Never stop thinking, never stop looking for an angle

Derek Lowe may soon be a very rich man if he owns some Vertex stock. An incredible pair of papers in the current Nature (vol. 505 pp. 492 – 493, 509 – 514 ’14, Science (vol 343 pp. 38 – 384, 428 – 432 ’14) has come up with a completely new way of possibly treating AIDs. Instead of attacking the virus, attack the cells it infects, and let them live (or at least die differently).

Now for some background. Cells within us are dying all the time. Red cells die within half a year, the cells in the lining of your gut die within a week and are replaced. None of this causes inflammation, and the cells die very quietly and are munched up by white cells. They even send out a signal to the white cells called an ‘eat me’ signal. The process is called apoptosis. It occurs big time during embryonic development, particularly in the nervous system. Neurons failing to make strong enough contacts effectively kill themselves.

Apoptosis is also called programmed cell death — the cell literally kills itself using enzymes called caspases to break down proteins, and other proteins to break down DNA.

We have evolved other ways for cell death to occur. Consider a cell infected by a bacterium or a virus. We don’t want it to go quietly. We want a lot of inflammatory white cells to get near it and mop up any organisms around. This type of cell death is called pyroptosis. It also uses caspases, but a different set.

You just can’t get away from teleological thinking in biology. We are always asking ‘what’s it for?’ Chemistry and physics can never answer questions like this. We’re back at the Cartesian dichotomy.

Which brings us to an unprecedented way to treat AIDS (or even prevent it).

As anyone conscious for the past 30 years knows, the AIDS virus (aka Human Immunodeficiency Virus 1 aka HIV1) destroys the immune system. It does so in many ways, but the major brunt of the disease falls on a type of white cell called a helper T cell. These cells carry a protein called CD4 on their surface, so for years docs have been counting their number as a prognostic sign, and, in earlier days, to tell them when to start treatment.

We know HIV1 infects CD4 positive (CD4+) T cells and kills them. What the papers show, is that this isn’t the way that most CD4+ cells die. Most (the papers estimate 95%) CD4+ cells die of an abortive HIV1 infection — the virus gets into the cell, starts making some of its DNA, and then the pyroptosis response occurs, causing inflammation, attracting more and more immune cells, which then get infected.

This provides a rather satisfying explanation of the chronic inflammation seen in AIDS in lymph nodes.

Vertex has a drug VX-765 which inhibits the caspase responsible for pyroptosis, but not those responsible for apoptosis. The structure is available (, and it looks like a protease inhibitor. Even better, VX-765 been used in humans (in phase II trials for something entirely different). It was well tolerated for 6 weeks anyway. Clearly, a lot more needs to be done before it’s brought to the FDA — how safe is it after a year, what are the long term side effects. But imagine that you could give this to someone newly infected with essentially normal CD4+ count to literally prevent the immunodeficiency, even if you weren’t getting rid of the virus.

Possibly a great advance. I love the deviousness of it all. Don’t attack the virus, but prevent cells it infects from dying in a particular way.

Never stop thinking. Hats off to those who thought of it.

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  • Herman Grid  On January 27, 2014 at 9:08 pm

    At present, I don’t think Vertex is moving forward w/ VX-765 in any clinical indication, though these data may convince them otherwise.

  • PPedroso  On January 28, 2014 at 2:01 pm

    Question: Won’t this be problematic for physiologic pyroptosis processes?

    • luysii  On January 28, 2014 at 2:39 pm

      Quite possibly, but VX-765 didn’t have any obvious bad effects in the (very brief) 6 week trial. Clearly, a lot more work is required. With any protease inhibitor, specificity is a problem. The human genome codes for a mere 560 of them — Science vol. 326 pp. 853 – 858 ’09.

  • Curious Wavefunction  On January 28, 2014 at 2:47 pm

    Scientific American reported this last month:

    “You just can’t get away from teleological thinking in biology. We are always asking ‘what’s it for?’ Chemistry and physics can never answer questions like this.”

    Sure chemistry can ask questions like that. That’s the beauty of synthesis; you can create alternative chemistries that can enable you to interrogate precisely those kinds of questions. For instance look at all the work done on modified DNA backbones and bases.

    Also, the link’s not working.

  • luysii  On January 28, 2014 at 11:09 pm

    “Sure chemistry can ask questions like that.” Do you mean answer questions like that? If so, I disagree.

    I subscribe to S. A. and never saw the article. I’ll have to take a look at my old issues.

  • Curious Wavefunction  On January 28, 2014 at 11:55 pm

    Sorry, I meant provide plausible answers to questions like that. Unlike physics chemists can actually make compounds that can ask questions about alternative purposes and functions. Biologists can ask these questions to a more limited extent through synthetic biology (although that capability is expanding). With physics it’s much more difficult since you are essentially trying to explore the purpose of universes with different fundamental laws.

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