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

Area of Science:

• Virology
• Molecular Biology
• Oncology

Background:

• The E7 oncoprotein of human papillomavirus (HPV) is essential for viral pathogenesis.
• Naturally occurring E7 variants can exhibit functional differences impacting viral persistence and oncogenic potential.
• The HPV11 A2 sublineage features an amino acid substitution (A45S) in its E7 protein.

Purpose of the Study:

• To investigate the functional impact of the A45S substitution in HPV11 E7.
• To compare the molecular properties of HPV11 E7 variants with and without the A45S substitution.

Main Methods:

• Comparative analyses using transfected primary keratinocytes and HPV-negative cancer cells.
• Assessment of interactions with cellular targets like pRb family proteins and PTPN14.
• Evaluation of E2F-driven gene expression and DNA double-strand break repair pathway activation.

Main Results:

• The A45S substitution significantly enhances HPV11 E7's interaction with pRb family proteins and PTPN14.
• The S45 variant demonstrates increased targeting of PTPN14 and pRb for degradation.
• Enhanced activation of E2F-driven gene expression, leading to elevated mRNA levels of homologous recombination factors.

Conclusions:

• The A45S substitution confers high-risk-like molecular properties to the low-risk HPV11 E7 oncoprotein.
• This study identifies the first functionally significant alteration in HPV11 E7 due to natural sequence variation.
• Understanding these mechanisms may offer new therapeutic strategies for HPV-associated conditions like recurrent respiratory papillomatosis.