightmare. Imagine the amount of test that would have to be made in order to prove that there is no chance of more harm being done than good. Not to mention that the talk about using a genetically modified organism in any capacity is likely to cause havoc in many sector irregardless. All that should not be used as excuse though. I will see if I can find any research in that capacity. Nice thinking Roedy!

  11. My support and positive energy goes out to you (forgive me if I don’t pray for you ;-) ), your attitude of looking forward to new possibilities is a model to all of us! If you need a stash of umbrellas, I can send some =)

    Why a Creationist can’t understand the absolute cruelty of a loving God who would create lethal viruses against his favorite creation, let alone lethal viruses capable of very quickly circumventing medications created by said favorite creation in an attempt to not be killed by the virus God created, makes me want to…well…beat a creationist with an umbrella. Roedy, shall we create Umbrella Day and make an event out of it? =)

  12. I’ll have to remember that the next time I argue with creationists. The only time I bring up my HIV is when arguing with anti-gay religious people who tell me that it’s a punishment from god. I tell them that their god is quite ineffective since science has made such amazing progress against his ‘punishment’. And their god is also very sloppy, for he seems to deliver his ‘punishment’ to millions who are not homosexual. (insert ‘mysterious ways’ clause here).

  13. I found out to be positive this year and after the initial tests (like giving the clinic 1 trillion liters of my blood…) it somehow turns out that my immune system is doing an astonishing job. I have really high CD4 rates and my virus level is only about 1% of the average patients.

    I do not have to take any drugs yet and my doc is confident that this is unlikely to change any time soon because he already had few cases like me where there was no change at all without drugs for several decades.

    But although I seem to be not really affected by this, I’m very interested in the development of a cure.
    For me it seems like there are several, mostly independent developments that could provide a cure for HIV in the not to distant future, one of them seems to be nanotechnology (i.e. new delivery systems based on nanotechnology or nano machines).

    The irony I think about HIV is that even if we never find a cure, it will in the end “cure” itself like most viruses do by adapting to the host and not killing it. HIV simply had not enough time to do that, but SIV in aps seems to had the time and is not doing that kind of damage to the host.

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