Characterization of in Vivo Expression of the Human Papillomavirus Type 16 E4 Protein in Cervical Biopsy Tissues

J Clin Invest. 1991 Jun;87(6):2132-41. doi: 10.1172/JCI115245.


The role of human papillomavirus (HPV) proteins in the pathogenesis of cervical intra-epithelial neoplasia (CIN) and invasive cervical cancer is poorly understood. To characterize E4 protein expression in 49 paraffin-embedded cervical biopsies representing different histopathologic grades of disease, antibodies were elicited to a synthetic peptide corresponding to amino acids 20-34 of a protein predicted to be encoded by the HPV 16 E4 open reading frame. The E4 protein was detected throughout the spectrum of CIN, from CIN1 to CIN3. Expression was localized to the cell nucleus, primarily in the superficial layers of the squamous cervical epithelium. Ultrastructural studies showed that the E4 protein was organized into compact, intranuclear arrays 25-35 nm in diameter. E4 protein expression was also demonstrated in some histologically normal tissues containing HPV 16 DNA, but not in any of five cervical cancers containing HPV 16 DNA. These results suggest that E4 protein expression may precede development of light microscopic tissue abnormalities, that it may continue through the spectrum of CIN, and that expression of this protein may be reduced or terminated in invasive cancer. The function of this protein remains unknown, but its nuclear localization may be consistent with a role in viral maturation.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • Amino Acid Sequence
  • Antibodies, Viral / immunology
  • Antibody Specificity
  • Carcinoma, Squamous Cell / microbiology*
  • Cervix Uteri / microbiology*
  • DNA, Viral / analysis
  • Female
  • Gene Expression Regulation, Viral
  • Humans
  • Immunoenzyme Techniques
  • Microscopy, Electron
  • Molecular Sequence Data
  • Nucleic Acid Hybridization
  • Oncogene Proteins, Viral / genetics*
  • Oncogene Proteins, Viral / immunology
  • Papillomaviridae / genetics*
  • Peptides / immunology
  • Uterine Cervical Neoplasms / microbiology*


  • Antibodies, Viral
  • DNA, Viral
  • Oncogene Proteins, Viral
  • Peptides
  • oncogene protein E4, Human papillomavirus type 16