Salk Researchers Capture HIV’s Enzyme in Motion, Opening Doors to New Drugs

On the left is integrase in its “intasome” structure of four identical four-part complexes (pink) that connect to create one 16-part complex that locks around viral DNA (blue). On the right is integrase in its simpler four-part complex (pink), as it interacts with viral RNA (green) inside an HIV capsid. Credit:Salk Institute

uncovering its unexpected role in viral replication. This breakthrough provides a foundation for developing next-generation HIV drugs that could more effectively target the virus and combat drug resistance.

Globally, HIV infection rates continue to rise, with nearly 40 million people living with HIV-1—the most common strain. Although antiretroviral therapies now enable patients to manage symptoms and live longer, there remains no complete cure. Many individuals still face challenges, including lifelong medication, side effects, social stigma, and the emergence of resistant viral strains.

A Dual Role in HIV Replication

Integrase, a critical HIV enzyme, is best known for inserting viral DNA into the human genome—a key step in the replication process. However, scientists have recently discovered that integrase has a second, lesser-known role: binding with viral RNA later in the replication cycle to help assemble new viral particles.

Performing these two different tasks—first with DNA, then RNA—requires the protein to shift between distinct structural forms. Using advanced cryo-electron microscopy, Salk Institute researchers have, for the first time, captured 3D models of integrase in both configurations. These insights reveal how structural flexibility enables integrase to multitask and open up new strategies for drug development targeting specific protein functions.

The study, published in Nature Communications on October 24, 2025, was led by Associate Professor Dmitry Lyumkis, PhD, holder of the Hearst Foundations Developmental Chair at Salk, and supported by the National Institutes of Health and private philanthropy.

“We’re just beginning to understand that these integrase proteins, long known for one function, actually play multiple roles—including interacting with RNA,” says Lyumkis. “Mapping how integrase connects with RNA helps us uncover its new functions and will guide the creation of better HIV therapeutics.”

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Redefining Drug Targets

When HIV infects a cell, it uses integrase to embed its genetic material into the host’s DNA, transforming the cell into a viral factory that produces new infectious particles. Drugs such as Dolutegravir target this integration step. But HIV evolves rapidly, often mutating to evade existing therapies.

In 2023, Lyumkis’s team revealed how integrase alters its shape to resist Dolutegravir. Building on that work, the new findings suggest an alternative strategy: developing drugs that block integrase’s RNA-binding role instead of its DNA-insertion function. Such treatments could disrupt the virus’s ability to package RNA into new virions, potentially stopping HIV in its tracks.

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Two Faces of Integrase

“Very little was known about integrase’s behavior in the later stages of replication,” says co-first author Tao Jing, PhD, a postdoctoral researcher in Lyumkis’s lab. “Using cryo-electron microscopy, we’ve visualized its structure during this crucial, yet mysterious, phase.”

The team captured two distinct integrase architectures:

1. The intasome complex- a massive 16-part structure that wraps around viral DNA to integrate it into the host genome.

   
   

2. A simpler four-part complex- that appears during interaction with RNA, likely guiding the formation of new viral particles.

   
   

This remarkable flexibility allows integrase to assemble and disassemble as needed—an adaptability that may explain how the virus so efficiently replicates and mutates.

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Toward New HIV Therapeutics

“We’ve generated the first blueprints of integrase’s structure during these pivotal stages of HIV replication,” adds co-first author Zelin Shan, PhD. “Now we can design targeted compounds to disrupt the virus’s life cycle at multiple points.”

By linking integrase’s form and function, the Salk team has opened a promising path toward more durable, effective HIV treatments—ones capable of outsmarting the virus’s notorious adaptability and helping millions of people worldwide live healthier, longer lives.