Pathogenesis of human papillomaviruses in differentiating epithelia

Abstract

Human papillomaviruses (HPV) are the etiological agents of cervical and other anogenital malignancies. Over 100 different types of HPVs have been identified to date, and all target epithelial tissues for infection. One-third of HPV types specifically infect the genital tract, and a subset of these are the causative agents of anogenital cancers. Other HPV types that infect the genital tract induce benign hyperproliferative lesions or genital warts. The productive life cycle of HPVs is linked to epithelial differentiation. Papillomaviruses are thought to infect cells in the basal layer of stratified epithelia and establish their genomes as multicopy nuclear episomes. In these cells, viral DNA is replicated along with cellular chromosomes. Following cell division, one of the daughter cells migrates away from the basal layer and undergoes differentiation. In highly differentiated suprabasal cells, vegetative viral replication and late-gene expression are activated, resulting in the generation of progeny virions. Since virion production is restricted to differentiated cells, infected basal cells can persist for up to several decades or until the immune system clears the infection. The E6 and E7 genes encode viral oncoproteins that target Rb and p53, respectively. During the viral life cycle, these proteins facilitate stable maintenance of episomes and stimulate differentiated cells to reenter the S phase. The E1 and E2 proteins act as origin recognition factors as well as regulators of early viral transcription. The functions of the E5 and E1--E4 proteins are still largely unknown, but these proteins have been implicated in modulating late viral functions. The L1 and L2 proteins form icosahedral capsids for progeny virion generation. The characterization of the cellular targets of these viral proteins and the mechanisms regulating the differentiation-dependent viral life cycle remain active areas for the study of these important human pathogens.

FIG. 1.

Genomic organization of high-risk HPV-31. Early ORFs are indicated in black, while capsid genes are shown in gray. Early and late promoters are designated by arrows.

FIG. 2.

Cartoon of uninfected (left) and HPV-infected (right) epithelia showing various differentiated layers and virion production.

FIG. 3.

Cartoon of cell cycle regulatory activities mediated by Rb, HDAC, and E2F/DP-1 proteins. The effects of E7 on Rb and HDAC binding are indicated. Rb-HDAC complexes repress the activity of E2F/DP-1 transcription complexes bound to DNA in G₁. As cells move into the S phase, Rb becomes phosphorylated by cyclin D/cdk4/6 kinases, leading to the release of Rb-HDAC proteins. E7 binds Rb and HDACs independently, resulting in the constituitive activation of E2F-inducible genes.