Persistence of human papillomavirus infection: keys to malignant progression

Abstract

Human papillomaviruses (HPVs) are the etiologic agents of cervical and other epithelial cancers. Persistence of infections by high-risk HPV types is the single greatest risk factor for malignant progression. Although prophylactic vaccines have been developed that target high-risk HPV types, there is a continuing need to understand better the virus-host interactions that underlie persistent benign infection and progression to cancer. In this review we summarize the molecular events that facilitate the differentiation-dependent HPV life cycle, how the life cycle is organized to facilitate virus persistence, and how the activities of HPV regulatory proteins result in malignancy.

Figure 1

Structure of the cervical epithelium. (a) The location of the endocervical and ectocervical epithelia. (b) Schematic of the stratified ectocervical epithelia, the columnar endocervical epithelia, and the transformation zone (TZ). HPV infections and both benign and malignant lesions preferentially develop in the TZ. Infection initiates through microwounds that expose the basement membrane and basal keratinocytes. Viral episomes are maintained in the basal cells. As host cells differentiate, HPV gene expression is coordinated to result in capsid assembly and virion release in the uppermost differentiated strata. Nuclei are colored to indicate the viral proteins expressed during the various phases of the life cycle (also see Figure 2).

Figure 2

Genetic organization of papillomaviruses. The circular HPV genome is shown linearized for simplicity. The replication origin and many transcriptional regulatory elements are found in the upstream regulatory region (URR). The viral early promoter, differentiation dependent late promoter, and two polyadenylation signals define three general groups of viral genes that are coordinately regulated during host cell differentiation. The E6 and E7 genes maintain replication competence. E1, E2, E4, E5, and E8 are involved in viral DNA replication, transcriptional control, and other late functions. L1 and L2 are the capsid proteins. ORFs are colored to indicate at which phase of the viral life cycle each is most highly expressed (see Figure 1).

Figure 3

Targets of E6 and E7. Both HPV oncogenes have a large number of interaction partners, including regulators of the cell cycle, gene expression, DNA replication, and cell signaling. Some binding interactions are result in inactivation or degradation of the target, and some result in activation.