Productive Lifecycle of Human Papillomaviruses that Depends Upon Squamous Epithelial Differentiation

Abstract

Human papillomaviruses (HPVs) target the stratified epidermis, and can causes diseases ranging from benign condylomas to malignant tumors. Infections of HPVs in the genital tract are among the most common sexually transmitted diseases, and a major risk factor for cervical cancer. The virus targets epithelial cells in the basal layer of the epithelium, while progeny virions egress from terminally differentiated cells in the cornified layer, the surface layer of the epithelium. In infected basal cells, the virus maintains its genomic DNA at low-copy numbers, at which the viral productive lifecycle cannot proceed. Progression of the productive lifecycle requires differentiation of the host cell, indicating that there is tight crosstalk between viral replication and host differentiation programs. In this review, we discuss the regulation of the HPV lifecycle controlled by the differentiation program of the host cells.

Keywords: HPV; differentiation; epithelial cell; keratinocyte.

Figure 1

The genome organization of HPV16. The HPV genome has a circular double-stranded DNA structure. The viral genes are transcribed in a single direction (clockwise). There are genes coding for non-structural proteins (E1, E2, E4, E5, E6, and E7) and structural proteins (L1, L2), and a transcriptional control region (long control region; LCR). LCR contains a DNA replication origin and functions as the regulator for the DNA replication. The major promoters and polyadenylation signals are indicated (P97, P670, AE, AL).

Figure 2

The lifecycle of human papillomaviruses (HPVs). HPVs infect specifically the cells in the basal layer of the stratified epithelium through lesions. Viral genomes are maintained as episomal DNA in the nuclei of infected cells. The viral lifecycle is strictly controlled by host cell differentiation, and the late lifecycle (productive lifecycle) occurs in upper layers of the epithelia that are terminally differentiated, and the progenitor virions are released from the cornified keratinocytes.

Figure 3

The structure of HPV16 LCR (region of the control of early promoter P97). The early promoter P97 and replication origin are located in LCR, which are regulated by various cellular factors. Activity of P97 is regulated by AP-1, NF1, SP1, TFIID, TF1, Oct-1, PSM, and the viral transcription factor E2. Four E2-binding sites (E2BS) have been identified in HPV16 LCR and the consensus sequence for E2BS is shown in an inset. A glucocorticoid receptor and progesterone receptor (GR/PR) recognition element was also identified in the LCR. The existence of a keratinocyte-specific enhancer (KE) has been proposed (Desaintes and Demeret, 1996).

Figure 4

The splicing signals and the transcripts of HPV16. P97 and P670 are the early and late promoters, respectively, for HPV16. AE and AL indicate the early and late polyadenylation signals, respectively. Open triangles indicate splicing acceptors and filled triangles indicate splicing donors. Major mRNAs and their products are indicated. This figure is cited from a review (Schwartz, 2008).

Figure 5

Regulatory mechanisms for mRNA processing. The HPV16 genome with the promoters, the poly(A) signals, and the splicing signals are shown at the top of the figure. Open triangles indicate splicing acceptors and filled triangles indicate splicing donors. (A) HPV16 splicing regulatory elements are indicated as filled stars (splicing enhancers) or filled circles (splicing silencers). (B) HPV16 polyadenylation regulatory elements are indicated as filled hexagons (polyadenylation stimulatory elements) and a filled rectangle (polyadenylation inhibitory element). (C) The regulatory elements for the instability and nuclear export of HPV16 late mRNA are indicated. This figure is cited from a review (Schwartz, 2008).

Figure 6

Regulatory mechanisms of the differentiation-dependent lifecycle of HPV.