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New Insights on HIV Replication Revealed at Atomic Resolution

Cartoon representation of the HIV-1 Pol structure. Credit: Francesc Xavier Ruiz from the Center for Advanced Biotechnology and Medicine at Rutgers.

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A new study by scientists at the Salk Institute and Rutgers University reveals the molecular structure of HIV Pol, a large protein that is key for human immunodeficiency virus (HIV) replication. The research is published in Science Advances.

Structural biology aids the development of new drugs

When developing novel drugs to target a disease, understanding how the disease manifests in the body at the molecular level is a critical step. Infectious diseases occur due to interactions between the host and the pathogen that enable the pathogen to replicate, a process conducted by proteins. Through studying how these interactions occur, gaining insight into the molecular structures of the proteins involved, researchers can explore their potential as drug targets.

HIV is a disease that affects ~40 million people around the globe. While treatment is available in the form of antiretroviral therapies (ART, this requires lifelong daily medication and an effective cure remains sought after.

The mechanisms by which the virus replicates in the body have been understood to a degree, but one particular protein – HIV Pol, has puzzled scientists. HIV Pol breaks into three enzymes: a protease, integrase and a reverse transcriptase. These proteins work in union to help assemble the “mature” version of the virus that can replicate inside the body. This process is initiated by the protease, which effectively “chops up” the viral molecule to enable each of the three components to be separated from one another. But how does the protease itself break free to enable this process to occur? It’s a “chicken and the egg”-like conundrum that has now been solved by researchers at the Salk Institute and Rutgers University using cryogenic electron microscopy, or cryo-EM.

“It was known (but not understood) that there is a coupling between these enzymes before HIV Pol breaks apart. Visualizing the HIV Pol structure explains the basis for this complex mechanism,” co-senior author Eddy Arnold, board of governors professor and distinguished professor in the Center for Advanced Biotechnology and Medicine at Rutgers University, said in a news release.

What is cryogenic electron microscopy?

A revolutionary technique, cryo-EM involves rapidly cooling samples to cryogenic temperatures to fix the proteins in a thin layer of ice. This effectively locks the proteins in their native-state confirmations, meaning they can be imaged individually at incredibly high resolutions.  

HIV Pol is a dimer

Using cryo-EM, the research team were able to uncover the 3D structure of the HIV Pol protein, revealing that Pol is actually a dimer, formed through the binding of two proteins. Within this dimer structure, the protease of Pol is attached loosely to the reverse transcriptase such that the connection is somewhat flexible. “It’s holding the protease at arm’s length, loosely, and we believe that gives the protease a little bit of movement, which in turn allows it to initiate the cutting of polyproteins that is a prerequisite for viral maturation,” co-first author Dario Passos, a former researcher in Dmitry Lyumkis’ lab at Salk, said.

The researchers believe this finding points to a vulnerability in HIV’s replication machinery that could be targeted by therapeutics. “Structure informs function, and the insights we gained from visualizing the molecular architecture of Pol give us a new understanding of the mechanism by which HIV replicates,” co-senior author Dmitry Lyumkis, assistant professor in the Laboratory of Genetics and Hearst Foundation Developmental Chair at Salk, said in a news release.

The team encourage follow-up research that explores the structure of the larger complex polyprotein Gag-Pol, which is also integral to viral assembly, in addition to further probing how integrase is implicated in assembling the mature form of the virus.

Reference: Harrison JJEK, Passos DO, Bruhn JF, et al. Cryo-EM structure of the HIV-1 Pol polyprotein provides insights into virion maturation. Sci Adv. 2022;8(27):eabn9874. doi: 10.1126/sciadv.abn9874

This article is a rework of a press release issued by the Salk Institute. Material has been edited for length and content.

Meet the Author
Molly Campbell
Molly Campbell
Senior Science Writer