Lymphoproliferative responses to human papillomavirus (HPV) type 16 proteins E6 and E7: Outcome of HPV infection and associated neoplasia

Background: Infection with human papillomavirus (HPV) type 16 (HPV16) is a major cause of high-grade cervical intraepithelial neoplasia (GIN). Experiments were planned to evaluate the role of cell-mediated immunity (e.g., lymphocyte proliferation) against HPV in the natural history of HPV-associated neoplasia and to identify antigenic sequences of the HPV16 proteins E6 and E7 against which an immune response may confer protection. Methods: Forty-nine women with abnormal cervical cytology and biopsy-confirmed CIN were followed through one or more clinic visits, Lymphoproliferative responses of peripheral blood mononuclear cells to HPV16 E6 and E7 peptides were assessed in long-term (3-week) cultures, HPV DNA was detected in cervicovaginal lavage by means of polymerase chain reaction and Southern blotting. Disease status was determined by cervical cytologic examination and colposcopy, Reported P values are two-sided, Results: Subjects with positive lymphoproliferative responses to E6 and/or E7 peptides were more likely to be HPV negative at the same clinic visit than were nonresponders (P=.039). Subjects who were negative for HPV and those with a low viral load were more likely to be responders than were those with a high viral load (P for trend=.037). Responses to N-terminal E6 peptide 369 were associated with absence of HPV infection at the same clinic visit (P=.015). Subjects with positive responses to E6 or E7 peptides at one clinic visit were 4.4 times more likely to be HPV negative at the next visit than were nonresponders (P=.142). Responses to E6 peptide 369 and/or E7 C-terminal peptide 109 were associated with an absence of HPV infection (P=.02 for both) and an absence of CIN (P=.04 and .02, respectively) at the next visit, Conclusions: Lymphoproliferative responses to specific HPV16 E6 and E7 peptides appear to be associated with the clearance of HPV infection and the regression of GIN.