California [USA], Jul 22 (ANI): Researchers from the Salk Institute and the National Institutes of Health have identified a genetic pathway in which the human immunodeficiency virus (HIV) develops resistance to dolutegravir, one of the most powerful anti-HIV drugs currently available. The new study, published in Science Advances, reveals how changes in the 3D structure of the entry, HIV protein, can lead to resistance to dolutegravir and how other compounds can overcome this resistance. "With HIV, you have to be two steps ahead of the virus," says Salk Associate Professor Dmitry Lyumkis, who holds the Hearst Foundation Chair in Development. "We have now determined how this virus can progress against drugs such as dolutegravir, which is important to consider for the development of future treatments." HIV infection depends on the virus's ability to insert its own genes into human cells, exporting the cells as virus-producing factories. Dolutegravir and similar drugs work by blocking insertion, a protein essential for the virus's ability to insert its own DNA into the host's genome. Without active binding, HIV cannot successfully infect human cells. However, HIV is a rapidly changing virus and an increasing number of HIV-infected patients are resistant to dolutegravir. In the past, the Lyumkis lab has discovered the 3D structure of protein binding when it binds to DNA, and how drugs such as dolutegravir bind to and block binding. But the researchers weren't sure exactly how the pattern of entry changed when the virus stopped responding to dolutegravir. In a new study, Lyumkis and his colleagues at the National Institutes of Health created a version of the integrase protein with a mutation known to make HIV resistant to Dolutegravir. They determined the structure of each mutant, revealing why dolutegravir could not bind to and inhibit any type of protein. Scientists also analyzed the virulence of the virus (its ability to produce infectious offspring) and enzyme activity to better understand what leads to drug resistance in patients. "We were very surprised by how resistant these integrase variants were," says Lyumkis. "The ability of Dolutegravir to work has been completely compromised." The researchers also tested the effectiveness of an experimental HIV drug, 4d, in blocking the activity of dolutegravir-resistant proteins. Lyumkis' collaborators developed 4d as a drug targeting the next generation and it is now in direct trials in animals. In a different model, they found that 4d still inhibits HIV's ability to insert its genes into human cells. This suggests that 4d or variants of this offering can be used effectively to treat infections in patients who have developed resistance to dolutegravir. Structural data on how 4d binds to dolutegravir-resistant proteins also suggest how new drugs can overcome drug resistance. "4d is really an example of how to fight, but it gives us some principles that we can learn when we develop other treatments," says Robert Craigie, lead author of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health. "The way one part of the 4d molecule folds like a flat sheet on top of the other part of the protein-DNA complex can be replicated in other compounds." Next, scientists will study how integrase variants are developed, including those that have not been found in patients and are possible in the future, and how they affect the response of the best medicine in the clinic and the ability of HIV to transmit to humans.