The codon context provides cis-acting immune evasion for the human papilloma virus (HPV) E6.

Human papilloma viruses (HPV) are linked to cancers, but how virus-carrying tumor cells express HPV-encoded antigens without attracting the immune system is still poorly understood. Here, we show how low- and high-risk HPV types equally exploit a cis-acting mechanism to limit the translation of the E6 mRNA, reducing the production of antigenic peptide substrates for the major histocompatibility class I (MHC-I) pathway. Introducing particular combinations of preferable codons throughout the HPV-16 E6 mRNA promotes mRNA translation and production of antigenic peptide substrates in mammalian cells but has minimal impact on E6 synthesis in Saccharomyces cerevisiae Using a gradual synonymous codon exchange, we identified a codon series with a significant effect on E6 translation rate. Unexpectedly, changing four nonpreferable codons to preferable codons in the wild-type sequence resulted in an ∼50% reduction in E6 expression. However, five additional changes to preferable codons further upstream shifted this inhibition to a strong induction of E6 expression, while they had no effect when introduced alone. These findings suggest a nuanced relationship between tRNA pools and translation rate, emphasizing how HPV uses codon usage to evade immune detection.