New Strategy Revealed for HIV-1 to Ensure Its Own Replication While Suppressing Host Cell Defenses

In a new study, a research team from the Helmholtz Institute for RNA Infection Research and the University of Regensburg has provided new insights into how HIV-1, the virus that causes AIDS, cleverly hijacks cellular machinery to maintain its own survival. By dissecting the molecular interactions between the virus and its host, they identified a new strategy for HIV-1 to ensure its own replication while suppressing host cell defenses. The relevant research results were published online in the journal Nature Structural & Molecular Biology in January 2025, with the title "The translational landscape of HIV-1 infected cells reveals key gene regulatory principles".

HIV-1, like other viruses, lacks the machinery to produce its own proteins and must rely on host cells to translate its genetic instructions. Once inside the host cell, it takes control of the translation process, converting messenger RNA (mRNA) into proteins.

"In this study, we combined ribosome profiling, RNA sequencing, and RNA structure probing to map the translation landscape of the virus and host and the pauses during viral replication," said Neva Caliskan, corresponding author of the paper.

One of the key findings was the discovery of previously unrecognized sequence elements in HIV-1 RNA, namely the upstream open reading frame (uORF) and the internal open reading frame (iORF). These "hidden gene fragments" may play a key role in fine-tuning the production of viral proteins and interactions with the host immune system.

"For example, uORFs and iORFs can act as regulators, ensuring the precise timing and level of protein synthesis," explains Anuja Kibe, first author of the study and postdoctoral researcher at the Helmholtz Institute for RNA Infection.

Another key finding is the complex RNA structure near a key "frameshift site" in the HIV-1 viral genome. This frameshift site is essential for the virus to produce the correct ratio of two key proteins, Gag and Gag-Pol, which are required for the assembly of infectious particles and HIV-1 replication. The authors showed that this extended RNA fold not only promotes ribosome collisions upstream of this frameshift site - which appears to be a mechanism for regulating translation - but also maintains frameshift efficiency.

"Our team also showed that targeting this RNA structure with antisense molecules can significantly reduce frameshift efficiency by nearly 40%, providing a promising new avenue for antiviral drug development," reports Caliskan.

"Interestingly, our analysis shows that while HIV-1 mRNA is efficiently translated throughout the infection, the virus inhibits protein production in the host, particularly at the translation initiation stage," says co-author Redmond Smyth.

Figure 1. Global transcriptional and translational changes in HIV-1 infected cells. (Kibe A, et al., 2025)

This allows HIV-1 to prioritize its own needs while effectively blocking host defense mechanisms. The virus can thus manipulate host cell machinery in a way that remains robust even under stressful conditions. The authors also observed ribosome collisions at specific regions of the HIV-1 mRNA, in particular upstream of this frameshift site. "These collisions are not accidental, but rather tightly regulated pauses that may affect the interaction of the ribosome with downstream RNA structures," says co-author Florian Erhard.

Overall, this study not only provides a detailed map of the translational landscape of HIV-1 infected cells, but also offers a rich potential target for therapeutic intervention. The identification of RNA structural and sequence elements that are critical for HIV-1 viral replication provides new opportunities for the development of drugs aimed at disrupting these processes.