denialism blog

Biology

Most living or quasi-living things have, as their information storage molecule, a collection of nucleic acids. In humans, we have chromosomes made up of two strands of DNA wound around each other. This DNA serves as a blue print to make new DNA, RNA, and ultimately proteins. Some viruses, being rather odd, have RNA as their genetic blueprint rather than DNA. This makes things a little tricky when it comes to making more viruses.

When a human cell needs to make another human cell, one of the steps is to make a complete copy of the DNA, using the DNA that is already there as a template. The enzymes in human cells can make DNA from a DNA template, RNA from DNA template, and proteins from RNA template.

So, given that information, let's look at HIV. HIV is a retrovirus. Retroviruses use RNA rather than DNA for their genetic information. As a retrovirus, HIV is incapable of replicating on its own, so it hijacks the human cell to do its dirty little business. Part of that business is turning its RNA into DNA so that it can perform some important work.

View image

After entering a cell (never mind how for now), HIV needs to find a way to makes copies of itself, which requires DNA. Since human cells don't know how to make RNA into DNA, retroviruses bring their own tools, in the form of an enzyme called reverse transcriptase (RT). This molecule allows the viral RNA to become DNA, and then to use the human cell's own machinery to crank out copies of itself. Nasty. Another consequence of RT is that it (along with another important enzyme) allows for this new HIV DNA to integrate into our own DNA, essentially becoming part of it, so that when an infected cell divides, the HIV genome is copied right along with the cell's own genome, meaning that all the daughter cells are also infected.

There are lots of ways to target this process. One of the first was the molecule azidothymidine, or AZT (also known as zidovudine, or ZDV). This molecule was developed in the '60s as a potential cancer drug, but didn't really do much. Based on what was known of the biology of HIV, AZT was tested in the lab in the mid-80's and was found, at least in a petri dish, to halt HIV replication. It does this by inhibiting our friend reverse transcriptase (RT). When RT is making DNA from viral RNA, AZT hops into the machinery and gums up the works (of course, it's a bit more complicated...details are easy to find online, but basically, the enzyme confuses the DNA-like substance (AZT) for the real deal, tries to incorporate it into the growing DNA chain, and stops. It also competes with real thymidine for binding sites, yada yada yada).

Clinical Implications

AZT was the first effective HIV medication. It belongs to a class of medications called nulceoside analog reverse transcriptase inhibitors (NRTIs). This class is still a mainstay of HIV therapy. But just because it works in the lab doesn't mean it works on people. So science was done.

First, in a landmark study in 1987, AZT was shown to have significant positive effects on AIDS patients with advanced disease. Hope was tempered by the fact that HIV was found to develop resistance to AZT fairly quickly.

Evolutionary digression

HIV replicates in huge numbers, perhaps billions of copies per day. When exposed to a single medication, a few of these billions of copies will have random mutations rendering them resistant to AZT. These copies will be favored in an environment containing AZT, and soon enough, most of the HIV virions will be immune. Once the population becomes resistant to AZT, viral numbers go up, and the patient becomes sicker. This is the essential fact underlying HIV therapy. Effective antiretroviral therapy requires a combination of medications that target different parts of the viral lifecycle so that no single mutation can render the viral population immune. End digression.

Why am I reading this long, boring post?

Over the last 20 years, HIV treatment has become extraordinarily effective. Using our knowledge of biology, evolution, and pharmacology, evidence-based HIV treatments have emptied out the HIV wards that popped up all over urban American in the mid-1980's. The quality and quantity of the work done on HIV has advanced the whole of microbiological and medical science. I'm hoping non-scientist readers will walk away with a hint of the beauty and complexity of the topic. What you'll see shortly is a host of denialists claiming that HIV doesn't cause AIDS, HIV treatment doesn't work, and other such nonsense. What you won't see is any data from the denialists that can compete in volume, quality, or results with real science. If you're not lucky, I may follow this up with similar posts. Be afraid. Be very afraid.

References

Fischl MA; Richman DD; Grieco MH; Gottlieb MS; Volberding PA; Laskin OL; Leedom JM; Groopman JE; Mildvan D; Schooley RT; et al. The efficacy of azidothymidine (AZT) in the treatment of patients with AIDS and AIDS-related complex. A double-blind, placebo-controlled trial. N Engl J Med 1987 Jul 23;317(4):185-91.