Researchers from the University of Regensburg and the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg have revealed new information about how HIV-1, the virus that causes AIDS, deftly manipulates cellular processes to ensure its own survival. The researchers discovered new tactics that HIV-1 uses to guarantee its proliferation while squelching the host’s cellular defenses by analyzing the molecular interactions between the virus and its host. The journal Nature Structural and Molecular Biology published the study.
HIV-1, like other viruses, lacks the equipment to generate 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 turns messenger ribonucleic acid (mRNA) into proteins. According to corresponding author Neva Caliskan, “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.” Currently serving as the Director of the Department of Biochemistry III, she was previously a group leader at the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg, which is part of the Braunschweig Helmholtz Centre for Infection Research (HZI) in collaboration with Julius-Maximilians-Universität Würzburg (JMU).
The identification of hitherto unknown components in HIV-1 RNA known as internal open reading frames (iORFs) and upstream open reading frames (uORFs) was one of the major discoveries. These “hidden gene fragments” might be essential for regulating both the interaction with the host immune system and the synthesis of viral proteins. Anuja Kibe, a postdoctoral researcher at the HIRI and the study’s first author, adds that “for example, uORFs and iORFs can act as regulators, ensuring precise timing and levels of protein synthesis.” The work was published in the journal Nature Structural and Molecular Biology.
An complicated RNA structure close to the crucial “frameshift site” in the viral genome was another significant finding. The production of the proper amounts of two critical proteins, Gag and Gag-Pol, which are required for the assembly of infectious particles and HIV-1 replication, depends on this frameshift region. The researchers showed that this prolonged RNA fold preserves the frameshifting efficiency in addition to encouraging ribosome collisions upstream of the location, a mechanism that seems to control translation.
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.
Neva Caliskan
“Interestingly, our analysis revealed that, while HIV-1 mRNAs are translated efficiently throughout infection, the virus suppresses the host’s protein production, particularly at the translation initiation stage,” says Redmond Smyth, a former Helmholtz Young Investigator Group Leader at the HIRI and now a group leader at the Centre National de Recherche Scientifique (CNRS) in Strasbourg, France. This successfully stalls the host defensive mechanisms while enabling HIV-1 to prioritize its own requirements. As a result, the virus may control the host cell’s machinery in ways that are resilient even in the face of stress.
Additionally, the scientists noticed that ribosomes clash at particular locations on the viral RNA, especially upstream of the frameshift site. Florian Erhard, a co-author of the study and the Chair of Computational Immunology at the University of Regensburg, states that these collisions are not random but rather carefully controlled pauses that could affect how ribosomes interact with downstream RNA structures.
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All things considered, the work offers a variety of possible targets for therapeutic intervention in addition to a thorough map of the translational landscape of HIV-1-infected cells. The discovery of genetic components and RNA structures essential to viral replication opens up new avenues for the creation of medications that target these mechanisms.
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.
Neva Caliskan
Source: Helmholtz Centre for Infection Research
Journal Reference: Kibe, Anuja, et al. “The Translational Landscape of HIV-1 Infected Cells Reveals Key Gene Regulatory Principles.” Nature Structural & Molecular Biology, 2025, pp. 1-12, DOI: https://doi.org/10.1038/s41594-024-01468-3.
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Graduated from the University of Kerala with B.Sc. Botany and Biotechnology. Attained Post-Graduation in Biotechnology from the Kerala University of Fisheries and Ocean Science (KUFOS) with the third rank. Conducted various seminars and attended major Science conferences. Done 6 months of internship in ICMR – National Institute of Nutrition, Hyderabad. 5 years of tutoring experience.
