How HIV develops resistance to key drugs discovered

How HIV develops resistance to key drugs discovered


Today, a number of drugs are available which help to control HIV infection, including a group called integrase strand transfer inhibitors. There are four drugs within this family of medication: raltegravir, elvitegravir, dolutegravir and bictegravir. They all work by binding with one of HIV's key enzymes, called integrase, to stop it from inserting the virus' genetic information into DNA of human cells. While initially highly effective, over time HIV can develop resistance to these drugs.

The study, published in Science, discovered the mechanism HIV uses to develop resistance to this group of drugs. Although the drugs are normally very effective at binding and blocking integrase, over time, the virus can weaken this bond and thus enable its key enzyme to work again.

The researchers uncovered this by exploring the structure of integrase from a virus that is highly similar to the ancestor of HIV, using cryo-electron microscopy. This technique uses a powerful microscope which fires electrons at a frozen sample of the drug-enzyme complex. By recording how the electrons interact with the samples, the researchers created detailed images, at a nearly atom-by-atom level.

"The unusual property of these drugs is that they interact with metal ions, which normally allows them to make very strong bonds to the viral enzyme's active site. We found that HIV can subtly alter the chemical environment of the metals, and as if using a remote control, reduce the strength of drug binding. This is an unexpected chink in the armour of strand transfer inhibitors," says co-lead author and group leader.

"The good news is that we have finally visualised the precise structure of the viral enzyme's active site, right where the drugs bind. These blueprints will inform the design of more effective integrase inhibitors that could improve the lives of the many millions of people living with HIV," says another co-lead author.

"The weakening of drug binding occurs due to a combined effect of mutations and a loss of key water molecules in the active site. Understanding this mechanism will help improve this class of drugs in the future," comments a co-author.

https://www.crick.ac.uk/news/2020-01-30_how-hiv-develops-resistance-to-key-drugs-discovered

https://science.sciencemag.org/content/early/2020/01/30/science.aay4919

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