Mechanism That Drives HIV Resistance to Inhibitors Discovered

Researchers from the Crick and Dana-Farber Cancer Institute have discovered the mechanism behind how HIV can develop resistance to integrase strand transfer inhibitors. The findings may lead to the development of more effective treatments.

There are 4 drugs within the integrase strand transfer inhibitors: raltegravir, elvitegravir, dolutegravir, and bictegravir. They work by binding with 1 of HIV’s enzymes, integrase, to stop it from inserting the virus’ genetic information into DNA in human cells. Although initially highly effective, HIV can develop resistance to these drugs over time.

Published in Science, the study showed the mechanism that HIV uses to develop resistance to this class. Although the drugs are normally effective at binding and blocking integrase, HIV can weaken the bond and enable its enzyme to work again over time.

Using cryo-electron microscopy, researchers examined the structure of integrase from a virus similar to the ancestor of HIV. By recording how the electrons interact with the samples, the researchers created detailed images at an atomic level. This process allowed the researchers to visualize the precise structure of the viral enzyme’s active site, informing the design of more effective integrase inhibitors that could improve treatment for patients living with HIV.

“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 armor of strand transfer inhibitors,” said Peter Cherepanov, PhD, co-lead author and group leader in the Chromatin and Mobile DNA Laboratory at the Francis Crick Institute, in a press release.

The weakening of drug binding occurs due to the combined effect of mutations and a loss of key water molecules in the active site, according to the press release. Understanding this mechanism will help to improve this class and treatment for patients living with HIV.

“This research is an outstanding example of how we can use cryo-electron microscopy to reveal the intricate relationships between drugs and their targets, providing results that could lead to clinical benefit,” said Peter Rosenthal, the head of the Structural Biology of Cells and Viruses laboratory at the Francis Crick Institute, in a press release.

Reference

• How HIV develops resistance to key drugs discovered [news release]. The Francis Crick Institute website. Published January 30, 2020. https://www.crick.ac.uk/news/2020-01-30_how-hiv-develops-resistance-to-key-drugs-discovered. Accessed Februray 3, 2020.