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Productive or Transforming? How Epithelial Compartmentalization of HPV DNA and E6/E7 Transcripts Shapes Cervical
Konstanze Schichl1, John Doorbar1
1Department of Pathology, University of Cambridge, Cambridge, UK.
Abstract:
The human papillomavirus (HPV) life cycle is linked to epithelial cell differentiation, with viral genome amplification, E6/E7 transcription, and virion assembly spatially compartmentalized within the cervical epithelium. This organization is disrupted in transforming lesions. These fundamental observations determine what 'bulk' nucleic acid amplification tests (NAATs) of cervical exfoliates allow us to establish. DNA-based assays sensitively report high-risk HPV genome presence, which includes transient infections and virus particles. RNA-based assays target the E6/E7 transcripts in transcriptionally active disease, which accounts for their slightly higher clinical specificity for high-grade squamous intraepithelial lesions. No single assay defines both viral presence and disease significance, however. Cytology, p16/Ki-67 dual stain, extended genotyping and host-cell methylation interrogate complementary axes of risk with strong biological rationale. The loss of spatial information that limits bulk NAAT approaches matters most in mixed-grade lesions and immunocompromised populations. Emerging spatial methods, AI-assisted cytology and cervical cell-lifts offer recovery of biological resolution.