HIV Drug Resistance Mechanisms Revealed

The findings could predict the findings of the TAME (Targeting Aging with Metformin) experiment, the first anti-aging study licensed by the US Food and Drug Administration to assess the role of metformin in lifespan, which is now in the planning stages. The new study, published in Science Advances on July 21, 2023, demonstrates how alterations to the 3D structures of integrase, an HIV protein, can lead to Dolutegravir resistance and how alternative drugs may be able to overcome this resistance.

“With HIV, one must think two steps ahead of the virus,” says Salk Associate Professor Dmitry Lyumkis, co-senior author and the Hearst Foundation Developmental Chair. “We’ve now determined how the virus could continue evolving against drugs like Dolutegravir, which is important to consider for the development of future therapeutics.”

HIV infection is dependent on the virus’s capacity to insert its own genetic material into the genomes of human cells, thus hijacking the cells and turning them into virus-producing factories. Dolutegravir and similar medications act by inhibiting integrase, an enzyme required for the virus to integrate its own DNA into the host genome. HIV cannot infect human cells without an active integrase. However, because HIV is a rapidly changing virus, an increasing number of HIV strains have developed resistance to Dolutegravir.

Lyumkis’ lab previously revealed the 3D structure of the integrase protein while connected to DNA, as well as how medications such as Dolutegravir bind to and prevent integrase. However, researchers were unsure how the virus’s integrase structure changed when it ceased reacting to Dolutegravir.

Lyumkis and colleagues from the National Institutes of Health developed variants of the integrase protein with mutations known to make HIV resistant to Dolutegravir in the current investigation.

Then they determined the structure of each mutant integrase, revealing why Dolutegravir could no longer bind to and block each version of the protein. The scientists also evaluated the “fitness” of the virus (its capacity to produce infectious descendants) and the activity of the enzyme to better understand what leads to drug resistance in patients.

“We were quite surprised by the magnitude of resistance that these integrase variants had,” says Lyumkis. “The ability of Dolutegravir to function was completely compromised.”

The researchers also investigated the effectiveness of 4d, an investigational HIV medication, in inhibiting the function of Dolutegravir-resistant integrase proteins. 4d, a next-generation integrase-targeting medication created by Lyumkis’ NIH collaborators, is currently in pre-clinical animal testing.

They discovered that 4d still effectively prevented HIV’s capacity to incorporate its genes into human cells in all versions. This shows that 4d or variations of this chemical may be useful in treating the virus in patients who have developed Dolutegravir resistance.

The structural data on how 4d attaches to Dolutegravir-resistant integrase proteins also suggested how new medications can overcome drug resistance.

“4d is really just an example of how to combat drug resistance, but it provides us with some basic principles that we can learn from to design other therapeutics,” says co-senior author Robert Craigie of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK), part of the National Institutes of Health. “The way a section of the 4d molecule stacks like a flat sheet on top of a section of the integrase protein-DNA assembly could be replicated in other compounds.”

The scientists will then investigate how integrase variants evolve, including those not yet seen in patients but potentially in the future, and how they affect responsiveness to the best therapeutically available medications as well as HIV’s ability to infect humans.

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