HIV-1's Secret RNA Structures Offer Clues for Fighting the Virus

HIV-1, like other viruses, lacks the machinery to produce its own proteins and must rely on the host cell to translate its genetic instructions. After entering host cells, it seizes control of the translation process, which converts messenger ribonucleic acid (mRNA) into proteins. “In this study, we combined ribosome profiling, RNA sequencing and RNA structural probing to map the viral and host translational landscape and pausing during replication of the virus in unprecedented detail,” says corresponding author Neva Caliskan. She is a former group leader at the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg, a site of the Braunschweig Helmholtz Centre for Infection Research (HZI) in cooperation with the Julius-Maximilians-Universität Würzburg (JMU), and is currently the Director of the Department of Biochemistry III at the University of Regensburg.

Cheat Codes of Viral Translation

One of the key findings was the discovery of previously unrecognized elements in HIV-1 RNA called upstream open reading frames (uORFs) and internal open reading frames (iORFs). These “hidden gene fragments” may play a crucial role in fine-tuning the production of viral proteins as well as the interaction with the host immune system. “For instance, uORFs and iORFs can act as regulators, ensuring precise timing and levels of protein synthesis”, explains Anuja Kibe, a postdoctoral researcher at the HIRI and first author of the study, which was published in the journal Nature Structural and Molecular Biology.

Another important discovery was an intricate RNA structure near the critical “frameshift site” in the viral genome. This frameshift site is essential for the virus to produce the correct proportions of two key proteins, Gag and Gag-Pol, which are necessary for assembling infectious particles and replication of HIV-1. The researchers demonstrated that this extended RNA fold not only promotes ribosome collisions upstream of the site—a mechanism that appears to regulate translation—but also maintains the frameshifting efficiency. “Our team also showed that targeting this RNA structure with antisense molecules could significantly reduce frameshift efficiency by nearly 40 percent, offering a promising new avenue for antiviral drug development”, reports Caliskan.

A Game of Priorities

Redmond Smyth, a former Helmholtz Young Investigator Group Leader at the HIRI and currently a group leader at the Centre National de Recherche Scientifique (CNRS) in Strasbourg, France, mentions, “Interestingly, our analysis revealed that, while HIV-1 mRNAs are translated efficiently throughout infection, the virus suppresses the protein production of the host, particularly at the translation initiation stage.” This allows HIV-1 to prioritize its own needs while effectively stalling the host defense mechanisms. Thus, the virus can manipulate the host cell machinery in ways that remain robust even under stress conditions.

More Than Traffic Jams

The researchers also observed that ribosomes collide at specific regions of the viral RNA, particularly upstream of the frameshift site. “These collisions are not accidental but are instead tightly regulated pauses that may influence how ribosomes interact with downstream RNA structures,” says Florian Erhard, study co-author and Chair of Computational Immunology at the University of Regensburg.

Overall, the study provides not only a detailed map of the translational landscape of HIV-1 infected cells but also a wealth of potential targets for therapeutic intervention. The identification of RNA structures and genetic elements critical for viral replication highlights new opportunities for the development of drugs aimed at disrupting these processes. “By understanding how the virus cleverly manipulates our cells, these discoveries will bring us closer to innovative treatments that could one day turn tables and outsmart the virus itself,” Caliskan adds.

Reference: Kibe A, Buck S, Gribling-Burrer AS, et al. The translational landscape of HIV-1 infected cells reveals key gene regulatory principles. Nat Struct Mol Biol.  2025. doi: 10.1038/s41594-024-01468-3

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