In my earlier post about HIV therapy (a post I strongly recommend), I wrote, “After entering a cell (never mind how for now), HIV needs to find a way to makes copies of itself, which requires DNA.” Because of some recently released data, it’s time to look at how HIV enters the cell, and to expand a bit on the biology of HIV infection (but this is really a “Part II” so please refer to the above-linked post, even though this should stand on its own). This will also allow us another glimpse into how real science works. proceeding from observation, though hypothesis, and hypothesis testing.
Once again, as in all of my science-y posts, please forgive any oversimplification.
It has been observed that HIV requires a “lock-and-key” mechanism to bind to and enter human cells. The key is the HIV gp120 complex on the HIV envelope. The lock is the human CD4 receptor on certain human white blood cells, but this lock requires a little help to engage. Forming a proper lock-and-key fit requires the CCR5 or the CXCR4 receptor in the human cell membrane.
It has been further observed that some people are rather resistant to HIV infection, and that these people have a mutation in the CCR5 gene that doesn’t allow it to appear on the cell surface. People with this mutation are otherwise normal. (Incidentally, this mutation is present pretty much only in Europeans, not in Africans or Asians.)
Finally, the most common strains of HIV require CCR5 (rather than CXCR4) as a co-receptor.
If a chemical can be found that blocks human CCR5 receptors, and it can be made into a drug, it should be effective against HIV infection.
Using modern biochemical techniques, a CCR5 inhibitor, known as Maraviroc, was discovered. When tested against the virus in vitro, it blocked viral entry into cells. Further, it didn’t interfere with other HIV medications. Because this worked in the lab, pilot studies were down on small numbers of patients, and these patients had significant drops in the numbers if virus particles in their blood, without serious side-effects.
DrPal, didn’t you say that there were strains of HIV that use the CXCR4 receptor (X4 strain) rather than the CCR5 receptor (R5 strain)? Yeah, I said that. This fact has a couple of consequences. First, before using this new drug, patients are tested to see if their virus is X4 or R5. Second, we might predict the following: if a mixed population of R5 and X4 strains is exposed to a drug that inhibits replication of R5 viruses, selection pressures should favor X4 strains. According to the cited studies, this does appear to happen, although the clinical significance of this fact is not yet clear.
I’m thinking about winding this up soon, but first…
Maraviroc represents an entirely new class of HIV medications. It’s discovery is a nice example of the way science-based medicine works: an idea consistent with observable reality is posited, tested, and implemented. Implausible medical claims, such as homeopathy, acupuncture, and chiropractic, start off with ideas that contradict what science tells us about how reality works. If that weren’t enough, they then are used despite overwhelming evidence against their efficacy. And if that weren’t enough, when the apologists for these practices run out of anecdotes to support their use, they fall back on the deus ex machina of conspiracy theories and “other ways of knowing”. When it comes to medicine, there are no other ways of knowing. Abhorring science in favor of various forms of mysticism will do nothing more than waste your time and money. Science may be hard, but it’s awfully fun, and it’s still the best way we have of understanding and manipulating reality.
Roy M. Gulick, M.D., Jacob Lalezari, M.D., James Goodrich, M.D., Ph.D., Nathan Clumeck, M.D., Ph.D.,, Edwin DeJesus, M.D., Andrzej Horban, M.D., Ph.D., Jeffrey Nadler, M.D., Bonaventura Clotet, M.D., Ph.D.,, Anders Karlsson, Ph.D., Michael Wohlfeiler, M.D., John B. Montana, M.D., Mary McHale, M.B., B.S., M.R.C., John Sullivan, B.Sc., Caroline Ridgway, M.Sc., Steve Felstead, M.B., Ch.B., Michael W. Dunne, M.D.,, Elna van der Ryst, M.B., Ch.B., Ph.D., and Howard Mayer, M.D., for the MOTIVATE Study Teams* (2008). Maraviroc for Previously Treated Patients with R5 HIV-1 Infection New England Journal of Medicine, 359 (14), 1429-1441
Gerd FÃ¤tkenheuer, M.D., Mark Nelson, F.R.C.P., Adriano Lazzarin, M.D., Irina Konourina, M.D., Andy I.M. Hoepelman, M.D., Ph.D., Harry Lampiris, M.D., Bernard Hirschel, M.D., Pablo Tebas, M.D., FranÃ§ois Raffi, M.D., Ph.D., Benoit Trottier, M.D., Nicholao (2008). Subgroup Analyses of Maraviroc in Previously Treated R5 HIV-1 Infection New England Journal of Medicine, 359 (14), 1442-1455