Fig. (2) Organization of the HPV genome and sequence of viral gene expression along keratinocyte differentiation in the cervical stratified epithelium. Initially, HR-HPVs infect basal keratinocytes. The viral genome resides in the nuclei of basal cells as a low-copy plasmid, which expresses its early genes at very low levels. The E6 and E7 proteins cause up-regulation of cellular proteins necessary for entry into S-phase. As the infected basal cells migrate towards the epithelial surface, the late promoter becomes activated and drives expression of proteins necessary for viral genome amplification (E4). Only a subset of E4(+) cells express the L1 major and minor L2 capsid proteins, allowing packaging of viral genome into infectious particles. During cancer progression, the normal papillomavirus life cycle is disrupted and virus particles are not produced. This represents an abortive infection for the virus. In high-grade cervical neoplasia, cells expressing the viral E7 protein can be found close to the epithelial surface. Expression of the E4 protein and the onset of viral genome amplification do not occur. (Slightly modified from J Doorbar, with permission) [15].