Codon optimization of the adenoviral fiber negatively impacts structural protein expression and viral fitness.
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.
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.
Eneko
E
Villanueva
Research Programme on Biomedical Informatics, Department of Experimental and Health Sciences, Pompeu Fabra University, Hospital del Mar Medical Research Institute, Barcelona, Spain.
Maria
M
Martí-Solano
Institut d'Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), Barcelona, Spain.|Centro de Investigación Biomédica en Red de Enfermedades Raras (CIBERER), Barcelona, Spain.
Cristina
C
Fillat
D000072283:A549 Cells; D000256:Adenoviridae / Q000235:genetics*; D036022:Capsid Proteins / Q000235:genetics; D003062:Codon; D015967:Gene Expression Regulation, Viral; D005818:Genetic Engineering; D016679:Genome, Viral; D049452:Green Fluorescent Proteins / Q000378:metabolism; D057809:HEK293 Cells; D006367:HeLa Cells; D006801:Humans; D009369:Neoplasms / Q000628:therapy; D050130:Oncolytic Virotherapy; D010957:Plasmids / Q000235:genetics; D025341:Principal Component Analysis; D017510:Protein Folding; D014764:Viral Proteins / Q000235:genetics*
D036022:Capsid Proteins; D003062:Codon; D014764:Viral Proteins; D049452:Green Fluorescent Proteins