Translation is one of the most fundamental biological processes essential for the continuation of life, and viruses depend on the host cell’s translational machinery for replication. However, a significant genetic mismatch exists between giant viruses such as mimiviruses and the amoeba hosts they infect. While the viral genome is rich in AT bases, the host genome is predominantly GC-rich, leading to substantial differences in codon usage patterns. Under normal circumstances, this incompatibility between the host’s tRNA pool and the codons preferred by the virus would be expected to reduce the efficiency of viral protein synthesis. Nevertheless, how giant viruses overcome this obstacle and replicate so efficiently within host cells remains one of the key unanswered questions in virology and molecular biology.
In this study, Zhang and colleagues investigated how codon mismatch between Acanthamoeba polyphaga mimivirus (APMV) and its host affects viral protein synthesis. Although previous studies have shown that the virus encodes only a limited repertoire of tRNA genes, the mechanism by which this deficiency is compensated for has not been fully understood. To address this question, the researchers examined whether the virus alters the host tRNA pool during infection and tested the hypothesis that viral protein synthesis occurs within a specialized intracellular region.
APMV-infected amoeba cells were analyzed at different stages of infection (0, 2, 4, and 8 hours post-infection). The researchers employed a multi-omics approach to comprehensively investigate genetic activity during infection. RNA sequencing (RNA-seq) was used to measure gene expression levels, ribosome profiling (Ribo-seq) was performed to monitor the instantaneous rate and efficiency of protein synthesis, and optimized modification-induced misincorporation tRNA sequencing (mim-tRNA-seq) was applied to characterize the cellular tRNA pool.
In addition to sequencing-based analyses, fluorescence in situ hybridization (FISH) and fluorescent non-canonical amino acid tagging (FUNCAT) imaging techniques were integrated to determine the intracellular localization of viral mRNAs and newly synthesized proteins. This hybrid methodology distinguishes the study from previous research by simultaneously mapping both the temporal dynamics and the spatial organization of viral protein production.
The findings revealed that the host’s global tRNA pool remained remarkably stable during APMV infection and that virus-derived tRNAs contributed only minimally to translation. However, imaging analyses demonstrated that viral mRNAs and ribosomes were not randomly distributed throughout the cytoplasm; instead, they accumulated around the periphery of the replication center known as the viral factory. Within this region, a high availability of compatible tRNAs for AU-rich viral codons was observed.
In conclusion, this study demonstrates that giant viruses overcome genetic incompatibility not by globally modifying the host cell’s tRNA pool, but by creating a specialized subcellular translation environment around the viral factory. This localized translation strategy is proposed as a critical mechanism underlying the evolutionary success of giant viruses.
Translated by: Ayşenur Güneş
Editor: Elinsu Ak
Reference: : Zhang, R., Mayer, L., Hikida, H. et al. A giant virus forms a specialized subcellular environment within its amoeba host for efficient translation. Nat Microbiol 11, 584–596 (2026). https://doi.org/10.1038/s41564-025-02234-x
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