On the left is integrase in its “intasome” construction of 4 an identical four-part complexes (pink) that connect with create one 16-part complicated that locks round viral DNA (blue). On the suitable is integrase in its easier four-part complicated (pink), because it interacts with viral RNA (inexperienced) inside an HIV capsid. Credit score: Salk Institute
The speed of HIV an infection continues to climb globally. Round 40 million folks stay with HIV-1, the commonest HIV pressure. Whereas signs can now be higher managed with lifelong remedy, there isn’t any remedy to completely get rid of the virus from the physique, so sufferers nonetheless typically battle with associated well being points, negative effects, social stigma, and drug resistance.
Some of the promising remedy avenues is disrupting HIV replication by impairing the operate of integrase, a protein named for its position in integrating viral genetic materials into the human host genome. Nonetheless, scientists have not too long ago seen that integrase does extra than simply integration. Later in HIV’s replication cycle, integrase interacts with viral RNA to assist the virus unfold and infect new cells.
Taking up these two distinct roles—first with DNA, then RNA—requires adjustments to integrase’s protein construction. Salk Institute researchers not too long ago captured these necessary structural adjustments for the primary time, creating novel 3D fashions of integrase in each roles. Now, scientists can join the dots between integrase’s type and performance to start growing compounds that might impair distinct capabilities of integrase and, in flip, higher deal with folks dwelling with HIV.
The brand new examine is revealed in Nature Communications at the moment.
“We are just now finding that these integrase proteins that we have studied for years perform unexpected functionalities, like interacting with RNA,” says senior writer Dmitry Lyumkis, Ph.D., an affiliate professor and holder of the Hearst Foundations Developmental Chair at Salk. “Determining how integrase interacts with RNA will help us better understand this new role and inform the design of novel and more effective HIV therapeutics.”
Paving the best way for brand spanking new integrase-targeting medication
When a virus infects a cell, it inserts its genetic materials (DNA or RNA) into the host genome and hijacks the cell’s equipment to make extra of the virus. Conventional RNA viruses should carry their very own RNA replication instruments as a result of the cells are solely designed to duplicate DNA.
Nonetheless, HIV is a retrovirus, that means it will possibly reverse-engineer DNA from RNA. As soon as it has contaminated a cell, the virus makes use of that RNA to create complementary viral DNA, which it then inserts into the cell’s personal genome. From there, the cell turns into an HIV manufacturing unit—churning out new viral RNA that will get packaged and despatched off to contaminate extra cells.
Integrase performs the DNA-insertion course of, which is a trademark of the viral replication cycle, making the protein an apparent goal for HIV-1 medication like Dolutegravir. Nonetheless, HIV-1 evolves quickly and is vulnerable to growing drug resistance. In 2023, Lyumkis found how integrase adapts its construction to evade Dolutegravir.
Learning the mechanisms of drug resistance is a method to deal with HIV-1’s speedy evolution. One other method is to develop new medication that focus on new processes. As an alternative of concentrating on integrase throughout DNA insertion, future medication may as a substitute goal integrase throughout its not too long ago found second position: interacting with the newly produced viral RNA because it’s packaged into nascent viruses which have left the cell.
Two distinct buildings reveal integrase’s stunning flexibility
“Very little is known about what integrase is doing in the later stages of HIV replication,” says co-first writer Tao Jing, Ph.D., a postdoctoral researcher in Lyumkis’s lab. “Our use of cryo-electron microscopy to discover the architecture of integrase during this mysterious period is a significant step for HIV research.”
Cryo-electron microscopy permits researchers to see a protein’s 3D construction because it happens in nature. Similar to a constructing’s structure informs its operate (consider a movie show’s format versus a restaurant’s), a protein’s structure informs its operate, too. With a structural blueprint of a protein in hand, scientists can start imagining the way it works and envisioning compounds that might match into its construction to reinforce or inhibit it.
The researchers used cryo-electron microscopy to gather two distinct integrase buildings: 1) the shape that integrates the viral DNA into the host cell’s genome, and a pair of) the shape that possible interacts with the newly produced viral RNA later within the HIV replication course of.
First, they decided integrase’s structure because it kinds the “intasome”—a particular meeting of proteins and viral DNA. On this intasome type, integrase is made up of 4 an identical four-part complexes that connect with create one 16-part complicated. This enormous construction encircles the viral DNA, holding it in place to facilitate its integration with the host genome.
Second, they decided integrase’s extra mysterious protein structure because it interacts with RNA. At this level, the protein ditches the enormous sixteen-part complicated in favor of a less complicated, smaller four-part complicated. Based mostly on this four-part construction, the group has an thought of how integrase may work together with RNA, and they’re planning follow-up research to verify their suspicions.
Integrase is a extremely adaptable protein, able to build up right into a 16-part complicated, then breaking again down right into a four-part complicated. Lyumkis says this flexibility is stunning, and although among the structural adjustments are refined, they’ll make substantial variations within the drug improvement course of.
“We’ve created the first blueprints for integrase’s structure during these crucial steps in HIV replication,” says co-first writer Zelin Shan, Ph.D., a postdoctoral researcher in Lyumkis’s lab. “Now we can use those blueprints to design new drugs that suit this structure and disrupt the destructive HIV-1 invasion and replication process.”
Extra info:
Tao Jing et al, Oligomeric HIV-1 integrase buildings reveal practical plasticity for intasome meeting and RNA binding, Nature Communications (2025). DOI: 10.1038/s41467-025-64479-8
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