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Peer-reviewedCC BY-NCScience Advances

A forward genetics platform for papillomavirus research

  • Yuka Takeo1
  • Sydney R. Hirsch1
  • Daniel DiMaio1
  1. 1Department of Genetics, Yale School of Medicine, New Haven, CT, USA.
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Abstract

The inability to perform forward genetics has been a major barrier to human papillomavirus (HPV) research. Here, we report a platform for phenotypic selection of HPV mutants. Our method relies on large "concordant" virus libraries, where each mutant virus particle encapsidates the mutant plasmid that encodes it, thereby directly linking viral genotype to phenotype. This platform can achieve a ∼2500-fold enrichment of an L1 capsid protein mutant from an excess of wild-type virus. To demonstrate that this system could select rare mutants from complex libraries, we selected and validated antibody escape mutants and showed that two neutralizing antibodies that recognize overlapping epitopes in L1 display distinct patterns of HPV recognition. This genetics approach unlocks previously inaccessible avenues of investigation into the HPV life cycle and provides a powerful engine to develop improved vaccines and novel antiviral strategies.

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Cite

BibTeXRIS
BibTeX
@article{takeo2026forward,
  title = {{A forward genetics platform for papillomavirus research}},
  author = {Yuka Takeo and Sydney R. Hirsch and Daniel DiMaio},
  journal = {Science Advances},
  year = {2026},
  month = oct,
  doi = {10.1126/sciadv.aei3417},
  url = {https://www.science.org/doi/10.1126/sciadv.aei3417},
  note = {CC BY-NC},
}
RIS
TY  - JOUR
TI  - A forward genetics platform for papillomavirus research
AU  - Yuka Takeo
AU  - Sydney R. Hirsch
AU  - Daniel DiMaio
PY  - 2026
DA  - 2026/10/02
JO  - Science Advances
DO  - 10.1126/sciadv.aei3417
UR  - https://www.science.org/doi/10.1126/sciadv.aei3417
AB  - The inability to perform forward genetics has been a major barrier to human papillomavirus (HPV) research. Here, we report a platform for phenotypic selection of HPV mutants. Our method relies on large "concordant" virus libraries, where each mutant virus particle encapsidates the mutant plasmid that encodes it, thereby directly linking viral genotype to phenotype. This platform can achieve a ∼2500-fold enrichment of an L1 capsid protein mutant from an excess of wild-type virus. To demonstrate that this system could select rare mutants from complex libraries, we selected and validated antibody escape mutants and showed that two neutralizing antibodies that recognize overlapping epitopes in L1 display distinct patterns of HPV recognition. This genetics approach unlocks previously inaccessible avenues of investigation into the HPV life cycle and provides a powerful engine to develop improved vaccines and novel antiviral strategies.
SN  - 2375-2548
ER  -