Not Exactly Rocket Science

Blogging on Peer-Reviewed ResearchHIV is an elusive adversary. The virus is so good at fooling the immune system that the quest for an HIV vaccine, or even a countermeasure to resist infections, has spanned two fruitless decades. But maybe a defence has been lurking in our genomes all this time.

i-f022d8022405d1ad31494fe962f388db-HIV_Daughter_Particles.jpgNitya Venkataraman from the University of Central Florida has managed to reawaken a guardian gene that has been lying dormant in our genomes for 7 million years. These genes, known as retrocyclins, protect monkeys from HIV-like viruses. The hope is that by rousing them from their slumber, they could do the same for us. The technique is several safety tests and clinical trials away from actual use, but it’s promising nonetheless.

Retrocyclins are the only circular proteins in our bodies, and are formed from a ring of 18 amino acids. They belong to a group of proteins called defensins that, as their name suggests, defend the body against bacteria, viruses, fungi and other foreign invaders. There are three types: alpha-, beta- and theta-defensins. The last group is the one that retrocyclins belong to. They were the last to be discovered, and have only been found in the white blood cells of macaques, baboons and orang-utans.

In previous experiments, Venkataraman’s group, led by Alexander Cole, showed that retrocyclins were remarkably good at protecting cells from HIV infections. They are molecular bouncers that stop the virus from infiltrating a host cell. The trouble is that in humans, the genes that produce retrocyclins don’t work. Over the course of human evolution, these genes developed a mutation that forces the protein-producing machinery of our cells to stop early. The result is an abridged and useless retrocyclin.

But aside from this lone crippling mutation, the genes are intact and 90% identical to the monkey versions. Now, Venkataraman has awakened them. She found two ways to fix the fault in human white blood cells, one involving gene transfer and the other using a simple antibiotic. Either way, she restored the cells’ ability to manufacture the protective proteins. And the resurrected retrocyclins did their job well – they stopped HIV from infecting a variety of human immune cells.

i-bf42088f6eb14e5a3d051e7e4bbef373-Retrocyclin.jpgVenkataraman says that we can think of retrocyclin deficiency as “an inherited disorder, albeit one with an incidence of 100%. To “cure” it, she created corrected versions of the faulty human retrocyclin genes and loaded them into white blood cells. Using glowing antibodies designed to stick to retrocyclins, she saw gleaming evidence under the microscope that the cells had made their own stock of these proteins. She even managed to purify the rekindled proteins themselves.

This clearly tells us that our cells have all the right machinery needed to actually make retrocyclins – it’s just that the instructions have a typo in them. Most importantly, the restored proteins worked. They prevented HIV from infecting up to 80% of the cells, and even reduced the levels of virus in cells that had already been infected.

Obviously, gene transfer techniques like this are hardly practical for poor African nations where HIV is most rampant. For retrocyclins to really play a role in the fight against HIV, we need a cheaper and easier way of reactivating them. And Venkataraman thinks she has found one – a group of antibiotics called aminoglycosides.

In bacteria, these drugs work by blocking them from creating proteins. But in the more complex cells of animals, they do something different – they react with the protein-making machinery of our cells so that they make slightly more mistakes than usual. Normally, that would be a bad thing but for retrocyclins, it’s an unexpected boon. It means that the machinery barrels straight through the mutation that causes retrocyclins to be built half-finished. It doesn’t stop prematurely, and produces a full-length protein.

Venkataraman found that one of these drugs, tobramycin, was especially good at restoring retrocyclins, and did so in both white blood cells and actual vaginal tissue. The drug slashed the rate of HIV infection by about 50% – a respectable figure but clearly a smaller one compared to the sizeable benefits bestowed by the gene transfer method. On the plus side, the technique didn’t seem to harm the cells in any way.

These results are promising ones indeed, and Venkataraman thinks that with more work, aminoglycoside-based creams could be used to prevent HIV infections in the real world.

HIV kills by infecting the very cells that are meant to defend us from infections and destroying them. But retrocyclins are something it hasn’t encountered before. Humans lost the ability to create these guardians millions of years ago and by reawakening them, we could have a new but ancient weapon against this sneakiest of foes.

Reference: Venkataraman, N., Cole, A., Ruchala, P., Waring, A., Lehrer, R., Stuchlik, O., Pohl, J., & Cole, A. (2009). Reawakening Retrocyclins: Ancestral Human Defensins Active Against HIV-1 PLoS Biology, 7 (4) DOI: 10.1371/journal.pbio.1000095

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Comments

  1. #1 Paul Browne
    April 29, 2009

    Very interesting, it’s always facscinating what you can learn by studying the differences between similar species…something that is recognized all too infrequently in discussions about the value of animal research.

    Hobby horses aside, this is an exciting result. The authors of the above study mention a new drug called PTC-124 (a.k.a. Ataluren) that acts in a similar way to the aminoglycosides. This drug has the benefit of being a lot less toxic than the antibiotics (important for long term use) and has performed well in phase II clinical trials for Duchenne Muscular dystrophy and Cystic Fibrosis.

    http://www.muscular-dystrophy.org/research/news/626_the_latest_news_from_the_ptc124_clinical_trial#1
    http://www.cff.org/research/DrugDevelopmentPipeline/#CFTR_MODULATION

    If the longer term monitoring and larger trials of PTC-124 for FC and DMD continue to indicate that it is safe and effective trials against HIV might start sooner than we might expect for such a novel approach.

  2. #2 PalMD
    April 29, 2009

    Really friggin’ cool, man. I bet abbie is drooling…

  3. #3 Ray Ingles
    April 29, 2009

    That is seriously cool, and your explanation was lucid and easy to follow. Thanks!

  4. #4 XiXiDu
    April 29, 2009

    This came to my mind:

    Genetic Mutation Immunity to Bubonic Plague and HIV http://is.gd/vmdF

    HIV Protection CCR5 Chemokine Receptor Mutation http://is.gd/vmfx

    Natural selection and resistance to HIV [PDF] http://is.gd/vmh2

    Evaluating plague and smallpox as historical selective pressures for the CCR5-Delta-32 HIV-resistance allele [PDF] http://is.gd/vmhF

    The geographic spread of the CCR5 HIV-resistance allele
    http://is.gd/vmm5

  5. #5 Tim Read
    April 29, 2009

    So tobramycin will allow translation other human pseudogenes (the authors elude to this in the discussion). Are there some potential side effects here?

  6. #6 Lilian Nattel
    April 29, 2009

    Wow. The title to this post was an attention grabber and the content lived up to the title. This is exciting. Thank you for sharing it.

  7. #7 David Marjanović, OM
    April 29, 2009

    Are there some potential side effects here?

    Vitamin C production? :-) Or maybe the vomeronasal organ might start working again.

    BTW, you mean allude, as shown by the “to” that follows it.

  8. #8 Mick
    April 29, 2009

    Ed,
    The one thing that is very questionable is using aminoglycosides in eukaryotes to “release” the retrocyclin. Aminoglycosides work by affecting the 30s subunit of the prokaryote ribosome. Eukaryotes–which includes the cells of humans–lack a 30s ribosome. You probably already know, but that is why antibiotics kill bacteria in us an don’t kill us. Humans have 80s ribosomes, consisting of 40s and 60s subunits. Because we don’t have 30s ribosome subunits, how would this be able to do anything to eukaryotic cells?
    Thanks.

  9. #9 Ed Yong
    April 30, 2009

    Mick, there’s an equivalent site on the eukaryotic ribosome that the aminoglycosides bind to weakly. From the paper:

    In bacteria, aminoglycosides bind strongly to the decoding site on the 16S rRNA, thereby hindering protein synthesis [26]. However, in eukaryotes, aminoglycosides bind to the eukaryotic decoding site with low affinity and induce a low level of translational misreading, which suppresses the termination codon through the incorporation of an amino acid in its place.

  10. #10 Paul Browne
    April 30, 2009

    Tim Read, there are theoretical risks associated with this approach, but so far research looks promising.

    Using aminoglycoside antibiotics for treatment of HIV is probably not a realistic option, while they are very useful as antibiotics they cause side effects in some patients that get more common and more serious the longer they are taken for. While they are benificial if taken for a few days or weeks they are probably appropriate for treating HIV where they will probably need to be taken for several years (and at the very least for several months).

    However the paper above also mentions a new drug named PTC-124 that has been developed to have the same property of allowing the translational machinery to read through premature stop codons. PTC-124 has successfully completed Phase IIa clinical trials for the treatment of Duchenne muscular dystrophy and Phase II trials for Cystic Fibrosis, and so far indications are that it is far less toxic than the aminoglycosides. It is now in longer (2 years) and larger (>100 participants) Phase IIb trials.

    http://www.muscular-dystrophy.org/research/news/626_the_latest_news_from_the_ptc124_clinical_trial

    If further research continues to support the reactivation of retrocyclin as a means of combatting HIV, and clinical trial results for PTC-124 for CF and DMD continue to be positive, than PTC-124 may start to look like a very promising new anti-HIV drug.

  11. #11 Karrasko
    April 30, 2009

    Far away from something tangible, buy looks very very promising. Very good post.
    http://esns.blogspot.com/
    http://twitter.com/ESS_BILBAO

  12. #12 toto
    April 30, 2009

    The obvious problem here is that we don’t know the consequences of reactivating a gene that has been switched off for 7 million years. First, there might very well be a reason why it was switched off in the first place (i.e. it may have provided some kind of selective advantage).

    Second, if the gene has indeed been dormant for 7My, we humans have evolved a lot during this time, and the reactivated gene might well interact badly with the new machinery that emerged while it was asleep.

  13. #13 Sandra Porter
    April 30, 2009

    This is amazing! thanks!

  14. #14 Steve
    May 3, 2009

    The answer to the concerns about the effect of restarting retrocyclin production in humans is a familiar statement that infuriates marketeers, politicians and pundits: We need more data. Between the “This has questionable consequences, do DON’T DO IT!” people and the “We gotta DO SOMETHING!” crowd, hardly anyone favors spending what it will take to actually answer the question.