Sublineage-Specific A45S Polymorphism Alters the Biological Function of the Human Papillomavirus 11 E7 Protein

The E7 oncoprotein of human papillomavirus (HPV) plays a crucial role in viral pathogenesis and replication. Although it is generally highly conserved across HPV genotypes, naturally occurring E7 variants can display functional differences that may affect viral persistence, oncogenic potential, and host cellular responses. The prevalent HPV11 A2 sublineage is characterized by a distinctive amino acid substitution at position 45 (A45S) within the E7 protein. In comparative analyses of transfected primary keratinocytes and HPV-negative cancer cells, we here demonstrate that the A45S substitution enhances the interaction of HPV11 E7 with key cellular targets, including pRb family proteins and PTPN14. A further consequence is an increased ability to target both PTPN14 and pRb family proteins for degradation. Functionally, these differences are exemplified by the S45 variant's enhanced ability to activate E2F-driven gene expression, particularly resulting in elevated mRNA levels of key factors involved in homologous recombination-mediated repair of DNA double-strand breaks, a pathway critical for preserving genomic integrity. Together, these findings indicate that the A45S substitution imparts high-risk-like molecular properties to the low-risk HPV11 E7 oncoprotein. To our knowledge, this is the first report to identify a functionally significant alteration in HPV11 E7 activity resulting from a naturally occurring sequence variation. Understanding the underlying mechanisms could provide new strategies for targeting the therapeutically challenging HPV-associated conditions, such as recurrent respiratory papillomatosis.