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Entry receptors are shown as a line with an arc above. Figure 3 View large Download slide Virus infection of the cervix, keratinocyte differentiation, and HPV protein expression HPV can bind receptors on the basement membrane gray line and go on to infect basal layer cells of the epithelium.

Close modal The early phase of the viral replication cycle: E1 and E2 Upon nuclear entry into the dividing cells of the basal layer or ectocervix viral early transcription is initiated. This makes sense because the first goal of the incoming virus is to carry out initial replication of its genome.

Moreover, early expression of the viral transcription factor E2 would allow correct regulation of the viral early promoter to direct expression of the E6 and E7 regulatory proteins that ensure continued survival of HPV-infected cells [ 75 ]. E2 possesses one DNA-binding and one protein-binding domain linked by a flexible hinge region [ 76 ]. Three of these sites are located adjacent to the origin of replication and are required for E1-activated viral replication [ 77 ].

E2 binds E1, which then binds as a dimer of hexamers to the viral origin of replication and recruits the cellular DNA replication machinery [ 78 , 79 ]. Initial replication of an incoming HPV genome generates approximately 50— episomal copies per nucleus [ 80 ]. This constitutes the first phase of viral DNA replication and genome maintenance. In infected basal cells, circular viral genomes are replicated in concert with replication of cellular DNA and equally partitioned into daughter cells through tethering of virus genomes to host cell chromosomes via E2 bound to the viral LCR and chromatin-binding proteins [ 77 ].

Brd4, via E2, is the most studied anchor for HPV genomes to cellular chromosomes [ 82 ]. On the other hand, the E1—E2 complex itself may be sufficient for some HPVs to locate to cellular chromosomes [ 77 ]. Viral proteins are probably expressed at low levels in infected basal cells [ 86 ] to avoid activating the local immune response [ 87 ]. This is achieved by E2 transcriptionally repressing the P97 promoter by inhibiting access of transcription factors to the promoter and by altering chromatin conformation [ 88 — 90 ].

In this way, HPV is capable of maintaining infection of epithelial cells over a significant period of time. Division of an infected basal epithelial cell can produce a transit amplifying cell that is capable of differentiating and moving into the upper epithelial layers [ 91 ]. These cells carry the viral genomes with them as they move through the upper epithelial layers. HPV has evolved to carry out its replication cycle in exquisite concert with epithelial differentiation and an orchestrated program of viral gene expression is carried out during epithelial differentiation Figure 3 [ 20 ].

These include the E6 and E7 viral oncoproteins [ 92 , 93 ]. Despite their designation as oncoproteins, their expression is essential for the normal replicative HPV life cycle. Early in situ hybridization studies indicated increased levels of the mRNA encoding these proteins in the lower to mid-upper epithelial layers [ 94 — 96 ]. However, expression of biomarkers that respond to E6 and E7 was found to decrease in the upper epithelial layers [ 97 ].

Therefore, biological activity of these proteins may be most important in the early phase of viral replication in basal epithelial cells. For example, E6 has been shown to be required for episomal genome maintenance [ 98 — ]. E7 expression, early in infection, activates the G1 to S-phase checkpoint in keratinocytes that would normally undergo terminal differentiation, thus expanding the compartment of epithelial cells active in DNA replication [ 93 ].

This is an important step to accomplish the second, productive, phase of viral genome replication in cells of the mid to upper epithelial layers that would normally exit the cell cycle. E7 activates the cell cycle of infected, differentiating cells by binding and releasing, or degrading, pRb and other pocket proteins, p and p, from a transcriptional repression complex containing the E2F transcription factor [ — ]. E2F becomes free to activate transcription of a number of cell cycle-related genes such as cyclins A and E, thus stimulating G1 to S-phase transition [ 75 ].

E7 can also interact with and abrogate E2F inhibitory transcription complex activity leading to stimulation of promoter activity of growth control genes [ ]. This suggests the potential of E7 to make very significant transcriptional changes in infected cells. However, the expression level of the protein, and where it is expressed in the different layers of the infected epithelium, will have some impact on these activities.

Therefore, activities of either protein will be affected by the other and it is clear that they often act co-operatively, for example in avoiding immune detection [ 87 ]. Normally, cells respond to any unscheduled cell proliferation event by inducing apoptosis. Therefore, HPV E7 activity might be expected to induce cell death. To avoid this, HR-HPVs express the E6 protein, which binds the ubiquitin ligase, E6AP E6-associated protein and p53, a key regulator of apoptosis and targets it for degradation [ 75 , ].

E6 proteins can also cause a conformation change in p53 through binding. This inhibits its transcriptional transactivation properties [ , ]. Finally, E6 can sequester p53 in the cytoplasm, meaning that it cannot carry out its nuclear transcription activation functions [ ]. The Notch pathway is responsible for promoting keratinocyte differentiation [ ]. E6 also promotes proteasomal degradation of tuberin, part of the TSC2 tuberous sclerosis complex 2 , to interfere with insulin signaling and maintain mTOR activity, protein translation, and cellular proliferation [ ].

HPV16 E6 has been shown to bind to, but not degrade, paxillin, a protein that plays essential roles in the structural organization of the cell [ ]. It is possible that this interaction could result in restructuring the infected cells to facilitate viral egress. Bak has been found to be most active in the upper layers of the skin where HPV replication occurs [ ].

It is thought that in uninfected cells, E6AP regulates the levels of Bak. This prevents Bak-mediated permeabilization of the mitochondrial and ER membranes, therefore avoiding the activation of the caspase cascade and apoptosis. Therefore, this is another route to inhibition of apoptosis and it has been proposed that this pathway specifically links to the DNA damage response [ , ].

PDZ domain-containing proteins can bind to and stabilize low levels of E6 expressed during an infection leading to enhanced episome maintenance [ ]. The fact that this E6 motif is missing in low risk E6 proteins suggests that it may be associated with tumor-promoting properties of the HR-HPVs [ ].

The E6 PBM also allows a regulatory interaction with SNX27 sorting nexin 27 , a protein that controls endosomal transport, nutrient acquisition, and cell proliferation [ ]. E6 control of these pathways via SNX27 could have importance in keratinocyte metabolism during viral infection. E7 control of miR has been shown to be important for viral genome amplification.

In fact, E6 and E7 control of many cellular transcription factors has the potential to alter expression of many RNA polymerase II-transcribed miRNAs that could be involved in the viral replication cycle. Importantly, miRNAs can modulate viral gene expression.

The subsequent loss of these viral replication factors results in a reduction in viral genome amplification and late gene expression [ ]. The late phase of the viral replication cycle The late phase of the viral life cycle involves vegetative viral DNA replication and subsequently, virion formation. Increased expression of the viral E1 and E2 proteins is required to accomplish this phase.

The late stage of the life cycle is marked by activation due to changes in cell signaling of the viral major late promoter HPV P; HPV P that is situated in the E7 gene region Figures 2 A and 4 A [ , ]. This results in increased expression, not only of E1 and E2, but also of E4 and E5 [ 13 ]. Late stage DNA replication, probably using a rolling circle mechanism, yields many thousands of progeny viral genomes [ ].

HR-HPV E4 proteins are the most abundant viral regulatory factors and play essential roles in the differentiated keratinocytes which support viral genome amplification [ 97 ] and late events in the life cycle [ — ]. In contrast, the low risk HPV11 E4 has been found not to be essential for viral genome amplification [ ].

Mechanisms of activation of E6 and E7 expression during cervical tumor progression Figure 4 View large Download slide Mechanisms of activation of E6 and E7 expression during cervical tumor progression A Linear diagram of the HPV16 genome showing the eight ORFs colored boxes the three characterized promoters forward facing arrows and the early and late polyadenylation sites thick black vertical lines.

Green colored boxes indicate the E6 and E7 coding regions. Blue colored boxes represent the L1 and L2 capsid encoding genes. This leads to overexpression from the P97 promoter of the viral oncoproteins. This can cause increased stability in the E6 E7 bicistronic mRNA leading to increased expression levels of the oncoproteins.

Integration may also cause insertional mutagenesis of the host gene, which could have oncogenic effects. The gene color scheme is the same as that used in A. The wavy blue line indicates a viral-host gene fusion transcript. Multiple integration can also occur but expression of the majority are epigenetically silenced by methylation of the P97 promoter region. Gray boxes, silenced viral genome copies not to scale. Arrows with a red cross, epigenetically silenced p97 promoters.

D Episomal genomes can be found in some cervical cancer cells. In this case, the P97 promoter is activated epigenetically leading to increased levels of viral oncogene mRNAs green wavy lines. Other viral proteins are also expressed not indicated [ ].

Figure 4 View large Download slide Mechanisms of activation of E6 and E7 expression during cervical tumor progression A Linear diagram of the HPV16 genome showing the eight ORFs colored boxes the three characterized promoters forward facing arrows and the early and late polyadenylation sites thick black vertical lines.

Close modal The roles of the E4 and E5 proteins HPV16 and 18 E4 proteins can associate with and stabilize, E2 suggesting the possibility of a regulatory loop centering on viral replication and transcription [ ]. E4 can also enhance genome amplification directly by regulating cell cycle arrest in G2-phase [ , ] and activating cellular kinases [ ]. E5 is a transmembrane ER-resident protein [ ] that can stabilize EGFR and stimulate MAPK mitogen-activated protein kinase activity, suggesting that it can control cell division pathways [ ].

The fact that HPV genomes containing inactivating mutations in the E5 ORF have lower levels of viral genome amplification than wild-type may also be related to E5 interaction with cellular signaling [ , ]. E4 and E5 have additional roles in the HPV life cycle. In the context of natural levels of expression from intact HPV genomes, the most important role for E4 late in the virus replication cycle may be to restructure cytokeratin filaments to render cells fragile and more liable to release progeny virions [ — ].

E5 helps the virus evade the immune response by repression of MHC presentation of viral peptides [ ]. However, further work is required to elucidate this potentially very important function of E5. A major cellular pathway crucial for completion of genome amplification and viral late gene expression is the DNA damage response pathway.

In the early phase of the life cycle, ATM may be necessary for establishment and maintenance of HPV genomes in basal epithelial cell via E1-mediated activation [ ]. In addition, E1 and E2 together create viral replication factories that contain a wide range of DNA damage repair proteins and this is likely to facilitate viral genome replication [ ].

In the late phase, E7 has been shown to activate the ATM DNA damage pathway required for vegetative viral genome amplification in differentiated keratinocytes [ ]. E7 seems to control stability of DNA repair proteins through its Rb-binding domain, but further work is required to elucidate the mechanism [ ]. Less is known about HPV control of ATR however, E7, in stimulating cell cycle activation in differentiating keratinocytes, may indirectly activate ATR through replication stress [ ].

Following viral genome amplification and capsid protein synthesis, virion formation takes place in the nucleus. At least for some HPVs e. HPV16 and 31 , capsid protein expression is delayed until infected cells reach the granular layer [ 97 ]. This delay in expression of the highly immunogenic capsid proteins the uppermost epithelial layer may allow the virus to evade the host immune response [ ]. However, the ability of other HPVs to yield a productive infection despite expression of their capsid proteins closer to the basal epithelial layer [ 86 ] suggests that other means to avoid the host immune response must exist.

Therefore, restriction of expression of the capsid proteins to differentiated granular layer keratinocytes is probably not controlled at the transcriptional level. Various post-transcriptional mechanisms have been described that may contribute to delayed capsid protein expression, including alternative splicing and polyadenylation, mRNA stability, and control of translation [ 13 , ].

Understanding the link between cellular differentiation and capsid protein expression could indicate strategies to disrupt it because unscheduled expression of the capsid proteins in the lower epithelial layers might allow activation of a robust antiviral immune response. L2 is synthesized prior to L1 and is imported into the nucleus [ ].

L1 proteins self-assemble into pentameric capsomeres in the cytoplasm and these structures are transported into the nucleus [ ]. Thus viral genomes are located adjacent to viral capsid proteins ready for assembly. L2 seems to be required for efficient DNA packaging and virion assembly [ ]. Fully formed virions are released inside dead squames that are shed from the epithelial surface. Free virions can survive for some time in the environment and normally reinfect cells at sites adjacent to where they are shed [ ].

Apart from the proteins mentioned above, there are potentially other viral proteins expressed during the life cycle. Proteins encoded by the other spliced isoforms have not yet been investigated. Viral proteins interact with each other Elucidating the role of the various viral proteins in viral replication is complicated by several facts: i protein multifunctionality, ii most viral proteins have been shown to bind to one another, iii changes in expression profiles of these proteins during epithelial differentiation, and iv subcellular compartmentalization.

As discussed above, E1 and E2 interact at the viral origin of replication to initiate viral replication [ 77 ]. E2 binding to L2 appears to have a role during establishment of infection in basal epithelial cells [ ] where it localizes with L2 to ND10 domains in infected cell nuclei. Thus, it is tempting to speculate that L2 could act as an early switch between activation of viral early transcription and the limited viral genome replication that occurs in newly infected cells.

E2 is capable of recruiting E7 to mitotic chromosomes in late mitosis [ ]. The interaction between E2 and E6 isoforms changes the subnuclear localization of the proteins, which has potential to alter their cellular functions [ ]. Similarly, upon binding to E4, E2 undergoes cytoplasmic relocation and stabilization [ ] but any role for cytoplasmic E2 has yet to be explored. E2 and L1 associate at PML nuclear bodies during virion assembly [ ]. It is likely that there are more functions to be discovered for each protein and co-operative complexes of viral proteins may have additional functions to those of the individual proteins.

The primary cause of progression to cancer seems to be persistent infection, over a period of several years, of basal and stem epithelial cells with at least one of the HR-HPVs [ 75 ]. However, although persistent infection is a necessary event, it may not be sufficient to drive full tumorigenesis. For cervical cancer, HR-HPV infection of the region between the ecto- and endocervix may be more prone to result in a persistent infection because HPV productive replication cannot be properly controlled in this single cell basal layer [ 48 ].

Given that most people become infected with HPV as young adults, the normal decades-long time for progression to cancer, and the rarity of this event, indicates that other secondary events can co-operate with persistent HR-HPV infection to lead to cancer formation. The main risk factors for cervical cancer have been identified as immune status immunocompromised, immunosuppressed , smoking, oral combined contraceptive use, high parity, and other sexually transmitted infections, particularly Chlamydia [ 87 , , ].

HIV patients have a five-fold greater risk of developing HPV-associated cervical cancer [ ] probably due to increased likelihood of acquiring a persistent HPV infection. More recently, there is evidence that the vaginal microbiome can have either a protective or stimulatory effect on cervical disease progression [ ]. This could be due to the specific composition of any bacterial population that might exert different effects on anogenital HPV persistence. Persistent infection may equal an elongated maintenance phase of viral genome replication in the undifferentiated epithelial cell s initially targetted for infection [ ].

Whatever anatomical site is infected, the key change required for progression to malignancy is increased expression of the viral oncoproteins E6 and E7 in dividing, infected cells. Increased E6 and E7 activity can stimulate cell growth, inhibit differentiation, and induce chromosomal instability that will result in tumorigenesis. Integration is not a part of the normal HPV replication cycle. A common theme of either event is that the viral E2 transcription factor is no longer expressed and thus cannot repress the P97 promoter to restrict E6 and E7 expression [ 75 ].

The primary role of loss of E2-mediated repression of HR-HPV oncogene expression from integrated viral genomes was demonstrated by experiments where E2 overexpression in cervical tumor cells such as HeLa cells resulted in reversion of the tumor phenotype [ , ]. Moreover, acquisition of resistance to cytokine signaling can lead to cellular transcription factors such as the AP1 complex further activating viral transcription [ ].

The pathway to viral integration during persistence is still unclear [ ]. On the other hand, experiments in the HPVpositive W12 tumorigenesis model have indicated that although latent integrants may coexist with the normal complement of episomal genomes in the initially infected cell, selection of cells containing transcriptionally active integrants must be accompanied by loss of episomes that express the E2 transcriptional repressor [ ].

Integration could be an indirect result of tethering viral episomes adjacent to fragile site regions of chromosomes that accumulate the DNA break repair factors essential for viral DNA amplification [ ]. Therefore, its expression in persistently infected cells could predispose to genome damage and integration [ ]. Clinically, it is characterized by the formation of disseminated flat warts beginning in childhood. Twenty years ago in the Archives, Ostrow et al 9 reported the case of a patient with clinical features of EV and 2 additional findings that are not characteristic of patients with EV: congenital lymphatic dysplasia and HPV—positive carcinoma in situ of the thumb.

Moreover, their patient had a history of squamous cell carcinoma of the foot and the groin presenting as large, ulcerative lesions, again not typical conditions for patients with EV. We report the case of a patient presenting with similar findings. Based on the virological and molecular analyses performed in our patient, we speculate that the clinical characteristics of both individuals could represent a specific syndrome.

Report of a case A year-old German woman with primary lymphedema presented for evaluation of persisting generalized warts that appeared during adolescence, initially affecting the palms and soles. The patient's history excluded consanguinity in her family, and none of her relatives had similar findings. Lower extremity edema was first noted at 6 months of age, and later progressed to involve the groin, vulva, anal region, and distal upper extremities Figure 1.

During adolescence, the patient developed disseminated reddish and brownish flat warts on areas including the facial skin, palms, and soles. There was no history of opportunistic or other notable bacterial or fungal infections, and no other relevant medical history. Figure 1. View Large Download Clinical photograph of the patient demonstrating widespread flat warts and pityriasis versicolor-like lesions. Extensive primary lymphedema of the extremities is present. The first physical examination at our institution, performed in November , showed numerous plane warts, particularly located on the dorsa of the hands and limbs Figure 2 A.

Her palms and soles demonstrated confluent warts in a bas relief—like pattern, destroying the conventional plantar lines and fingerprints Figure 2 B. The face, upper trunk, and extremities were predominantly affected by disseminated reddish flat warts and pityriasis versicolor—like macules.

The genitoanal region showed widespread flat, brownish warts and several red papules and plaques ranging from 5 to 15 mm in diameter Figure 3 A. Genital and anal mucosa showed numerous verrucous lesions suspicious for condylomata acuminata Figure 3 B and Figure 4. The oral mucosa appeared normal. Figure 2. Clinical presentation of the patient's hands.

A, Extensive flat-topped reddish warts affecting the dorsal aspect of the left hand. B, Disseminated flat warts in a bas relief—like pattern destroying the conventional plantar lines and fingerprints. Figure 3. View Large Download Clinical presentation of the patient's thighs and perianal area.

A, Multiple reddish wartlike nodules and brown flat lesions located on the inner aspects of the thighs. B, Condylomata acuminata of the anal canal adjacent to flat bowenoid papulosis—like lesions of the perianal skin. Figure 4. View Large Download High-power field view of numerous histopathologically confirmed intravaginal condylomata acuminata.

Histopathologic evaluation of the red and brown wartlike lesions showed hyperkeratosis, acanthosis, and elongation of the rete ridges and enlargement of squamous cell nuclei with surrounding halos characteristic of cutaneous warts Figure 5 A. No signs of dysplasia were present. Specimens of several verrucous lesions of the anogenital region including the vulva, perianal skin, and anal canal revealed irregular nuclei, dyskeratosis, and mitotic alterations in the lower two-thirds of the epidermis consistent with intraepithelial neoplasia grades I to II Figure 5 B.

Cytological swab samples obtained from the anal and genital vulva, vagina, cervix area showed high-grade squamous intraepithelial lesions according to the Bethesda classification consistent with severe dysplasia in several samples. Figure 5. View Large Download Representative histopathologic findings of the lesions. A, Skin biopsy specimen from a reddish wart on the right thigh shows an exophytic tumor with marked acanthosis and parakeratosis.

The HPV types consistently found in more than two-thirds of the samples included HPV types 6, 51, 52, 61, and 84 in the anogenital region; HPV in the skin biopsy specimens; and HPV types 51, 52, 57, 61, and 84 in the skin swab samples Table 1. View Large Download Table 1. To convert protein to grams per liter, multiply by

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Natural History of HPV Infection

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