Overriding of cyclin-dependent kinase inhibitors by high and low risk human papillomavirus types: evidence for an in vivo role in cervical lesions

High risk types of human papillomavirus (HPV) are agents in the aetiology o f cervical carcinoma. The products of two early genes, E6 and E7, appear to be the principal transforming proteins. Studies of various monolayer cell culture systems have shown that the E7 oncoprotein of human papillomavirus type 16 is able to neutralize or bypass the inhibitory effect of the cell c ycle-dependent kinase (CDK) inhibitors (CKIs) p21(WAF1/CIP1) and p27(KIP1). To understand whether the p21(WAF1/CIP1) Or p27(KIP1) neutralization also plays a role in vivo, we performed studies on clinical specimens. Forty-fiv e cervical biopsies, including HPV-negative mucosa, HPV 16-positive preinva sive (low and high grade lesions) and invasive neoplasia as well as HPV 6-p ositive condyloma acuminatum were analysed by single and double immunohisto logy. We examined the positive cell cycle regulator cyclin A and the univer sal cell cycle marker Ki67 as well as the negative cell cycle regulators p2 1(WAF1/CIP1) and p(27KIP1). Here, we show that in a significant fraction of cells the G1 block can be overcome despite high levels of CKIs in HPV lesi ons. This phenomenon, which was more evident for p21(WAF/CIP1) than for p27 (KIP1) was most marked in low grade lesions and in condylomata acuminata, i n which a high viral productivity is expected. These results indicate that the overriding of CKI inactivation by viral oncoproteins appears to be a co nserved property between low and high risk HPV types. We conclude that the CKI neutralization by HPVs is likely to be required for viral DNA replicati on rather than for malignant transformation of the host cell.