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.

Department of Medical Biosciences Building 6M Umeå University 901 85 Umeå Sweden

Inserm UMRS1131 Institut de Génétique Moléculaire Université Paris 7 Hôpital St Louis 75010 Paris France

RECAMO Masaryk Memorial Cancer Institute 65653 Brno Czech Republic

Université de Brest; Inserm UMR1078; Établissement Français du Sang Bretagne; CHRU Brest Hôpital Morvan Laboratoire de Génétique Moléculaire F 29200 Brest France

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Ando D, Rashad S, Begley TJ, Endo H, Aoki M, Dedon PC, Niizuma K. 2025. Decoding codon bias: the role of tRNA modifications in tissue-specific translation. Int J Mol Sci 26: 706. 10.3390/ijms26020706 PubMed DOI PMC

Apcher S, Komarova A, Daskalogianni C, Yin Y, Malbert-Colas L, Fahraeus R. 2009. mRNA translation regulation by the Gly-Ala repeat of Epstein-Barr virus nuclear antigen 1. J Virol 83: 1289–1298. 10.1128/JVI.01369-08 PubMed DOI PMC

Apcher S, Daskalogianni C, Lejeune F, Manoury B, Imhoos G, Heslop L, Fahraeus R. 2011. Major source of antigenic peptides for the MHC class I pathway is produced during the pioneer round of mRNA translation. Proc Natl Acad Sci 108: 11572–11577. 10.1073/pnas.1104104108 PubMed DOI PMC

Bach S, Talarek N, Andrieu T, Vierfond JM, Mettey Y, Galons H, Dormont D, Meijer L, Cullin C, Blondel M. 2003. Isolation of drugs active against mammalian prions using a yeast-based screening assay. Nat Biotechnol 21: 1075–1081. 10.1038/nbt855 PubMed DOI

Barrington CL, Galindo G, Koch AL, Horton ER, Morrison EJ, Tisa S, Stasevich TJ, Rissland OS. 2023. Synonymous codon usage regulates translation initiation. Cell Rep 42: 113413. 10.1016/j.celrep.2023.113413 PubMed DOI PMC

Chandrasekaran V, Juszkiewicz S, Choi J, Puglisi JD, Brown A, Shao S, Ramakrishnan V, Hegde RS. 2019. Mechanism of ribosome stalling during translation of a poly(A) tail. Nat Struct Mol Biol 26: 1132–1140. 10.1038/s41594-019-0331-x PubMed DOI PMC

Chen Y, Egawa N, Zheng K, Doorbar J. 2025. How can HPV E6 manipulate host cell differentiation process to maintain the reservoir of infection. Tumour Virus Res 19: 200313. 10.1016/j.tvr.2025.200313 PubMed DOI PMC

Dittmar KA, Goodenbour JM, Pan T. 2006. Tissue-specific differences in human transfer RNA expression. PLoS Genet 2: e221. 10.1371/journal.pgen.0020221 PubMed DOI PMC

Doorbar J. 2013. Latent papillomavirus infections and their regulation. Curr Opin Virol 3: 416–421. 10.1016/j.coviro.2013.06.003 PubMed DOI

Fusee L, Salomao N, Ponnuswamy A, Wang L, Lopez I, Chen S, Gu X, Polyzoidis S, Vadivel Gnanasundram S, Fahraeus R. 2023. The p53 endoplasmic reticulum stress-response pathway evolved in humans but not in mice via PERK-regulated PubMed DOI PMC

Gajjar M, Candeias MM, Malbert-Colas L, Mazars A, Fujita J, Olivares-Illana V, Fahraeus R. 2012. The PubMed DOI

Garcia A, Maldonado G, Gonzalez JL, Svitkin Y, Cantu D, Garcia-Carranca A, Sonenberg N, Hernandez G. 2021. High-risk human papillomavirus-18 uses an mRNA sequence to synthesize oncoprotein E6 in tumors. Proc Natl Acad Sci 118: e2108359118. PubMed PMC

Gingold H, Tehler D, Christoffersen NR, Nielsen MM, Asmar F, Kooistra SM, Christophersen NS, Christensen LL, Borre M, Sorensen KD, et al. 2014. A dual program for translation regulation in cellular proliferation and differentiation. Cell 158: 1281–1292. 10.1016/j.cell.2014.08.011 PubMed DOI

Gnanasundram SV, Pyndiah S, Daskalogianni C, Armfield K, Nylander K, Wilson JB, Fahraeus R. 2017. PI3Kδ activates E2F1 synthesis in response to mRNA translation stress. Nat Commun 8: 2103. 10.1038/s41467-017-02282-w PubMed DOI PMC

Gorochowski TE, Ignatova Z, Bovenberg RA, Roubos JA. 2015. Trade-offs between tRNA abundance and mRNA secondary structure support smoothing of translation elongation rate. Nucleic Acids Res 43: 3022–3032. 10.1093/nar/gkv199 PubMed DOI PMC

Heck DV, Yee CL, Howley PM, Munger K. 1992. Efficiency of binding the retinoblastoma protein correlates with the transforming capacity of the E7 oncoproteins of the human papillomaviruses. Proc Natl Acad Sci 89: 4442–4446. 10.1073/pnas.89.10.4442 PubMed DOI PMC

Hernandez-Alias X, Benisty H, Schaefer MH, Serrano L. 2021. Translational adaptation of human viruses to the tissues they infect. Cell Rep 34: 108872. 10.1016/j.celrep.2021.108872 PubMed DOI PMC

Juszkiewicz S, Slodkowicz G, Lin Z, Freire-Pritchett P, Peak-Chew SY, Hegde RS. 2020. Ribosome collisions trigger PubMed DOI PMC

Kwun HJ, da Silva SR, Shah IM, Blake N, Moore PS, Chang Y. 2007. Kaposi's sarcoma-associated herpesvirus latency-associated nuclear antigen 1 mimics Epstein-Barr virus EBNA1 immune evasion through central repeat domain effects on protein processing. J Virol 81: 8225–8235. 10.1128/JVI.00411-07 PubMed DOI PMC

Kwun HJ, da Silva SR, Qin H, Ferris RL, Tan R, Chang Y, Moore PS. 2011. The central repeat domain 1 of Kaposi's sarcoma-associated herpesvirus (KSHV) latency associated-nuclear antigen 1 (LANA1) prevents PubMed DOI PMC

Lista MJ, Martins RP, Billant O, Contesse MA, Findakly S, Pochard P, Daskalogianni C, Beauvineau C, Guetta C, Jamin C, et al. 2017. Nucleolin directly mediates Epstein-Barr virus immune evasion through binding to G-quadruplexes of EBNA1 mRNA. Nat Commun 8: 16043. 10.1038/ncomms16043 PubMed DOI PMC

Longworth MS, Laimins LA. 2004. Pathogenesis of human papillomaviruses in differentiating epithelia. Microbiol Mol Biol Rev 68: 362–372. 10.1128/MMBR.68.2.362-372.2004 PubMed DOI PMC

Martins RP, Malbert-Colas L, Lista MJ, Daskalogianni C, Apcher S, Pla M, Findakly S, Blondel M, Fahraeus R. 2019. Nuclear processing of nascent transcripts determines synthesis of full-length proteins and antigenic peptides. Nucleic Acids Res 47: 3086–3100. 10.1093/nar/gky1296 PubMed DOI PMC

Okunade KS. 2020. Human papillomavirus and cervical cancer. J Obstet Gynaecol 40: 602–608. 10.1080/01443615.2019.1634030 PubMed DOI PMC

Pal A, Kundu R. 2019. Human papillomavirus E6 and E7: the cervical cancer hallmarks and targets for therapy. Front Microbiol 10: 3116. 10.3389/fmicb.2019.03116 PubMed DOI PMC

Prado Martins R, Findakly S, Daskalogianni C, Teulade-Fichou MP, Blondel M, Fahraeus R. 2018. In cellulo protein-mRNA interaction assay to determine the action of G-quadruplex-binding molecules. Molecules 23: 3124. 10.3390/molecules23123124 PubMed DOI PMC

Samorski R, Gissmann L, Osen W. 2006. Codon optimized expression of HPV 16 E6 renders target cells susceptible to E6-specific CTL recognition. Immunol Lett 107: 41–49. 10.1016/j.imlet.2006.07.003 PubMed DOI

Scheffner M, Huibregtse JM, Vierstra RD, Howley PM. 1993. The HPV-16 E6 and E6-AP complex functions as a ubiquitin-protein ligase in the ubiquitination of p53. Cell 75: 495–505. 10.1016/0092-8674(93)90384-3 PubMed DOI

Steinbach A, Riemer AB. 2018. Immune evasion mechanisms of human papillomavirus: an update. Int J Cancer 142: 224–229. 10.1002/ijc.31027 PubMed DOI

Tellam J, Connolly G, Green KJ, Miles JJ, Moss DJ, Burrows SR, Khanna R. 2004. Endogenous presentation of CD8 PubMed DOI PMC

Torrent M, Chalancon G, de Groot NS, Wuster A, Madan Babu M. 2018. Cells alter their tRNA abundance to selectively regulate protein synthesis during stress conditions. Sci Signal 11: eaat6409. 10.1126/scisignal.aat6409 PubMed DOI PMC

Tuller T, Waldman YY, Kupiec M, Ruppin E. 2010. Translation efficiency is determined by both codon bias and folding energy. Proc Natl Acad Sci 107: 3645–3650. 10.1073/pnas.0909910107 PubMed DOI PMC

Verweij MC, Horst D, Griffin BD, Luteijn RD, Davison AJ, Ressing ME, Wiertz EJ. 2015. Viral inhibition of the transporter associated with antigen processing (TAP): a striking example of functional convergent evolution. PLoS Pathog 11: e1004743. 10.1371/journal.ppat.1004743 PubMed DOI PMC

Voisset C, Daskalogianni C, Contesse MA, Mazars A, Arbach H, Le Cann M, Soubigou F, Apcher S, Fahraeus R, Blondel M. 2014. A yeast-based assay identifies drugs that interfere with immune evasion of the Epstein-Barr virus. Dis Models Mech 7: 435–444. 10.1242/dmm.014308 PubMed DOI PMC

Werness BA, Levine AJ, Howley PM. 1990. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248: 76–79. 10.1126/science.2157286 PubMed DOI

Yewdell JW, Hill AB. 2002. Viral interference with antigen presentation. Nat Immunol 3: 1019–1025. 10.1038/ni1102-1019 PubMed DOI

Yewdell JW, Dersh D, Fahraeus R. 2019. Peptide channeling: the key to MHC class I immunosurveillance? Trends Cell Biol 29: 929–939. 10.1016/j.tcb.2019.09.004 PubMed DOI

Yin Y, Manoury B, Fahraeus R. 2003. Self-inhibition of synthesis and antigen presentation by Epstein-Barr virus-encoded EBNA1. Science 301: 1371–1374. 10.1126/science.1088902 PubMed DOI

Zareie AR, Verma SC. 2023. Nucleolin regulates the expression of Kaposi's sarcoma-associated herpesvirus’ latency-associated nuclear antigen through G-quadruplexes in the mRNA. Viruses 15: 2438. 10.3390/v15122438 PubMed DOI PMC

Zhang G, Hubalewska M, Ignatova Z. 2009. Transient ribosomal attenuation coordinates protein synthesis and co-translational folding. Nat Struct Mol Biol 16: 274–280. 10.1038/nsmb.1554 PubMed DOI

Zhao KN, Gu W, Fang NX, Saunders NA, Frazer IH. 2005. Gene codon composition determines differentiation-dependent expression of a viral capsid gene in keratinocytes in vitro and in vivo. Mol Cell Biol 25: 8643–8655. 10.1128/MCB.25.19.8643-8655.2005 PubMed DOI PMC

Zheng AJ, Thermou A, Guixens Gallardo P, Malbert-Colas L, Daskalogianni C, Vaudiau N, Brohagen P, Granzhan A, Blondel M, Teulade-Fichou MP, et al. 2022a. The different activities of RNA G-quadruplex structures are controlled by flanking sequences. Life Sci Alliance 5: e202101232. 10.26508/lsa.202101232 PubMed DOI PMC

Zheng AJL, Thermou A, Daskalogianni C, Malbert-Colas L, Karakostis K, Le Senechal R, Trang Dinh V, Tovar Fernandez MC, Apcher S, Chen S, et al. 2022b. The nascent polypeptide-associated complex (NAC) controls translation initiation in PubMed DOI PMC