The math behind how HIV drugs work

If you’re still on an antiretroviral high from this week’s double announcement of anti-HIV pills that protect uninfected people… here’s more good news.

Scientists reveal the secrets of how HIV drugs for infected people work their magic. The findings point towards new targets for antiviral drugs and way to combat drug resistance.

Since they appeared in the mid-1990s, antiretroviral therapy has improved both length and quality of life. Though there’s no cure yet, they provide long-lasting (or even lifelong) control over the virus.

But surprisingly enough, scientists haven’t quite sussed out why they’re as successful as they are, and why some combinations are more successful than others.

The new model reveals that slightly boosting the dose of some HIV drugs has a profound effect if those drugs are attacking multiple targets.

Finding that more bullets can kill more targets may seem obvious, says study researcher Robert Siliciano of Johns Hopkins University. But this required a shift in thinking about the relationship between dose and effect.

Drug effectiveness has always been visualized with the ‘dose-response curve’ – an S-shaped relationship when graphed.

The steepness of the S’s incline – its slope – varied with different kinds of HIV drugs. A gradual climb meant that increases in concentration gradually improved the response. But a very steep slope meant that tiny increases in concentration could wipe out significantly more target molecules.

For example, increasing the dose of the most effective protease inhibitors can make them billions of times more powerful against the virus, Science New explains. But increasing the amount of AZT might yield an effect only 10 times greater than the lesser dose.

In particular, two classes of HIV drugs inhibit HIV enzymes in a cooperative way. Normally, cooperative binding occurs when the binding of one drug molecule to its target enzyme allows other drug molecules to quickly bind to multiple sites on the same target.

However, HIV enzymes have only one binding site per molecule, which means more of a drug shouldn’t necessarily be effective. So how does it work?

To explain this unexpected cooperation, Siliciano and colleagues came up with a mathematical model and watched as the S curves changed according to various dose experiments (pictured).

They found that at certain times in the HIV life cycle, there is so much viral machinery to attack, that the drugs are cooperatively binding – but to many, many targets rather than many sites on one target.

The new model takes into account that some drugs enter the battle during parts of HIV’s life cycle when infection is halted only if a critical mass of targets are killed. If the virus had fewer working enzymes for the drug to disable, the virus was inhibited with a lower dose.

These results may help researchers determine when in the viral cycle to target for drug development.

The study was published in Science Translational Medicine this week.

Via Science News.

Image: C. Bickel / Science AAAS

This post was originally published on Smartplanet.com