New concepts on the role of human papillomavirus in cell cycle regulation

Human papillomaviruses (HPVs) are strictly host-specific and also show a di stinct tropism to squamous epithelial cells. Upon HPV infection, only a por tion of the virus reaching the nucleus seems to undergo replication, sugges ting that HPV replication remains confined to a small number of cells. HPVs critically depend on the cellular machinery for the replication of their g enome. Viral replication is restricted to differentiated keratinocytes that are normally growth arrested. Hence, HPVs have developed strategies to sub vert cellular growth regulatory pathways and are able to uncouple cellular proliferation and differentiation. Endogenous growth factors and cellular o ncogenes modify HPV E (early) and L (late) gene expression and influence on the pathogenesis of HPV infections. HPV oncoproteins (E5, E6, E7) are impo rtant proteins not only in cell transformation but also in the regulation o f the mitotic cycle of the cell, thus allowing the continuous proliferation of the host cells. Cyclins are important regulators of cell cycle transiti ons through their ability to bind cyclin-dependent kinases (cdks). Cdks hav e no kinase activity unless they are associated with a. cyclin. Several cla sses of cyclins exist which are thought to coordinate the timing of differe nt events necessary for cell cycle progression. Each cdk catalytic subunit can associate with different cyclins, and the associated cyclin determines which proteins are phosphorylated by the cdk-cyclin complex. The effects of HPVs on the cell cycle are mediated through the inhibition of antioncogens (mostly p53 and retinoblastoma) and through interference with the cyclins and cdks, resulting in target cell proliferation, their delayed differentia tion, and as a side-effect, in malignant transformation.