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Author Topic: Varying efficacy of HIV drug cocktails explained  (Read 1791 times)

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Offline John2038

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Varying efficacy of HIV drug cocktails explained
« on: July 16, 2011, 04:46:36 PM »
Increasing dose works at critical times in virus’s life cycle

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

For centuries, drug effectiveness has been visualized with what’s called the dose-response curve. This relationship often takes on a stretched-out “S” shape when graphed.

But in 2008, Siliciano’s then graduate student Lin Shen realized that the steepness of the incline of the “S” — its slope — varied with different classes of HIV drugs. A gradual climb meant that increases in drug concentration gradually improved the response. But a very steep slope meant that tiny increases in a drug’s concentration could wipe out significantly more target molecules.

That the steepness of this slope mattered for HIV drugs was puzzling, says Siliciano.  “The differences were huge — orders of magnitude,” he says.

For example, increasing the dose of the most effective protease inhibitors, drugs that block an HIV protein that snips up virus parts for assembly, can make them billions of times more powerful against the virus, he says. But increasing the amount of the drug AZT, which attacks virus machinery that translates genetic material, might yield an effect only 10 times greater than the lesser dose.

Incremental increases in dose that yield a vast improvement in response is a phenomenon that usually happens with drugs that attack a target molecule at multiple sites, an effect known as cooperative binding. Yet HIV has only one site that drugs can latch onto, so more of a drug shouldn’t necessarily be more effective.

Fig: The dose required to kill 50 percent of target molecules is 1 (dotted line) for both of these hypothetical HIV drugs. But the steeper slope of the red drug reveals that a very small increase in dose can have a big effect on response. Drugs that attack HIV at points in the virus’s life cycle that involve many molecules have these steep slopes, new research shows.



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