Scientists have recently uncovered new details about how HIV-1, the virus that leads to AIDS, cleverly exploits the cellular machinery for its own survival. By examining the complex interactions between the virus and the cells it infects, the researchers discovered unique tactics HIV-1 uses to replicate itself while undermining the host’s cellular defenses. This important research has been published in the journal Nature Structural and Molecular Biology.
A team of scientists at the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg and the University of Regensburg has unveiled insights into how HIV-1, the virus responsible for AIDS, skillfully hijacks cellular machinery for its own survival. By dissecting the molecular interplay between the virus and its host, the researchers identified novel strategies that HIV-1 employs to ensure its replication while suppressing the host’s cellular defenses. The study was published in the journal Nature Structural and Molecular Biology.
HIV-1, similar to other viruses, doesn’t have the tools to produce its own proteins and depends on the host cell’s machinery to translate its genetic material. After infecting a host cell, the virus takes control of the translation process, which transforms messenger ribonucleic acid (mRNA) into proteins. “In this study, we combined ribosome profiling, RNA sequencing, and RNA structural probing to create an in-depth map of the viral and host translational landscapes during viral replication,” says Neva Caliskan, the study’s leading author. Once a group leader at the Helmholtz Institute for RNA-based Infection Research (HIRI) in Würzburg, which collaborates with the Julius-Maximilians-Universität Würzburg (JMU), she is currently the Director of the Biochemistry III Department at the University of Regensburg.
Viral Translation Tactics
One significant finding was the identification of unknown components in HIV-1 RNA, termed upstream open reading frames (uORFs) and internal open reading frames (iORFs). These “hidden gene segments” are likely vital in regulating the production of viral proteins and influencing interactions with the host’s immune system. “For example, uORFs and iORFs can serve as regulators, ensuring precise timing and optimal levels of protein production,” explains Anuja Kibe, a postdoctoral researcher at HIRI and the primary author of this research published in Nature Structural and Molecular Biology.
Another critical discovery was a complex RNA structure located near the “frameshift site” within the viral genome, essential for producing the right proportions of two crucial proteins, Gag and Gag-Pol. These proteins are key for assembling infectious particles and the replication of HIV-1. The researchers showed that this extended RNA structure not only causes ribosome collisions upstream of the site—possibly regulating translation—but also helps maintain the efficiency of frameshifting. “We also demonstrated that targeting this RNA structure with antisense molecules could reduce frameshift efficiency by nearly 40 percent, paving the way for new antiviral drug development,” Caliskan notes.
Shifting Priorities
Redmond Smyth, a former Helmholtz Young Investigator Group Leader at HIRI and now a group leader at the Centre National de Recherche Scientifique (CNRS) in Strasbourg, France, highlights, “Interestingly, our analysis showed that while HIV-1 mRNAs are efficiently translated during infection, the virus suppresses the host’s protein production, especially at the initiation stage of translation.” This strategy allows HIV-1 to focus on its needs while effectively stunting the host’s defensive responses. Consequently, the virus can continue to steer the host cell machinery effectively, even amid stress.
Beyond Simple Disruptions
The researchers also discovered that ribosomes encounter collisions in specific areas of the viral RNA, particularly in front of the frameshift site. “These collisions aren’t random but are instead carefully regulated pauses that might affect how ribosomes interact with the following RNA structures,” states Florian Erhard, co-author of the study and Chair of Computational Immunology at the University of Regensburg.
In summary, this study not only provides a comprehensive overview of the translation landscape within HIV-1 infected cells but also reveals many potential targets for therapeutic strategies. The discovery of vital RNA structures and genetic elements critical to viral replication presents new possibilities for developing drugs that can interfere with these processes. “By gaining insights into the clever methods the virus uses to manipulate our cells, these findings can help us move towards innovative treatments that may one day outsmart the virus,” adds Caliskan.
