The enzyme reverse transcriptase copies viral RNA into viral DNA -- the genetic material used in all organisms except some viruses.
© George Eade
After HIV's genetic material enters a cell (did you miss our report?), it must make a DNA copy of itself. That's because HIV is a retrovirus -- it's made of RNA, not the DNA found in most viruses and all cellular genes.Thus HIV must make a mirror copy of itself -- in DNA, rather than RNA.
(This is the opposite of what usually happens: DNA in genes usually serves as a pattern for RNA, which then exits the nucleus to serve as a pattern for making proteins.)
To make this DNA copy, HIV relies on an enzyme (defined) called reverse transcriptase. Since scientists have long known that retroviruses rely on reverse transcriptase, the enzyme was an obvious target of attack early in the epidemic. (At this point, we should point out that the battle on HIV has relied on finding and exploiting the steps in its reproduction).
The first drugs that actually worked against HIV inhibited reverse transcriptase. To date, six reverse transcriptase inhibitors, including AZT, ddI and ddC, have reached the market. But reverse transcriptase inhibitors are not a permanent solution, since HIV eventually mutates into a form that resists them. With increasing experience with AZT and the other reverse transcriptase inhibitors, scientists have gained detailed knowledge about the strategy HIV uses to evade them.
Here's an image of reverse transcriptase showing active sites where drug resistance can develop.
This strategy is to make millions of variant viruses and to test them against the medicine. HIV is an unstable virus, and when it reproduces, errors -- AKA mutations -- creep in. From that point, it's simple survival of the fittest on a viral scale. Most mutations probably fail -- killed or inhibited by the medicine. But even if only one in a million -- or one in a billion -- manages to prosper in the presence of the drug, that virus can spawn a whole new viral strain that's immune or resistant to that drug.
It's not much different than the way bacteria sometimes mutate to form drug-resistant bugs, except that HIV is much more variable, forming many more mutations, each of which could be the so-called "escape mutation."
Escape mutations
To the patient, says Dr. Mark Markowitz of the Aaron Diamond AIDS Research Center, the goal of multiple-drug therapy is simply this: to find the most effective combination of drugs with the lowest level of side effects.
Getting back to our story, after reverse transcriptase does its job, the viral DNA enters the nucleus and gets set to make more viral RNA.
The problem of escape mutations has forced patients to shift from one drug to another. And it has sparked the rise of multiple-drug therapy. Here's the rationale: If HIV is under attack by one drug, the chance that any single mutation would resist it might be, say, one in a million. But if it's under attack by three drugs at once, there's only a tiny chance (something like one in a million cubed -- or one in a trillion trillion) that any single mutation would allow the virus to resist all three drugs.
Thus the drug treatment would be effective much longer, and the possibility of a new, super-vicious mutation escaping into the general population would be much lower.
