Fighting HIV---the boring version

The fight against HIV occurs on several different levels: prevention of transmission and acquisition, treatment of the infection, and prevention and treatment of opportunistic illnesses.

Prevention has been addressed extensively (and perhaps will be again later), and opportunistic illnesses is a huge topic, so first I'll delve a bit into the origins and biology of the treatment of HIV infection (and of course the usual caveat; this is grossly oversimplified, and Abbie has a whole lot of good, ungrammatical science over at her place).

For better or worse, this requires another short biology primer...

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.

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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.

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Cue pec to tell us all how wrong PalMd is and how dangerous AZT is in

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<evil grin>

"Hope was tempered by the fact that HIV was found to develop resistance to AZT fairly quickly."

HIV doesn't develop resistance; development is something that happens in the lifetime of a single organism, like a tadpole developing legs. HIV populations evolve resistance. It may seem like a minor pedantic nitpick, but I think it's worthwhile to emphasize the importance of evolution whenever possible.

*giggle*
HIV-1 doesnt evolve resistance. HIV-1 exists as a quasispecies, and resistant variants are naturally present in the population. They usually have a fitness cost, however, so they are outcompeted by non-drug resistant variants in a drug naive individual. BUT after you add drugs, variants that were once 'less fit' suddenly become the dominant component of the quasispecies. From there, compensatory mutations evolve to regain fitness and maintaining drug resistance, or you take the patient off drugs, and the non-drug resistant variants of the quasispecies bounce back.

:P

Not being snarky, just poking fun, John *giggle*

Cue Creationists screaming 'ERV ADMITS HIV DOESNT EVOLVE!!' in
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hehehehehehehehehe!

"Why am I reading this long, boring post?"

By Orac standards it is very short. ;-)

Develop vs. Evolve ...

Around 30 years ago, there was an explosion in a chemistry lab that was reported in "Chemical and Engineering News" with the warning that the particular mixture was "unstable." Someone wrote in to explain the proper term was "labile." Another person wrote in wonderment "This guy is shoveling the wreckage out of his lab, and you are debating semantics?"

Nuclear scientists often speak of "burning" nuclear fuel. When speaking of enzymes to a non-scientific audience, I often say they "cause" (rather than "catalyze") reactions. If anyone wishes to challenge me, I choose skunks at two paces (I promise- you will lose).