Abstract
Codon usage adaptation of lytic viruses to their hosts is determinant for viral fitness. In this work, we analyzed the codon usage of adenoviral proteins by principal component analysis and assessed their codon adaptation to the host. We observed a general clustering of adenoviral proteins according to their function. However, there was a significant variation in the codon preference between the host-interacting fiber protein and the rest of structural late phase proteins, with a non-optimal codon usage of the fiber. To understand the impact of codon bias in the fiber, we optimized the Adenovirus-5 fiber to the codon usage of the hexon structural protein. The optimized fiber displayed increased expression in a non-viral context. However, infection with adenoviruses containing the optimized fiber resulted in decreased expression of the fiber and of wild-type structural proteins. Consequently, this led to a drastic reduction in viral release. The insertion of an exogenous optimized protein as a late gene in the adenovirus with the optimized fiber further interfered with viral fitness. These results highlight the importance of balancing codon usage in viral proteins to adequately exploit cellular resources for efficient infection and open new opportunities to regulate viral fitness for virotherapy and vaccine development.
Highlights
Codon usage adaptation of lytic viruses to their hosts is determinant for viral fitness
To assess if there was a bias in codon usage that differentiated Ad5 proteins, we initially calculated the frequency of each codon for every Ad5 protein and used these frequencies as protein descriptors in a principal component analysis (PCA)
As previously described for other adenoviruses[24], analysis of the PCA loadings showed that this protein separation in PC1 could be explained by their differential use of A/T versus G/C at the third codon position
Summary
Codon usage adaptation of lytic viruses to their hosts is determinant for viral fitness. During the late phase of their replicative cycle, adenoviruses block the translation of cellular proteins by preventing phosphorylation of the translation initiation factor eIF4G through expression of the viral protein 100-kDa6 This prevents binding of the translation initiation factor to the cap region of cellular mRNAs. the late adenoviral genes, which are all expressed under the same promoter, can still be correctly translated thanks to a shared highly organized loop structure, known as the tripartite leader structure, in their 5′-UTR7,8. Considering that viruses use the cellular translational machinery to translate their own mRNAs, they are subjected to a high pressure to adapt to the available pool of tRNAs in the cell Some viruses such as HIV or herpesviruses maintain codons in their genes which show a low prevalence in their host cells[13,14]. The impact of this strategy on viral fitness remains unclear
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