Researchers have made another crucial step in the fight against HIV. A team from the Salk Institute has discovered how a powerful class of HIV drugs bind with the virus at an atomic level. This opens a door to better understand current and upcoming treatments, and to design even more effective ones in the future.
As reported in Science, the work focused on the intasome, a key protein that enables the virus to infect human cells. This particular structure has the task of moving into each human cell and integrating the virus’s genetic material into human DNA. A class of drugs known as integrase strand transfer inhibitors (INSTIs) can block the intasome.
Isolating intasome is far from easy. Previous work used a different retrovirus, called prototype foamy virus, to work out how INSTIs and intasome interact. This team was also the first to determine the structure of the HIV intasome in 2017. The new work has produced a detailed structure of the intasome while it is blocked by the INSTIs.
“The drugs we studied are the latest compounds available in the clinic today, as well as several important pre-clinical molecules. Until now, no one knew exactly how they bound to this HIV complex,” the study’s senior author Dmitry Lyumkis, an assistant professor in Salk’s Laboratory of Genetics, said in a statement. “A better understanding of how the drugs work will help us improve them and design new therapeutic compounds.”
The analysis showed why these drugs have been so effective and why the virus is not adapting to them. The drug fills the entire space occupied by the DNA, so if the intasome ever developed a mutation that stopped the drug from working it would also block DNA from attaching, making the newly mutated intasome totally useless.
“We and many others have been working towards this goal for several decades and it is exciting that at long last we can now understand how HIV inhibitors work in detail and aid the development of new drugs,” added Min Li, co-first author and a staff scientist at the National Institute of Diabetes and Digestive and Kidney Diseases.
The team is now looking at a particular compound called 4d and plans to continue studying how the intasome develops resistance to INSTIs.