DIFFERENTIAL T-HELPER CELL RESPONSES TO HUMAN-PAPILLOMAVIRUS TYPE-16 E7 RELATED TO VIRAL CLEARANCE OR PERSISTENCE IN PATIENTS WITH CERVICALNEOPLASIA - A LONGITUDINAL-STUDY

T-cell-mediated immune responses against oncogenic human papillomaviru ses (HPVs) are believed to play a role in the prevention of cervical c arcinogenesis. The in vitro production of interleukin 2 by CD4+ T help er (Th) cells in response to overlapping 20-mer peptides covering the HPV-16 E7 oncoprotein sequence was determined in 72 women with cytolog ical evidence of premalignant cervical intraepithelial neoplasia (CIN who participated in a nonintervention follow-up (FU) study. In additio n, 15 HPV-16 + cervical carcinoma patients were tested. Positive Th ce ll reactivity was restricted to patients infected by HPV-16 and relate d types and showed a strong association with viral persistence and dis ease progression, as evidenced by the high frequency of positive respo nders among women with persistent HPV-16 infections who ended FU with high-grade CIN III lesions [14 of 15 (93%)]. Women with cervical carci noma showed responses at a significantly reduced rate [7 of 15 (47%); P = 0,014], Over the FU period (10-34 months), the level of E7-induced interleukin 2 production from the lymphocytes of CIN patients who had cleared HPV-16 infection showed an inverse correlation with time rela tive to the last positive HPV DNA test, with 8 of 13 of these patients showing positive responses after clearance. By contrast, among women with persistent HPV-16 infections and developing CIN III lesions (n = 8), there was a rise in Th cell activity over the course of FU, The ma jority of women responded to an immunogenic region in the carboxyl ter minus of the E7 protein (amino acids 67-98), The observed HPV-16 E7-sp ecific Th cell responses may develop as a consequence of increased ant igen availability resulting either from clearance or from progression of cervical lesions.