HPVs (human papillomaviruses) infect epithelial cells and their replication cycle is intimately linked to epithelial differentiation. There are over 200 different HPV genotypes identified to date and each displays a strict tissue specificity for infection. HPV infection can result in a range of benign lesions, for example verrucas on the feet, common warts on the hands, or genital warts. HPV infects dividing basal epithelial cells where its dsDNA episomal genome enters the nuclei. Upon basal cell division, an infected daughter cell begins the process of keratinocyte differentiation that triggers a tightly orchestrated pattern of viral gene expression to accomplish a productive infection. A subset of mucosal-infective HPVs, the so-called ‘high risk’ (HR) HPVs, cause cervical disease, categorized as low or high grade. Most individuals will experience transient HR-HPV infection during their lifetime but these infections will not progress to clinically significant cervical disease or cancer because the immune system eventually recognizes and clears the virus. Cancer progression is due to persistent infection with an HR-HPV. HR-HPV infection is the cause of >99.7% cervical cancers in women, and a subset of oropharyngeal cancers, predominantly in men. HPV16 (HR-HPV genotype 16) is the most prevalent worldwide and the major cause of HPV-associated cancers. At the molecular level, cancer progression is due to increased expression of the viral oncoproteins E6 and E7, which activate the cell cycle, inhibit apoptosis, and allow accumulation of DNA damage. This review aims to describe the productive life cycle of HPV and discuss the roles of the viral proteins in HPV replication. Routes to viral persistence and cancer progression are also discussed.

Introduction

HPVs (human papillomaviruses) are non-enveloped icosahedral, circular, dsDNA viruses of approximately 55 nm in diameter. They infect cutaneous and mucosal epithelia. There are over 200 different HPV genotypes that mainly cause benign lesions or warts [1,2]. For example, HPV genotypes 1 and 2 (HPV1, HPV2) cause verrucas on the feet (plantar lesions), while HPV2 and 4 cause common warts on the hands. However, approximately 40 HPVs are sexually transmitted infections of the anogenital region where infection manifests either as genital warts (caused by HPV6 and 11) or other anogenital lesions (condyloma accuminata; caused by the other anogenital-infective HPVs) [3]. Such lesions have been identified on the cervix, the vulva, vagina, and anus in women [3,4]. There evidence for HPV-associated lesions of the anus and penis in men but these are less well characterized [57]. Lack of knowledge of HPV-associated diseases of these sites is due to low rates of presentation in the clinic [8]. For a specific subset of anogenital HPVs, the HR (high risk) HPVs, persistent infection, over a period of several years, together with associated changes in the infected host cell, can cause anogenital cancers. It is estimated that HPVs are the cause of more than 5% of all the human cancers [9]. The most prevalent HR-HPV is HPV16 (HR-HPV genotype 16). It is the most prevalent sexually transmitted viral infection worldwide [10]. There are approximately 14 other HPVs classified as HR but other types may also be associated with anogenital cancers (Table 1) [3]. HPVs are associated with cancers at anatomical sites other than the anogenital region. Over the last 20 years, there has been a highly significant increase in incidence of HPV-associated tumors of the oropharynx, particularly in young men in developed countries [11]. Although vaccines against HR-HPV infection have been widely available since 2006–2008, they are prophylactic and normally delivered only to girls [12]. Vaccine acceptability has been low in many countries and recently, it has dropped drastically in some countries where vaccination rates were originally high [12]. Moreover, these vaccines are the most expensive ever produced, and so are difficult to roll out in the developing world where over 80% of significant HPV-associated diseases occur. Thus, new therapies require to be developed to aid the worldwide effort to treat HPV-associated diseases. Knowledge of the HPV infectious life cycle and HPV-associated cancer progression has increased substantially over the last decades leading to several potential new avenues for diagnosis and treatment of HPV-associated cancers [13]. This review will focus on the HPV infectious life cycle and how this is linked to HPV-associated diseases.

Table 1
Sites of infection of HPVs
Site HPV-associated diseases HPV types 
Skin Wart 1, 2, 3, 4, 7, 10, 26, 27, 28, 29, 41, 48, 50, 57, 60, 63, 65, 75, 76, 77, 88, 95 
 EV wart 5, 8, 9, 12, 14, 15, 17, 19, 20, 21, 22, 23, 24, 25, 36, 37, 38, 46, 47, 49, 75, 76, 80, 92, 93, 96 
Oropharynx, larynx, oral cavity Head and neck cancers 16 mainly (also other HR types at low frequency) 
Oral cavity FEH 13,32 
Larynx Laryngeal papillomatosis 6,11 
Anogenital tract Genital warts (low risk) 6, 11 
 Intraepithelial neoplasia (low risk) 40, 42, 43, 44, 53, 54, 61, 72, 73, 81 
 Intraepithelial neoplasia and cervical cancer (high risk) 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 68, 73, 82 (26, 53, 66) 
Site HPV-associated diseases HPV types 
Skin Wart 1, 2, 3, 4, 7, 10, 26, 27, 28, 29, 41, 48, 50, 57, 60, 63, 65, 75, 76, 77, 88, 95 
 EV wart 5, 8, 9, 12, 14, 15, 17, 19, 20, 21, 22, 23, 24, 25, 36, 37, 38, 46, 47, 49, 75, 76, 80, 92, 93, 96 
Oropharynx, larynx, oral cavity Head and neck cancers 16 mainly (also other HR types at low frequency) 
Oral cavity FEH 13,32 
Larynx Laryngeal papillomatosis 6,11 
Anogenital tract Genital warts (low risk) 6, 11 
 Intraepithelial neoplasia (low risk) 40, 42, 43, 44, 53, 54, 61, 72, 73, 81 
 Intraepithelial neoplasia and cervical cancer (high risk) 16, 18, 31, 33, 35, 39, 45, 51, 52, 56, 58, 68, 73, 82 (26, 53, 66) 

This is not an exhaustive list.

HPV types in brackets may be high risk (HR). Abbreviations: EV wart, epidermodysplasia verruciformis; FEH, focal epithelial hyperplasia.

HPV clasification

There are over 207 HPVs classified to date [1,2]. Characterization of new HPVs involves sequencing of the viral genome and comparison with known HPV genomes. Therefore, HPVs are categorized into genotypes. Each genotype differs from another by at least 10% sequence difference in the highly conserved L1 gene region [14]. Currently, five evolutionary HPV genotype groups (α, β, γ, μ, and ν) have been defined [1,2]. Of these, the largest group is the α group [1,2]. This group contains 64 HPVs that mainly infect mucosal epithelia. Approximately 40 of these HPVs can infect the anogenital tract and include the approximately 15 so-called ‘HR’ types (HPVs 16, 18, 31, 33, 35, 39, 45, 51, 51, 56, 58, 59, 68, 73, 82) that have been classified as oncogenic and are found to cause anogenital cancers (Table 1) [3]. Over 80% of the population will experience an anogenital α-HPV infection during their lifetime [15]. Indeed, the majority of adults become infected with HR-HPV upon sexual debut and the highest incidence age range of infection is 20–25 years of age in the developed world [16].

The next largest group is the β-group HPVs that mainly infect cutaneous epithelia (Table 1) [17]. More than 50 types have been identified and characterized, but it is likely that many more exist because fragments of uncharacterized HPVs continue to be isolated from cutaneous lesions [14,18]. The β group, together with UV irradiation, can be associated with human tumors, especially non-melanoma squamous cell carcinomas, the most common human cancer [19]. HPVs of the remaining three groups (γ, μ, and ν) normally cause only benign disease.

HPV-associated diseases

The vast majority of HPV research has focussed on HPV16, its replicative life cycle, and its role in cervical cancer. In 1995, WHO (World Health Organization) defined HPV16 as a viral tumor-promoting agent. HPV16 causes approximately 55% of cervical cancers, HPV18 causes approximately 15% of cases and the remainder are caused by the other HR-HPVs [3]. Nowadays, over 270000 women die from cervical cancer per annum worldwide with over 500000 cases diagnosed per annum [15]. It is the fourth most common cancer in women but is the most common cause of cancer-related deaths in women under the age of 35. The peak age of incidence of cervical cancer is 49 years and the majority of diagnoses are in women aged 30–55 [16]. Normally, HR-HPVs cause transient infections that are eventually cleared over a period of several months by the immune system. Cancer formation does not result from such infections [3]. However, over time, if changes occur to the viral genome, and/or to the infected host cell, transient infection can become persistent. If persistent infection is not detected and cleared by the immune system, there is a possibility of progression to cancer (Figure 1) [20]. Cancer progression is not a good outcome for the virus because the associated changes to the infected cell abrogate the viral replicative life cycle and progeny virions cannot be produced. It is important to point out that cancer progression due to persistent HR-HPV infection is a rare event.

Cervical-disease progression and lists of contributing factors

Figure 1
Cervical-disease progression and lists of contributing factors

The images show Hematoxylin and Eosin-stained cervical lesions. On the left hand side is shown a tissue section of low-grade disease (CIN1 (cervical intraepithelial neoplasia 1) (LSIL; low-grade squamous intraepithelial lesion)). On the right hand side is shown a tissue section of high-grade disease (CIN3 (HSIL; high-grade SIL)). Nuclei are stained purple, cytoplasms are stained pink. The granular, spinous, and basal layers are indicated for CIN1. A typical koilocyte is indicated with an arrow. The approximate extend of the significantly expanded basal compartment in CIN3 is indicated. Progression from CIN1 to CIN3 is due to persistent infection and up-regulation of E6 and E7 oncoprotein expression. A bullet point list of features of each stage of disease is beneath each image. A bullet point list of factors contributing to cervical-disease progression is shown beneath the purple block arrow.

Figure 1
Cervical-disease progression and lists of contributing factors

The images show Hematoxylin and Eosin-stained cervical lesions. On the left hand side is shown a tissue section of low-grade disease (CIN1 (cervical intraepithelial neoplasia 1) (LSIL; low-grade squamous intraepithelial lesion)). On the right hand side is shown a tissue section of high-grade disease (CIN3 (HSIL; high-grade SIL)). Nuclei are stained purple, cytoplasms are stained pink. The granular, spinous, and basal layers are indicated for CIN1. A typical koilocyte is indicated with an arrow. The approximate extend of the significantly expanded basal compartment in CIN3 is indicated. Progression from CIN1 to CIN3 is due to persistent infection and up-regulation of E6 and E7 oncoprotein expression. A bullet point list of features of each stage of disease is beneath each image. A bullet point list of factors contributing to cervical-disease progression is shown beneath the purple block arrow.

Cervical cancer is preceded by cervical disease, which is a direct result of HPV infection [9]. Cervical disease is common. It is currently detected by Pap smear testing wherein cells are scraped from the surface of the cervix and examined under the microscope for abnormalities: koilocytes (cells containing a compressed nucleus with a perinuclear vacuole), and abnormally dividing cells that may indicate HPV infection (Figure 1). Following a positive cytological test, women are referred to colposcopy clinics for further diagnosis and treatment. In the U.K., over 100000 women are referred to colposcopy (detailed examination of the cervix) per annum. Cervical disease is classified either into a three-stage system, termed as ‘cervical intraepithelial neoplasia’ (CIN) or a two-stage system, termed as SIL (squamous intraepithelial lesion) [21]. CIN is categorized into CIN1, CIN2, and CIN3, and there is good evidence for a progression from CIN1 to 3 (or LSIL to HSIL) underlying cervical cancer formation (Figure 1) [22]. CIN1 is thought to represent transient HPV infection that has a low probability of progression to cervical cancer [23]. This corresponds to low-grade (L) SIL. Infection with multiple HPV types is very common in CIN1 [24] but infection is eventually cleared over a period of several months by the immune system. Approximately 80–90% of cases of CIN1 regress [23]. CIN2 or CIN3 (high grade (H) SIL)) in most cases represent a persistent, unproductive infection (Figure 1). This equates to precancerous disease, but even for CIN3, up to 60% of lesions will regress spontaneously [23]. High-grade CIN lesions harbor a similar range of anogenital-infective HPVs to that found in cervical cancer [25].

As noted above, HR-HPV can cause other anogenital preneoplastic diseases (VIN; vulvar intraepithelial neoplasia, AIN; anal intraepithelial neoplasia etc.) and cancers such as vulvar, vaginal, and anal cancers in women, and anal and penile cancers in men. The HPV genotype distribution in these cancers is still being worked out. However, at least for female anogenital cancers, they seem to harbor the same HR-HPV set as observed in cervical cancers, and multifocal HR-HPV-associated lesions are frequently observed [26]. This makes sense because of the sexually transmitted nature of the disease. Unlike cervical disease and cervical cancer, a smaller proportion of cancers at other sites are attributable to HR-HPV infection. For example, HR-HPV was detected in 84% of vulvar intraepithelial neoplasia [27] and 74% of vaginal cancers [28]. The one exception to the rule is that penile cancers can sometimes be associated with the low risk anogenital-infective HPV6 and 11 [5]. Information on the etiology and pathogenesis associated with the activities of HPV6 and 11 in these lesions is still lacking and it remains to be determined how viruses that normally do not cause cancer in other sites can do so on the penis. Anal infections are common in women, and men who have sex with men. These usually regress in immunologically competent individuals [6] but anal precancerous disease and anal cancers are a significant problem in HIV-positive patients [29]. Women who experience high-grade cervical disease (CIN3) or vulvar cancer are more likely to develop anal cancer due to persistent HPV infection across the anogenital region [30]. Finally, many people, especially young adults (up to 2% of the population), can suffer from genital warts caused by the two well-defined low risk anogenital infective HPVs, HPV6 and 11 [31]. In some cases, multiple visible lesions, and the stigma of a sexually transmitted infection, can lead to sexual dysfunction in affected individuals. Although benign, treatment of these lesions is costly in terms of clinical time [31].

Over the last 20 years, there has been an exponential increase in HPV-associated oropharyngeal cancers (tongue base, soft palate, and pharyngeal walls), particularly in young males in high-income countries [11]. For example, in the U.S.A., rates of HPV detection in oropharyngeal cancers have increased over three-fold over the last two decades [32]. HPV infection of the oropharynx is thought to be due to changes in oral sexual practices [33]. In the U.S.A., the numbers of these HPV-associated cancers has already exceeded cervical cancers (CDC: http://www.cdc.gov/cancer/hpv/statistics/index.html.) and this trend is predicted to be observed in other high-income countries by 2020. HPV has been detected at highest levels in cancers of the tonsil, tongue base, and pharynx (Table 1) [34]. Of all the HPV-positive cases, between 80 and 90% are positive for HPV16, depending on the anatomical site [11]. Surprisingly, although other HPVs can be present, they are usually not detected at equivalent levels to anogenital types [34] suggesting that, although all anogenital HPVs could be sexually transmitted to the oral cavity, HPV16 replicates or persists better, or more readily causes cancer progression in certain sites in the head and neck. Interestingly, HPV positivity appears to indicate better response to radio- and chemotherapy in patients, although this may be related to the younger age distribution of these patients compared with the relatively older age group of HPV-negative patients [35].

HPV has been found to be associated with a number of other cancers, including prostate, colon, bladder, esophageal, and breast cancers [7]. The evidence includes detection of viral nucleic acid, and/or EM observation of viral particles, but in most cases a causative association has not been demonstrated. Breast cancer studies have been the most frequently reported [36]. HPV DNA and RNA detection and observation of HPV-associated morphological changes in breast epithelial cells, including koilocytes, a morphological feature of cervical disease, comprise the evidence [37]. However, there are many studies where HPV has not been detected in breast cancer casting doubt on the causative role of HPV infection [38]. HPV could be present, but not active, in HPV-positive breast tumors.

Many HPVs of each of the different genotypic groups cause transient infection of the cutaneous epithelium at a wide range of anatomical sites (Table 1) [39,40]. Skin lesions, such as common warts on the hands or verrucas on the feet, are benign but they can become medically important if the lesions are unsightly or cause embarrassment, spread rapidly or persist, or are prone to injury. The β-HPVs all infect the cutaneous epithelium and are a part of the normal human virome from infancy [39,40]. However, in some cases β-HPVs can cause cancer. The majority of such cancers occur in immunosuppressed individuals and in patients with the inherited recessive genetic disorder EV (epidermodysplasia verruciformis) [41,42]. Key β-HPV types associated with increased risk of non-melanoma squamous cell carcinomas include HPVs, 5, 8, 17, 20, 24, 36, and 38 (Table 1) [43]. β-HPV types 5 and 8 were first isolated and identified as carcinogenic in EV patients. EV patients accumulate increased cutaneous HPV infections from birth, and in infancy, can develop flat warts on sun-exposed areas of the skin that can eventually progress to squamous cell carcinomas [44]. Individuals with EV harbor mutations in two genes, EVER1 (TMC6) or EVER2 (TMC8). These mutations alter the way in which HPV is detected and cleared by the immune system [45]. This results in the possibility of massive persistent infection of the cutaneous epithelium, which, if not cleared, can lead to cancer.

The HPV infectious life cycle

Virion structure

All HPVs possess an episomal DNA genome of approximately 8 kb in size (Figure 2A) [1,2]. The genome can be divided into three functional sections, the early (E) region encoding at least seven viral proteins that have regulatory functions in the infected epithelial cell (E1, E2, E4, E5, E6, E7, E8), the late (L) region that encodes the two viral structural proteins L1 and L2, that form the viral capsid, and the LCR (long control region) otherwise called the upstream regulatory region (URR) (Figure 2B) [1,2]. The LCR contains the viral cis-acting regulatory sequences that control viral replication and transcription, and post-transcriptional control via the LRE (late regulatory element) [13]. The genome is encapsidated in an icosahedral shell that comprises 360 copies of the L1 protein organized into 72 pentameric capsomeres that probably have one copy of L2 at the center [46].

The HPV16 genome

Figure 2
The HPV16 genome

(A) Diagram of the circular dsHPV16 genome (gray circle). Other HPV genomes are very similar in organization. Viral ORFs are indicated with colored arcs above the genome. Promoters are indicated with P and chevrons (P97, P670, PE8). Early (pAE) and late (pALs) polyadenylation sites are indicated with short straight lines above the circular genome. The LCR is indicated with a blue line. (B) Details of the LCR sometimes called the URR. The E6 ORF is shown as an open rectangle. The end of the L1 ORF is shown as a partial open rectangle. The early promoter (P97) is indicated with and arrowhead. The proximal promoter region is indicated with a double arrowhead red line. Four E2 binding sites in the LCR are indicated with green squares. The origin of replication (ori) to which E1 binds is shown as a purple circle. The late polyadenylation site is indicated by Poly(A)L and a straight line. The late regulatory element that controls late gene expression is indicated with a blue box. Locations of the different features are not to scale.

Figure 2
The HPV16 genome

(A) Diagram of the circular dsHPV16 genome (gray circle). Other HPV genomes are very similar in organization. Viral ORFs are indicated with colored arcs above the genome. Promoters are indicated with P and chevrons (P97, P670, PE8). Early (pAE) and late (pALs) polyadenylation sites are indicated with short straight lines above the circular genome. The LCR is indicated with a blue line. (B) Details of the LCR sometimes called the URR. The E6 ORF is shown as an open rectangle. The end of the L1 ORF is shown as a partial open rectangle. The early promoter (P97) is indicated with and arrowhead. The proximal promoter region is indicated with a double arrowhead red line. Four E2 binding sites in the LCR are indicated with green squares. The origin of replication (ori) to which E1 binds is shown as a purple circle. The late polyadenylation site is indicated by Poly(A)L and a straight line. The late regulatory element that controls late gene expression is indicated with a blue box. Locations of the different features are not to scale.

HPV cell entry

HPV can gain entry into the epithelium through microabrasions [47] or for the HR-HPVs infecting the cervical epithelium, by entering cells of the single layered squamous cellular junction between the endo- and ectocervix, (Figure 3) [48]. At least for the HR-HPVs, it seems necessary for efficient establishment of infection that they infect actively dividing basal, or stem, epithelial cells [49,50]. HPV L1 capsid protein binds cellular receptors located on the basement membrane or on the surface of basal layer cells [51]. Heparin sulphate proteoglycans (HSPGs) seem to be the primary receptor for initial binding [52]. When HPV binds HSPGs, there is a cyclophilin B-mediated conformational change in the viral capsid such that the N-terminus of the L2 component is exposed on the surface of the virion [53]. The N-terminus is then cleaved by furin and/or PC5/6 and this allows binding to a secondary receptor on the plasma membrane of the target cell [54,55]. Recent studies have revealed the involvement of epidermal growth factor (EGF) receptors (EGFRs) [56], integrins (α6 integrin) [5658], tetraspanin-enriched membrane microdomains [59], laminins [60], syndecan-1 [56,61], the annexin-A2 heterotetramer [62,63], and vimentin [64] as entry receptors of HR-HPV. The receptor strategy used may be dependent upon the HPV genotype, the cell type to be infected, or several different receptor strategies may be applicable in a single infection. HPV enters cells by an endocytosis mechanism that has most similarities with micropinocytosis [65]. The virus travels through membrane-bound cytoplasmic components and the trans-Golgi network [6668], although there may be some involvement of the ER (endoplasmic reticulum) in trafficking [68,69]. Finally, the viral episomal genome is transported through a tubulin-mediated pathway [70] to the nucleus where it may enter via nuclear pores or following breakdown of the nuclear membrane during mitosis [49,71]. HPV reaches the nucleus approximately 24 h following cellular attachment where the capsid disassembles and incoming L2 and the viral genome associated with PML (promyelocytic leukaemia) nuclear bodies [72]. This nuclear location is commonly used by DNA viruses to initiate viral transcription [73] but while many viruses disrupt PMLs upon nuclear infection, HPV seems to require PML integrity to establish nuclear infection [72].

Virus infection of the cervix, keratinocyte differentiation, and HPV protein expression

Figure 3
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. Alternatively, HPV can enter cells in the squamous columnar junction. Most cervical cancers are thought to arise from this zone [48]. Division of an infected basal epithelial cells can give rise to a transit amplifying cell that is capable of differentiation. Viral genomes are segregated into daughter cells upon basal cell division and can be carried into upper epithelial layers. The keratinocyte differentiation process allows an orchestrated pattern of viral gene expression as indicated on the right hand side. Cells are shown in beige, nuclei in pink, and virus particles in pale blue. The basement membrane is shown as a gray line. Entry receptors are shown as a line with an arc above.

Figure 3
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. Alternatively, HPV can enter cells in the squamous columnar junction. Most cervical cancers are thought to arise from this zone [48]. Division of an infected basal epithelial cells can give rise to a transit amplifying cell that is capable of differentiation. Viral genomes are segregated into daughter cells upon basal cell division and can be carried into upper epithelial layers. The keratinocyte differentiation process allows an orchestrated pattern of viral gene expression as indicated on the right hand side. Cells are shown in beige, nuclei in pink, and virus particles in pale blue. The basement membrane is shown as a gray line. Entry receptors are shown as a line with an arc above.

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. One study on HPV31 revealed that RNA encoding the viral replication/transcription factors E1 and E2 was the first RNA species to be detected upon nuclear infection [74]. 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]. It forms a homodimer that can bind to four palindromic sites in the LCR (Figure 2B). 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 50–100 episomal copies per nucleus [80]. Limited viral genome amplification has been shown to be controlled by the E8 E2 protein via the cellular NCoR/SMRT complex [81]. 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]. However, there may be alternatives other than Brd4 for attachment of HPV genomes, including MKlp2 [83], ChlR1 [84], and TopBP1 [85]. 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 [8890]. 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].

HPV E6 and E7 protein activities during the replication cycle

HPVs possess an early promoter (for HPV16: P97; for HPV18: P105) that is responsible for expression of proteins at early stages of the replication cycle (Figure 2B) [13]. 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 [9496]. 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 [98100]. 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, p107 and p130, from a transcriptional repression complex containing the E2F transcription factor [101105]. 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 [106]. Added to this is a complex series of possible stimulatory and inhibitory activities of E7 on cellular transcription factors such as STAT1, NF-κB, IRF1, SMAD2/3, TBP, Miz 1, B-Myb, c-Myc, c-Jun, c-Fos, E2F1, and E2F6 [107]. 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. Moreover, during the viral life cycle, E7 is always present with E6 in the infected cells due to the bicistronic nature of the E6/E7 coding region of the genome [1,2]. 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 [75,108]. Further, HR E6 proteins can abrogate p53 function by binding the histone acetyltransferase CBP/p300, and inhibiting p53 transcriptional activity [109,110]. E6 proteins can also cause a conformation change in p53 through binding. This inhibits its transcriptional transactivation properties [111,112]. Finally, E6 can sequester p53 in the cytoplasm, meaning that it cannot carry out its nuclear transcription activation functions [113]. Some β-papillomavirus E6 proteins can bind p53 but cannot target it for degradation [114]. β-HPV E6 proteins can bind CBP/p300, but the mechanism of inactivation is different from that of the α HR-HPVs and involves blocking phosphorylation of p300 leading to destabilization of the protein and reduced levels in infected cells [115]. β-E6 proteins also bind MAML, and SMAD2 and 3, to inhibit Notch signaling [116,117]. The Notch pathway is responsible for promoting keratinocyte differentiation [118]. Thus, β-HPV E6 can directly inhibit differentiation, as can α-HR-HPV [119]. 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 [120]. 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 [121]. It is possible that this interaction could result in restructuring the infected cells to facilitate viral egress.

High and low risk, and β HPV E6 proteins can bind the proapototic Bak protein and target it for degradation [122125]. Bak has been found to be most active in the upper layers of the skin where HPV replication occurs [122]. It is thought that in uninfected cells, E6AP regulates the levels of Bak. However HPV18 E6 can decrease Bak levels through proteasomal degradation [122]. 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 [123,124]. These various roles of high and low risk, α and β E6 proteins are clearly important for viral replication.

E6 interaction with, and degradation of PDZ (PSD95/hDlg/ZO-1) domain proteins that control cell shape, cell signaling, and polarity is also important for the viral life cycle [126]. The E6 proteins of HR-HPVs contain a C-terminal PBM (PDZ-binding motif) allowing binding to PDZ proteins such as human homolog of Drosophila Discs Large (hDlg), Scribble, and MAGI 1, 2, and 3 [126]. The E6 PBM is required for episomal maintenance and genome amplification of HR-HPVs, indicating that PDZ proteins are important for the HPV life cycle [127129]. PDZ domain-containing proteins can bind to and stabilize low levels of E6 expressed during an infection leading to enhanced episome maintenance [129]. This PBM motif may also be required for cell cycle activation of HPV-infected cells and inhibition of apoptosis via NF-κB [130]. 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 [126]. However, a recent study revealed that PDZ-binding predates acquisition of oncogenic properties by the α papillomaviruses and it has been suggested that E6 regulation of PDZ proteins allowed ancient HPVs to gain access to new sites of infection such as the cervical transformation zone [131]. The E6 PBM also allows a regulatory interaction with SNX27 (sorting nexin 27), a protein that controls endosomal transport, nutrient acquisition, and cell proliferation [132]. E6 control of these pathways via SNX27 could have importance in keratinocyte metabolism during viral infection.

HPV16 E6 has been shown to bind to IRF-3 (interferon (IFN) regulatory factor-3) and abrogate transcriptional activity on the IFN-β promoter [133]. E6 also interferes with IFN α-mediated signaling via the STAT/Tyk2 pathway by inhibiting autophosphorylation of Tyk2 and ISG3α, a component of the ISGF3 transcription complex that activates IFN responsive genes [134]. HPV16 E6, together with E7, also prevents expression of TLR9 (toll-like receptor 9) that recognizes dsDNA in an infected cell to activate the innate immune response [135]. Recently the β-HPV type 38 E6 and E7 proteins were also shown to down-regulate TLR9 and importantly, this could be linked to cell cycle activation and increased keratinocyte proliferation [136]. Moreover, both E6 and E7 inhibit cytokines such as TNFα (tumor necrosis factor α), TGF β (transforming growth factor β), and the IFNs, thus altering cytokine signaling and innate immunity [87]. HR-HPV E6 represses IFNκ by DNA methylation to abrogate cellular responses to viral infection [137,138]. Finally, HPV E6 controls IL1-β via E6AP and p53-mediated degradation [139].

Recently, there has been an explosion of interest in the roles of non-coding RNAs during HPV infection. The majority of studies have examined miRNAs, 22–24 nt RNAs that control the stability and translation of mRNAs. Although other tumor viruses encode miRNAs, HR-HPVs do not [140]. However, E6 controls expression of cellular miRNAs, miR-23b, miR-218, and miR-34a. miR-34 is controlled via p53 and loss of this factor via E6-mediated degradation results in release of inhibition of a wide range of cell cycle and apoptosis-related gene expression [141]. E7 control of miR-203 has been shown to be important for viral genome amplification. miR-203 controls expression of ΔNp63 and an increase in levels of this transcription factor by E7 suppression of miR-203 leads to prolonged cell cycle activation in differentiating keratinocytes [142]. 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. miR-145 targets sequences in the HPV31 E1 and E2 gene regions. The subsequent loss of these viral replication factors results in a reduction in viral genome amplification and late gene expression [143].

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 (HPV16: P670; HPV18: P811) that is situated in the E7 gene region (Figures 2A and 4A) [144,145]. This results in increased expression, not only of E1 and E2, but also of E4 and E5 [13]. The E8 promoter remains active at this stage and E8 E2 can still repress viral genome amplification [81]. Late stage DNA replication, probably using a rolling circle mechanism, yields many thousands of progeny viral genomes [146]. 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 [147149]. In contrast, the low risk HPV11 E4 has been found not to be essential for viral genome amplification [150].

Mechanisms of activation of E6 and E7 expression during cervical tumor progression

Figure 4
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. Orange/yellow colored boxes indicate E1 and E2 coding regions. Lilac/purple colored boxes indicate the E4 and E5 coding regions. Blue colored boxes represent the L1 and L2 capsid encoding genes. (B) This diagram illustrates insertion of a single copy of the HPV genome with disruption in the E2 ORF. This leads to overexpression from the P97 promoter of the viral oncoproteins. Integration of the HPV16 genome can disrupt a host gene leading to transcription from the P97 promoter of a truncated viral early gene region fused to the 3′-UTR and polyadenylation site of the host gene (open box). 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. (C). Multiple integration can also occur but expression of the majority are epigenetically silenced by methylation of the P97 promoter region. The gene color scheme is the same as that used in (A). 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) [200].

Figure 4
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. Orange/yellow colored boxes indicate E1 and E2 coding regions. Lilac/purple colored boxes indicate the E4 and E5 coding regions. Blue colored boxes represent the L1 and L2 capsid encoding genes. (B) This diagram illustrates insertion of a single copy of the HPV genome with disruption in the E2 ORF. This leads to overexpression from the P97 promoter of the viral oncoproteins. Integration of the HPV16 genome can disrupt a host gene leading to transcription from the P97 promoter of a truncated viral early gene region fused to the 3′-UTR and polyadenylation site of the host gene (open box). 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. (C). Multiple integration can also occur but expression of the majority are epigenetically silenced by methylation of the P97 promoter region. The gene color scheme is the same as that used in (A). 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) [200].

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 [151]. E4 can also enhance genome amplification directly by regulating cell cycle arrest in G2-phase [152,153] and activating cellular kinases [154]. E5 is a transmembrane ER-resident protein [155] that can stabilize EGFR and stimulate MAPK (mitogen-activated protein kinase) activity, suggesting that it can control cell division pathways [156]. 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 [157,158]. E4’s ability to arrest cells in G2-phase could counteract the effect of E7 stimulation of G1 to S-phase transition [147,152,159].

E4 and E5 have additional roles in the HPV life cycle. HPV1 E4 may control RNA processing in the infected cell through the SRPK1 (SR protein kinase 1) [160]; while HPV16 E4 can bind a DEAD box RNA helicase that could contribute to post-transcriptional control of viral gene expression [161]. 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 [162164]. E5 helps the virus evade the immune response by repression of MHC presentation of viral peptides [165]. Apart from EGFR and MAPK signaling, other signaling affected by E5 includes ERK (extracellular signal regulated kinase) 1/2, AKT, and p38 pathways and through these E5 can regulate apoptosis [155]. Finally, HPV16 E5 is capable of forming a viroporin that could have ion channel activity in infected cells and this may be linked to E5’s enhancement of EGFR activity [166]. 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. ATM (ataxia telangiectasia mutated) and ATR (ataxia telangiectasia and Rad3-related) kinases are the key sensors of DNA damage and regulators of damage repair [167]. Both kinases play a key role in HR HPV replication by helping to recruit cellular DNA replication and repair factors [168]. 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 [169]. 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 [170]. In the late phase, E7 has been shown to activate the ATM DNA damage pathway required for vegetative viral genome amplification in differentiated keratinocytes [171]. E7 seems to control stability of DNA repair proteins through its Rb-binding domain, but further work is required to elucidate the mechanism [172]. In addition, E1 can activate the DNA damage response that results in recruitment of ATM/ATR to viral replication centers [173175]. 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 [169].

Following viral genome amplification and capsid protein synthesis, virion formation takes place in the nucleus. At least for some HPVs (e.g. 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 [176]. 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. The capsid proteins are expressed from mRNAs that initiate at the late promoter (P670 for HPV16, P811 for HPV18) that becomes activated in cells supporting viral genome amplification [13]. 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 [13,177]. There are a number of cellular RNA-binding proteins that could control capsid protein expression through binding a regulatory element in the late 3΄ untranslated region, including the mRNA stability regulator HuR [178], hnRNP A1 [179], splicing factor 1 (SRSF1 (SF2/ASF)) [180], and U1snRNP (U1 small nuclear ribonucleoprotein) [181], all of which show increased expression upon keratinocyte differentiation [182]. 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 [183]. L1 proteins self-assemble into pentameric capsomeres in the cytoplasm and these structures are transported into the nucleus [184]. Post-synthesis, viral genomes locate to PML through E2 bound to its cognate sites in the LCR [185]. Thus viral genomes are located adjacent to viral capsid proteins ready for assembly. L1 and L2 interact and L2 is probably incorporated into assembling virus particles at the centers of the capsomeres, although the L1/L2 interface is poorly defined as yet [186,187]. L2 seems to be required for efficient DNA packaging and virion assembly [188]. 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 [163].

Apart from the proteins mentioned above, there are potentially other viral proteins expressed during the life cycle. For example, the E6E7 gene region of the HPV16 genome gives rise to at least four alternatively spliced mRNAs (E6 full length (E6fl), E6*I E6*II, E6*III (also called E6*X)) that have been detected in HPV-positive patient samples [189]. E6*I protein, which represents the N-terminal portion of E6, is significantly more abundant than E6fl, at least at the mRNA level. E6*I has antiapoptotic properties and may regulate E6 itself [190]. In addition, E6*I may cause oxidative stress and DNA damage, processes that could be important for the infectious viral life cycle but also for HPV-associated tumor progression [191]. 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]. However, E2 has also been shown to bind L1, L2, E6, E6*I, E7, and E4. E2 binding to L2 appears to have a role during establishment of infection in basal epithelial cells [185] where it localizes with L2 to ND10 domains in infected cell nuclei. Moreover, L2 can inhibit E2 transcriptional transactivation but not E2-mediated viral DNA replication [192]. 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 [193]. It has been suggested that E2–E7 oligomers might result in inhibition of E2 repression of E6 and E7 expression to contribute to HR-HPV-associated tumor progression [194]. The interaction between E2 and E6 isoforms changes the subnuclear localization of the proteins, which has potential to alter their cellular functions [195]. Similarly, upon binding to E4, E2 undergoes cytoplasmic relocation and stabilization [151] but any role for cytoplasmic E2 has yet to be explored. E2 and L1 associate at PML nuclear bodies during virion assembly [185]. 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.

HPVs can induce tumorigenesis

Although there is clear evidence that HR-HPVs have a causative association with a number of cancers, the progression of an HPV infection to an HPV-associated cancer is a rare event [3]. Most importantly, in terms of viral replication, cancer progression is an unproductive or ‘dead-end’ event for the virus. 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 [87,196,197]. HIV patients have a five-fold greater risk of developing HPV-associated cervical cancer [198] 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 [199]. 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 [200]. 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. In most cases (estimated to be between 70 and 85% of cases), changes in oncoprotein expression results from integration of the HR-HPV genome into the host genome (Figure 4) [201]. Integration is not a part of the normal HPV replication cycle. This is an ‘abortive’ infection where integration of a single viral genome copy results in concomitant deletion of parts of the viral genome but retention of the early P97 promoter and E6 and E7 coding regions (Figure 4 B), or integration of multiple viral genomes most of which become epigenetically silenced (Figure 4C) [75]. 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 [202,203]. Recently, it was demonstrated that integration could result in formation of a Brd4-controlled ‘super enhancer’ that could cause increased viral oncoprotein expression [204]. However, E6/E7 overexpression may also be achieved by increased oncoprotein mRNA stability due to integrant genomes being transcribed as a part of a cellular ORF where the resulting mRNA is more stable, and therefore, more efficiently translated [205]. Moreover, acquisition of resistance to cytokine signaling can lead to cellular transcription factors such as the AP1 complex further activating viral transcription [206].

The pathway to viral integration during persistence is still unclear [200]. Moreover, because approximately 15% of cervical cancers harbor episomal HPV genomes, it is considered possible that tumor progression can result from misregulation of episomal HPV genomes [200]. In this case, E2 expression is retained but E6 and E7 expression are increased, possibly through epigenetic and/or chromatin conformation changes around the P97 promoter. On the other hand, experiments in the HPV16-positive 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 [207]. 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 [208]. Alternatively, the E6*I protein has been shown to induce oxidative stress and DNA damage. Therefore, its expression in persistently infected cells could predispose to genome damage and integration [191]. However, a timeline for these events during persistence could be different for every tumor and difficult to work out.

Although continued expression of the E6 and E7 oncoproteins is required to maintain the transformed phenotype, it is not sufficient for cellular transformation. Expression of E7, but not E6, can immortalize keratinocytes. However, expression of both oncoproteins provide co-operative activity that can readily immortalize cells [75]. HR-HPV E6 proteins activate telomerase reverse transcriptase (TERT) and telomerase. These enzymes are essential for maintaining the lengths of telomeres at the end of chromosomes that is necessary for immortalization of cells [75,209]. Activation of telomerase and maintenance of the lengths of telomeres is a hallmark of cancer cells. Therefore, it has been proposed that this function of E6 has a key role in development of high-grade lesions and progression to cancer. HPV16 E6-mediated loss of p53 allows mutations to accumulate in cells in which apoptosis is inhibited [92]. In addition, HPV16 E6, HPV8 E6, and HPV1 E6 can all bind and inhibit the DNA repair protein XRCC1 to prevent repair of single-stranded breaks allowing accumulation of mutations in the host genome. This function of E6 may also release cellular DNA polymerase β and promote DNA replication [210].

There is a strong evidence that E7 can cause errors in centrosome duplication, perhaps through misregulation of cyclin E/cyclin-dependent kinase 2 (CDK2) complexes, leading to overduplication and genomic instability [211]. High and low risk E7 proteins interact with NuMA (nuclear mitotic apparatus protein 1) causing its delocalization and resulting in mitotic errors [212]. HPV16 E7 can bind and affect γ-tubulin recruitment to centrosomes [213], a process regulated by dynein, also relocalized by E7 [214]. Experimental evidence indicates that even prior to cancer progression E6 and E7 can co-operatively induce centrosome abnormalities as an early event in tumor progression [215]. E6 and E7 may also be able to bypass G2-M checkpoints that would otherwise signal cells with accumulated mutated chromosomes for destruction [216].

The increased levels of viral oncoproteins found in HPV-positive tumor cells may cause sustained activation or inhibition of growth control pathways. For example, the E6-mediated stimulation of growth-related (for example EGF and MAPK) signaling pathways [127] would abrogate cellular growth control allowing cell transformation and tumor invasion to occur [217]. Moreover, E6 control of PDZ proteins, tumor suppressors that control cell shape and polarity and integrate cellular signaling [218], has been shown to play a major role in tumor formation [126]. For example, the staining pattern of hDlg, the human homolog of the Drosophila Dlg tumor suppressor in transformed cells is very different from that of non-transformed cells [219,220]. In normal epithelial cells, hDlg is found predominantly at tight junction plaques between the neighboring cells, however in HR-HPV E6-transformed cells hDlg staining is predominantly cytoplasmic suggesting a loss of cell–cell communication between neighboring transformed cells [219,220]. As E6 has been shown to bind to PDZ domain containing proteins, it is thought that this protein is responsible for redistribution of hDlg during transformation [221,222]. However, E6 may misregulate many others such PDZ proteins to contribute to tumorigenesis [126]

E7 interacts with a wide range of transcription regulators and can repress or activate expression of cell cycle control proteins such as cyclin kinase inhibitors p21 and p27 and cyclins A and E [75]. Furthermore, E7 binds E2F6, a member of the polycomb repressor complex that normally associates with chromatin, and prevents its normal repressive functions on E2F-activated S-phase genes [223]. E7 also can allow anchorage-independent growth and cellular transformation by binding p600, a retinoblastoma-associated protein [224]. All these interactions and regulatory pathways are important for the normal infectious life cycle of HR-HPVs. However, when misregulated due to increased E6/E7 expression these signaling and cellular regulation pathways can contribute to tumor progression. E7 can also promote telomere maintenance, thus supporting the function of E6 in this regard [225]. Both oncoproteins can regulate the cellular miRNA profile and increased oncogenic, and in particular, decreased tumor suppressive miRNAs have been found in cervical tumors [226]

Finally, the role of HR-HPV E5 in the transformation process should be taken into account. Although there is convincing evidence of the role of E5 in the transformation process during infection with bovine papillomaviruses [227], HR-HPV E5 has only weak transforming activity and therefore its role during the transformation process is more obscure [155]. Following viral genome integration into host chromosomes, E5 is usually no longer expressed. However, E5 has many documented activities that could contribute to the transformation process and it appears to augment the functions of E6 and E7 in tumor progression [228230]. E5 controls cellular signaling in keratinocytes. It binds to the 16K subunit c of the proton pump vacuolar ATPase and reduces endosomal acidification [231,232]. This leads to the activation of the EGFR which stimulates proliferation of basal layer epithelial cells [233]. At the same time, E5 can interact with keratinocyte growth factor receptor signaling to inhibit autophagy [234] and cause a decrease in proliferation and differentiation of suprabasal keratinocytes [235]. Overall this would result in a significant increase in the proliferative compartment of the epithelium, which may be an early event in tumor progression. Indeed, E5 expression in transgenic mice leads to changes in growth and differentiation of keratinocytes and induces epithelial tumors in an EGFR-dependent fashion [236] and evidence suggests that E5 could contribute to the promotion and progression stages of tumorigenesis [237]. Other signaling pathways such as MAPK and PI3 kinase are also activated [156,238].

Conclusion

HPV infection and its relationship to HPV-associated tumor progression has been the subject of intense research activity for over 50 years. There are still significant gaps in our understanding of both strands of HPV pathogenesis. E6 and E7 clearly make a very significant contribution to tumor progression. Tight regulation by E2 of expression levels of these oncoproteins in the dividing cells of an infected epithelium is the key to avoid tumor formation. Dampening down amplification levels of viral genomes during a normal infectious cycle via the E8 E2 protein may also help to reduce the chances of elevated levels of E6 and E7 in differentiated keratinocytes. The fine balance between the activities of E6, E7, E2, E4, and E5 on the cell cycle and apoptosis to allow viral genome amplification, while avoiding viral genome integration into the host genome, is crucial for the virus to complete its infectious life cycle. There are still many fascinating aspects of the HPV life cycle to be elucidated, and our knowledge of the life cycle of HPVs other than the more common HR types is still limited. Understanding HPV-associated cancer progression in sites other than the cervix will be key to future development of interventions to alleviate HPV-associated diseases.

I thank Ms Arwa Ali A. Faizo for help with Figure 1 and also thank the Medical Research Council as core funding for the MRC University of Glasgow Centre for Virus Research. I apologize to those colleagues whose work is not referred to in this review. This is due to constraints on the length of the article and the reference list.

Funding

This work in the Graham lab was supported by the Wellcome Trust [grant number 088848/2/09/2 (to S.V.G.)].

Competing interests

The author declares that there are no competing interests associated with the manuscript.

Abbreviations

     
  • Akt

    Protein kinase B

  •  
  • AP1

    Activator protein 1

  •  
  • ATM

    ataxia telangiectasia mutated

  •  
  • ATR

    ataxia telangiectasia and Rad3-related

  •  
  • Brd4

    Bromodomain-containing protein 4

  •  
  • B-Myb

    Myeloblastosis oncoprotein B

  •  
  • CBP

    CREB binding protein

  •  
  • CIN

    cervical intraepithelial neoplasia

  •  
  • C-Jun

    Cellular JNK transcription factor

  •  
  • C-Fos

    Cellular Finkel-Biskis-Jinkins murine osteosarcoma virus oncogene

  •  
  • ChlR1

    Chromatin loss related 1

  •  
  • C-Myc

    Cellular myelocytomatosis oncogene

  •  
  • DEAD

    amino acids D-E-A-D-containing

  •  
  • Δp63

    Delta phosphorylated 63 protein

  •  
  • EGF

    epidermal growth factor

  •  
  • EGFR

    epidermal growth factor receptor

  •  
  • EM

    Electron microscopy

  •  
  • ER

    endoplasmic reticulum

  •  
  • ERK

    extracellular signal regulated kinase

  •  
  • EV

    epidermodysplasia verruciformis

  •  
  • E6AP

    E6-associated protein

  •  
  • hDlg

    homolog of Drosophila Discs Large

  •  
  • hnRNP

    heterongenous nuclear ribonucleoprotein

  •  
  • HPV

    human papillomavirus

  •  
  • HPV16

    HR-HPV genotype 16

  •  
  • HR

    high risk

  •  
  • HR-HPV

    high risk HPV

  •  
  • HSIL

    high-grade squamous intraepithelial lesion

  •  
  • HSPG

    heparin sulphate proteoglycan

  •  
  • HuR

    Human antigen R

  •  
  • IFN

    interferon

  •  
  • LCR

    long control region

  •  
  • LSIL

    low-grade squamous intraepithelial lesion

  •  
  • NCoR

    Nuclear receptor corepressor 2

  •  
  • MAGI 1

    Membrane-associated guanylate kinase 1

  •  
  • MAML

    Mastermind-like proteins 1

  •  
  • MAPK

    mitogen-activated protein kinase

  •  
  • Miz 1

    Mizu 1

  •  
  • MKIp2

    Mitotic kinesin-like proteins 2

  •  
  • mTOR

    Mechanistic target of rapamycin

  •  
  • ND10

    Nuclear domain 1

  •  
  • NF-kB

    Nuclear factor kB

  •  
  • Pap

    Papanikolaou

  •  
  • PBM

    PDZ-binding motif

  •  
  • PC5/6

    Proprotein convertase 5/6

  •  
  • PDZ

    PSD95/hDlg/ZO-1

  •  
  • PI3

    Phosphoinositide 3

  •  
  • PML

    promyelocytic leukaemia

  •  
  • pRb

    Phosphorylated retinoblastoma protein

  •  
  • SIL

    squamous intraepithelial lesion

  •  
  • SMAD2/3

    Similar to mothers against decapentaplegic 2/3

  •  
  • SMRT

    Silencing mediator of retinoic acid and thyroid hormone receptor

  •  
  • SNX27

    sorting nexin 27

  •  
  • SRSF1 (SF2/ASF)

    Serine arginine-rich splicing factor

  •  
  • SR

    Serine arginine-rich

  •  
  • STAT1

    Signal transducer and activator of transcription 1

  •  
  • TBP

    TAT binding protein

  •  
  • TLR9

    toll-like receptor 9

  •  
  • TopBP1

    Topoisomerase binding protein 1

  •  
  • URR

    upstream regulatory region

References

References
1
Van Doorslaer
K.
,
Li
Z.
,
Xirasagar
S.
,
Maes
P.
,
Kaminsky
D.
,
Liou
D.
et al
(
2012
)
Papillomavirus episteme: a comprehensive Papillomaviridae database and analysis resource
.
2
Van Doorslaer
K.
,
Li
Z.
,
Xirasagar
S.
,
Maes
P.
,
Kaminsky
D.
,
Liou
D.
et al
(
2017
)
The Papillomavirus Episteme: a major update to the papillomavirus sequence database
.
Nucleic Acids Res.
45
,
D499
D506
3
Stanley
M.
(
2010
)
Pathology and epidemiology of HPV infection in females
.
Gynecol. Oncol.
117
,
S5
S10
4
Giuliano
A.R.
,
Nyitray
A.G.
,
Kreimer
A.R.
,
Campbell
C.M.
,
Goodman
M.T.
,
Sudenga
S.L.
et al
(
2015
)
EUROGIN 2014 roadmap: differences in human papillomavirus infection natural history, transmission and human papillomavirus-related cancer incidence by gender and anatomic site of infection
.
Int. J. Cancer
136
,
2752
2760
5
Anic
G.M.
and
Giuliano
A.R.
(
2011
)
Genital HPV infection and related lesions in men
.
Prev. Med.
53
,
S36
S41
6
Benevolo
M.
,
Donà
M.G.
,
Ravenda
P.S.
and
Chiocca
S.
(
2016
)
Anal human papillomavirus infection: prevalence, diagnosis and treatment of related lesions
.
Expert Rev. Anti Infect. Ther.
14
,
465
477
7
Heidegger
I.
,
Borena
W.
and
Pichler
R.
(
2015
)
The role of human papillomavirus in urological malignancies
.
Anticancer Res.
35
,
2513
2519
8
Wentzensen
N.
,
Arbyn
M.
,
Berkhof
J.
,
Bower
M.
,
Canfell
K.
,
Einstein
M.
et al
(
2017
)
Eurogin 2016 Roadmap: how HPV knowledge is changing screening practice
.
Int. J. Cancer
140
,
2192
2200
9
Berman
T.A.
and
Schiller
J.T.
(
2017
)
Human papillomavirus in cervical cancer and oropharyngeal cancer: one cause, two diseases
.
Cancer
123
,
2219
2229
10
Smith
L.
and
Angarone
M.P.
(
2015
)
Sexually transmitted infections
.
Urol. Clin. North Am.
42
,
507
518
11
Gillison
M.L.
,
Chaturvedi
A.K.
,
Anderson
W.F.
and
Fakhry
C.
(
2015
)
Epidemiology of human papillomavirus–positive head and neck squamous cell carcinoma
.
J. Clin. Oncol.
33
,
3235
3242
12
Hofstetter
A.M.
and
Rosenthal
S.L.
(
2014
)
Factors impacting HPV vaccination: lessons for health care professionals
.
Expert Rev. Vaccines
13
,
1013
1026
13
Graham
S.V.
(
2010
)
Human papillomavirus: gene expression, regulation and prospects for novel diagnostic methods and antiviral therapies
.
Future Microbiol.
5
,
1493
1506
14
Kocjan
B.J.
,
Bzhalava
D.
,
Forslund
O.
,
Dillner
J.
and
Poljak
M.
(
2015
)
Molecular methods for identification and characterization of novel papillomaviruses
.
Clin. Microbiol. Infect.
21
,
808
816
15
Barrionuevo-Rosas
L.
,
Bosch
F.X.
,
Bruni
L.
,
de Sanjosé
S.
,
Gomez
D.
,
Munoz
M.M.
et al
(
2017
)
Human papillomavirus and related diseases in the world
.
16
Hammer
A.
,
Rositch
A.
,
Qeadan
F.
,
Gravitt
P.E.
and
Blaakaer
J.
(
2016
)
Age-specific prevalence of HPV16/18 genotypes in cervical cancer: A systematic review and meta-analysis
.
Int. J. Cancer
138
,
2795
2803
17
Van Doorslaer
K.
(
2013
)
Evolution of the papillomaviridae
.
Virology
445
,
11
20
18
Bzhalava
D.
,
Mühr
L.S.A.
,
Lagheden
C.
,
Ekström
J.
,
Forslund
O.
,
Dillner
J.
et al
(
2014
)
Deep sequencing extends the diversity of human papillomaviruses in human skin
.
Sci. Rep.
4
,
5807
19
Tommasino
M.
(
2017
)
The biology of beta human papillomaviruses
.
Virus Res.
231
,
128
138
20
Egawa
N.
,
Egawa
K.
,
Griffin
H.
and
Doorbar
J.
(
2015
)
Human papillomaviruses; epithelial tropisms, and the development of neoplasia
.
Viruses
7
,
3863
3890
21
Baldwin
P.
,
Laskey
R.
and
Coleman
N.
(
2003
)
Translational approaches to improving cervical screening
.
Nat. Rev. Cancer
3
,
217
226
22
Doorbar
J.
,
Egawa
N.
,
Griffin
H.
,
Kranjec
C.
and
Murakami
I.
(
2015
)
Human papillomavirus molecular biology and disease association
.
Rev. Med. Virol.
25
,
2
23
23
Martin
C.M.
and
O’Leary
J.J.
(
2011
)
Histology of cervical intraepithelial neoplasia and the role of biomarkers
.
Best Pract. Res. Clin. Obstet. Gynaecol.
25
,
605
615
24
Cuschieri
K.S.
,
Cubie
H.A.
,
Whitley
M.W.
,
Seagar
A.L.
,
Arends
M.J.
,
Moore
C.
et al
(
2004
)
Multiple high risk HPV infections are common in cervical neoplasia and young women in a cervical screening population
.
J. Clin. Pathol.
57
,
68
72
25
Mesher
D.
,
Cuschieri
K.
,
Hibbitts
S.
,
Jamison
J.
,
Sargent
A.
,
Pollock
K.G.
et al
(
2015
)
Type-specific HPV prevalence in invasive cervical cancer in the UK prior to national HPV immunisation programme: baseline for monitoring the effects of immunisation
.
J. Clin. Pathol.
68
,
135
140
26
Serrano
B.
,
de Sanjosé
S.
,
Tous
S.
,
Quiros
B.
,
Muñoz
N.
,
Bosch
X.
et al
(
2015
)
Human papillomavirus genotype attribution for HPVs 6, 11, 16, 18, 31, 33, 45, 52 and 58 in female anogenital lesions
.
Eur. J. Cancer
51
,
1732
1741
27
De Vuyst
H.
,
Clifford
G.M.
,
Nascimento
M.C.
,
Madeleine
M.M.
and
Franceschi
S.
(
2009
)
Prevalence and type distribution of human papillomavirus in carcinoma and intraepithelial neoplasia of the vulva, vagina and anus: a meta-analysis
.
Int. J. Cancer
124
,
1626
1636
28
Alemany
L.
,
Saunier
M.
,
Tinoco
L.
,
Quirós
B.
,
Alvarado-Cabrero
I.
,
Alejo
M.
et al
(
2014
)
Large contribution of human papillomavirus in vaginal neoplastic lesions: a worldwide study in 597 samples
.
Eur. J. Cancer
50
,
2846
2854
29
Wang
C.-c.J.
,
Sparano
J.
and
Palefsky
J.M.
(
2017
)
Human immunodeficiency virus/AIDS, human papillomavirus, and anal cancer
.
Surg. Oncol. Clin. N. Am.
26
,
17
31
30
Moscicki
A.-B.
,
Schiffman
M.
,
Burchell
A.
,
Albero
G.
,
Giuliano
A.R.
,
Goodman
M.T.
et al
(
2012
)
Updating the natural history of human papillomavirus and anogenital cancers
.
Vaccine
30
,
F24
F33
31
Scarbrough Lefebvre
C.D.
,
Van Kriekinge
G.
,
Gonçalves
M.A.
and
de Sanjose
S.
(
2011
)
Appraisal of the burden of genital warts from a healthcare and individual patient perspective
.
Public Health
125
,
464
475
32
Chaturvedi
A.K.
,
Engels
E.A.
,
Pfeiffer
R.M.
,
Hernandez
B.Y.
,
Xiao
W.
,
Kim
E.
et al
(
2011
)
Human papillomavirus and rising oropharyngeal cancer incidence in the United States
.
J. Clin. Oncol.
29
,
4294
4301
33
Heck
J.E.
,
Berthiller
J.
,
Vaccarella
S.
,
Winn
D.M.
,
Smith
E.M.
,
Shan’gina
O.
et al
(
2010
)
Sexual behaviours and the risk of head and neck cancers: a pooled analysis in the International Head and Neck Cancer Epidemiology (INHANCE) consortium
.
Int. J. Epidemiol.
39
,
166
181
34
Abogunrin
S.
,
Di Tanna
G.L.
,
Keeping
S.
,
Carroll
S.
and
Iheanacho
I.
(
2014
)
Prevalence of human papillomavirus in head and neck cancers in European populations: a meta-analysis
.
BMC Cancer
14
,
968
35
Chau
N.G.
,
Rabinowits
G.
and
Haddad
R.I.
(
2014
)
Human papillomavirus-associated oropharynx cancer (HPV-OPC): treatment options
.
Curr. Treat. Options Oncol.
15
,
595
610
36
Lawson
J.S.
,
Glenn
W.K.
and
Whitaker
N.J.
(
2016
)
Human papillomaviruses and breast cancer – assessment of causality
.
Front. Oncol.
6
,
207
37
Lawson
J.S.
,
Glenn
W.K.
,
Heng
B.
,
Ye
Y.
,
Tran
B.
,
Lutze-Mann
L.
et al
(
2009
)
Koilocytes indicate a role for human papillomavirus in breast cancer
.
Br. J. Cancer
101
,
1351
1356
38
Khoury
J.D.
,
Tannir
N.M.
,
Williams
M.D.
,
Chen
Y.
,
Yao
H.
,
Zhang
J.
et al
(
2013
)
Landscape of DNA virus associations across human malignant cancers: analysis of 3,775 cases using RNA-Seq
.
J. Virol.
87
,
8916
8926
39
de Koning
M.N.C.
,
Weissenborn
S.J.
,
Abeni
D.
,
Bouwes Bavinck
J.N.
,
Euvrard
S.
,
Green
A.C.
et al
(
2009
)
Prevalence and associated factors of betapapillomavirus infections in individuals without cutaneous squamous cell carcinoma
.
J. Gen. Virol.
90
,
1611
1621
40
Antonsson
A.
,
Forslund
O.
,
Ekberg
H.
,
Sterner
G.
and
Hansson
B.G.
(
2000
)
The ubiquity and impressive genomic diversity of human skin papillomaviruses suggest a commensalic nature of these viruses
.
J Virology
74
,
11636
11641
41
Howley
P.M.
and
Pfister
H.J.
(
2015
)
Beta genus papillomaviruses and skin cancer
.
Virology
479-480
,
290
296
42
Patel
T.
,
Morrison
L.K.
,
Rady
P.
and
Tyring
S.
(
2010
)
Epidermodysplasia verruciformis and susceptibility to HPV
.
Dis. Markers
29
,
199
206
43
Chahoud
J.
,
Semaan
A.
,
Chen
Y.
,
Cao
M.
,
Rieber
A.G.
,
Rady
P.
et al
(
2016
)
Association between β-genus human papillomavirus and cutaneous squamous cell carcinoma in immunocompetent individuals—a meta-analysis
.
JAMA Dermatol.
152
,
1354
1364
44
Orth
G.
(
2006
)
Genetics of epidermodysplasia verruciformis: insights into host defense against papillomaviruses
.
Semin. Immunol
18
,
362
374
45
Kalińska-Bienias
A.
,
Kowalewski
C.
and
Majewski
S.
(
2016
)
The EVER genes – the genetic etiology of carcinogenesis in epidermodysplasia verruciformis and a possible role in non-epidermodysplasia verruciformis patients
.
Postepy. Dermatol. Alergol.
33
,
75
80
46
Buck
C.
and
Trus
B.
(
2012
)
The papillomavirus virion: a machine built to hide molecular achilles’ heels
. In
Viral Molecular Machines
(
Rossmann
M.G.
and
Rao
V.B.
, eds), pp.
403
422
,
Springer
,
U.S.A.
47
Doorbar
J.
(
2005
)
The papillomavirus life cycle
.
J. Clin. Virol.
32S
,
S7
S15
48
Herfs
M.
,
Yamamoto
Y.
,
Laury
A.
,
Wang
X.
,
Nucci
M.R.
,
McLaughlin-Drubin
M.E.
et al
(
2012
)
A discrete population of squamocolumnar junction cells implicated in the pathogenesis of cervical cancer
.
Proc. Natl. Acad. Sci. U.S.A.
109
,
10516
10521
49
Pyeon
D.
,
Pearce
S.M.
,
Lank
S.M.
,
Ahlquist
P.
and
Lambert
P.F.
(
2009
)
Establishment of human papillomavirus infection requires cell cycle progression
.
PLoS Pathog.
5
,
e1000318
50
Egawa
K.
(
2003
)
Do human papillomaviruses target epidermal stem cells?
Dermatology
207
,
251
254
51
Raff
A.B.
,
Woodham
A.W.
,
Raff
L.M.
,
Skeate
J.G.
,
Yan
L.
,
Da Silva
D.M.
et al
(
2013
)
The evolving field of human papillomavirus receptor research: a review of binding and entry
.
J. Virol.
87
,
6062
6072
52
Schiller
J.T.
,
Day
P.M.
and
Kines
R.C.
(
2010
)
Current understanding of the mechanism of HPV infection
.
Gynecol. Oncol.
118
,
S12
S17
53
Bienkowska-Haba
M.
,
Patel
H.D.
and
Sapp
M.
(
2009
)
Target cell cyclophilins facilitate human papillomavirus type 16 infection
.
PLoS Pathog.
5
,
e1000524
54
Richards
R.M.
,
Lowy
D.R.
,
Schiller
J.T.
and
Day
P.M.
(
2006
)
Cleavage of the papillomavirus minor capsid protein, L2, at a furin consensus site is necessary for infection
.
Proc. Natl. Acad. Sci. U.S.A.
103
,
1522
1527
55
Kines
R.C.
,
Thompson
C.D.
,
Lowy
D.R.
,
Schiller
J.T.
and
Day
P.M.
(
2009
)
The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding
.
Proc. Natl. Acad. Sci. U.S.A.
106
,
20458
20463
56
Surviladze
Z.
,
Dziduszko
A.
and
Ozbun
M.A.
(
2012
)
Essential roles for soluble virion-associated heparan sulfonated proteoglycans and growth factors in human papillomavirus infections
.
PLoS Pathog.
8
,
e1002519
57
Abban
C.Y.
and
Meneses
P.I.
(
2010
)
Usage of heparan sulfate, integrins, and FAK in HPV16 infection
.
Virology
403
,
1
16
58
Evander
M.
,
Frazer
I.H.
,
Payne
E.
,
Qi
Y.M.
,
Hengst
K.
and
McMillan
N.A.
(
1997
)
Identification of the alpha6 integrin as a candidate receptor for papillomaviruses
.
J. Virol.
71
,
2449
2456
59
Scheffer
K.D.
,
Gawlitza
A.
,
Spoden
G.A.
,
Zhang
X.A.
,
Lambert
C.
,
Berditchevski
F.
et al
(
2013
)
Tetraspanin CD151 mediates papillomavirus type 16 endocytosis
.
J. Virol.
87
,
3435
3446
60
Culp
T.D.
,
Budgeon
L.R.
,
Marinkovich
M.P.
,
Meneguzzi
G.
and
Christensen
N.D.
(
2006
)
Keratinocyte-secreted laminin 5 can function as a transient receptor for human papillomaviruses by binding virions and transferring them to adjacent cells
.
J. Virol.
80
,
8940
8950
61
Shafti-Keramat
S.
,
Handisurya
A.
,
Kriehuber
E.
,
Slupetzky
K.
and
Kirnbauer
R.
(
2003
)
Different heparan sulfate proteoglycans serve as cellular receptors for human papillomaviruses
.
J. Virol.
77
,
13125
13135
62
Woodham
A.W.
,
Da Silva
D.M.
,
Skeate
J.G.
,
Raff
A.B.
,
Ambroso
M.R.
,
Brand
H.E.
et al
(
2012
)
The S100A10 subunit of the annexin A2 heterotetramer facilitates L2-mediated human papillomavirus infection
.
PLoS ONE
7
,
e43519
63
Dziduszko
A.
and
Ozbun
M.A.
(
2013
)
Annexin A2 and S100A10 regulate human papillomavirus type 16 entry and intracellular trafficking in human keratinocytes
.
J. Virol.
87
,
7502
7515
64
Schäfer
G.
,
Graham
L.M.
,
Lang
D.
,
Blumenthal
M.J.
,
Bergant Marušič
M.
and
Katz
A.A.
(
2017
)
Vimentin modulates infectious internalisation of HPV16 pseudovirions
.
J. Virol.
65
DiGiuseppe
S.
,
Bienkowska-Haba
M.
,
Guion
L.G.
and
Sapp
M.
(
2017
)
Cruising the cellular highways: How human papillomavirus travels from the surface to the nucleus
.
Virus Res.
231
,
1
9
66
Day
P.M.
,
Thompson
C.D.
,
Schowalter
R.M.
,
Lowy
D.R.
and
Schiller
J.T.
(
2013
)
Identification of a role for the trans-Golgi network in human papillomavirus 16 pseudovirus infection
.
J. Virol.
87
,
3862
3870
67
DiGiuseppe
S.
,
Bienkowska-Haba
M.
,
Hilbig
L.
and
Sapp
M.
(
2014
)
The nuclear retention signal of HPV16 L2 protein is essential for incoming viral genome to transverse the trans-Golgi network
.
Virology
458–459
,
93
105
68
Lipovsky
A.
,
Popa
A.
,
Pimienta
G.
,
Wyler
M.
,
Bhan
A.
,
Kuruvilla
L.
et al
(
2013
)
Genome-wide siRNA screen identifies the retromer as a cellular entry factor for human papillomavirus
.
Proc. Natl. Acad. Sci. U.S.A.
110
,
7452
7457
69
Zhang
W.
,
Kazakov
T.
,
Popa
A.
and
DiMaio
D.
(
2014
)
Vesicular trafficking of incoming human papillomavirus 16 to the Golgi apparatus and endoplasmic reticulum requires γ-secretase activity
.
mBio
5
,
e01777
14
70
DiGiuseppe
S.
,
Luszczek
W.
,
Keiffer
T.R.
,
Bienkowska-Haba
M.
,
Guion
L.G.M.
and
Sapp
M.J.
(
2016
)
Incoming human papillomavirus type 16 genome resides in a vesicular compartment throughout mitosis
.
Proc. Natl. Acad. Sci. U.S.A.
113
,
6289
6294
71
Aydin
I.
,
Weber
S.
,
Snijder
B.
,
Samperio Ventayol
P.
,
Kühbacher
A.
,
Becker
M.
et al
(
2014
)
Large scale RNAi reveals the requirement of nuclear envelope breakdown for nuclear import of human papillomaviruses
.
PLoS Pathog.
10
,
e1004162
72
Day
P.M.
,
Baker
C.C.
,
Lowy
D.R.
and
Schiller
J.T.
(
2004
)
Establishment of papillomavirus infection is enhanced by promyelocytic leukemia protein (PML) expression
.
Proc. Natl. Acad. Sci. U.S.A.
101
,
14252
14257
73
Everett
R.D.
(
2013
)
The spatial organization of DNA virus genomes in the nucleus
.
PLoS Pathog.
9
,
e1003386
74
Ozbun
M.A.
(
2002
)
Human papillomavirus type 31b infection of human keratinocytes and the onset of early transcription
.
J. Virol.
76
,
11291
11300
75
Moody
C.A.
and
Laimins
L.A.
(
2010
)
Human papillomavirus oncoproteins: pathways to transformation
.
Nat. Rev. Cancer
10
,
550
560
76
Hegde
R.S.
(
2002
)
The papillomavirus E2 proteins
.
Annu. Rev. Biophys. Biomol. Struct.
31
,
343
360
77
McBride
A.A.
(
2013
)
The papillomavirus E2 proteins
.
Virology
445
,
57
79
78
Sanders
C.M.
and
Stenlund
A.
(
1998
)
Recruitment and loading of the E1 initiator protein: an ATP‐dependent process catalysed by a transcription factor
.
EMBO J.
17
,
7044
7055
79
Sanders
C.M.
and
Stenlund
A.
(
2000
)
Transcription factor-dependent loading of the E1 initiator reveals modular assembly of the papillomavirus origin melting complex
.
J. Biol. Chem.
275
,
3522
3534
80
Maglennon
G.A.
,
McIntosh
P.
and
Doorbar
J.
(
2012
)
Persistence of viral DNA in the epithelial basal layer suggests a model for papillomavirus latency following immune regression
.
Virology
414
,
153
163
81
Dreer
M.
,
van de Poel
S.
and
Stubenrauch
F.
(
2017
)
Control of viral replication and transcription by the papillomavirus E8∧E2 protein
.
Virus Res.
231
,
96
102
82
Iftner
T.
,
Haedicke-Jarboui
J.
,
Wu
S.-Y.
and
Chiang
C.-M.
(
2017
)
Involvement of Brd4 in different steps of the papillomavirus life cycle
.
Virus Res.
231
,
76
82
83
Yu
T.
,
Peng
Y.-C.
and
Androphy
E.J.
(
2007
)
Mitotic kinesin-like protein 2 binds and colocalizes with papillomavirus E2 during mitosis
.
J. Virol.
81
,
1736
1745
84
Parish
J.L.
,
Bean
A.M.
,
Park
R.B.
and
Androphy
E.J.
(
2006
)
ChlR1 Is required for loading papillomavirus E2 onto mitotic chromosomes and viral genome maintenance
.
Mol. Cell
24
,
867
876
85
Donaldson
M.M.
,
Boner
W.
and
Morgan
I.M.
(
2007
)
TopBP1 regulates human papillomavirus type 16 E2 interaction with chromatin
.
J. Virol.
81
,
4338
4342
86
Peh
W.L.
,
Middleton
K.
,
Christensen
N.
,
Nicholls
P.
,
Egawa
K.
,
Sotlar
K.
et al
(
2002
)
Life cycle heterogeneity in animal models of human papillomavirus-associated disease
.
J. Virol.
76
,
10411
10416
87
Westrich
J.A.
,
Warren
C.J.
and
Pyeon
D.
(
2017
)
Evasion of host immune defenses by human papillomavirus
.
Virus Res.
231
,
21
33
88
Smith
J.A.
,
Haberstroh
F.S.
,
White
E.A.
,
Livingston
D.M.
,
DeCaprio
J.A.
and
Howley
P.M.
(
2014
)
SMCX and components of the TIP60 complex contribute to E2 regulation of the HPV E6/E7 promoter
.
Virology
468–470
,
311
321
89
Smith
J.A.
,
White
E.A.
,
Sowa
M.E.
,
Powell
M.L.C.
,
Ottinger
M.
,
Harper
J.W.
et al
(
2010
)
Genome-wide siRNA screen identifies SMCX, EP400, and Brd4 as E2-dependent regulators of human papillomavirus oncogene expression
.
Proc. Natl. Acad. Sci. U.S.A.
107
,
3752
3757
90
Wu
S.-Y.
,
Lee
A.-Y.
,
Hou
S.Y.
,
Kemper
J.K.
,
Erdjument-Bromage
H.
,
Tempst
P.
et al
(
2006
)
Brd4 links chromatin targeting to HPV transcriptional silencing
.
Genes Dev.
20
,
2383
2396
91
Oldak
M.
,
Smola
H.
,
Aumailley
M.
,
Rivero
F.
,
Pfister
H.J.
and
Smola-Hess
S.
(
2004
)
The human papillomavirus type 8 E2 protein supresses beta4-integrin expression in primary human keratinocytes
.
J. Virol.
78
,
10738
10746
92
Vande Pol
S.B.
and
Klingelhutz
A.J.
(
2013
)
Papillomavirus E6 oncoproteins
.
Virology
445
,
115
137
93
Roman
A.
and
Munger
K.
(
2013
)
The papillomavirus E7 proteins
.
Virology
445
,
138
168
94
Beyer-Finkler
E.
,
Stoler
M.H.
,
Girardi
F.
and
Pfister
H.J.
(
1990
)
Cell differentiation-related gene expression of human papillomavirus 33
.
Med. Microbiol. Immunol.
179
,
185
192
95
Stoler
M.H.
,
Rhodes
C.R.
,
Whitbeck
A.
,
Wolinsky
S.M.
,
Chow
L.T.
and
Broker
T.R.
(
1992
)
Human papillomavirus type 16 and 18 gene expression in cervical neoplasia
.
Hum. Pathol.
23
,
117
128
96
Stoler
M.H.
,
Wolinsky
S.M.
,
Whitbeck
A.
,
Broker
T.R.
and
Chow
L.T.
(
1989
)
Differentiation-linked human papillomavirus types 6 and 11 transcription in genital condylomata revealed by in situ hybridisation with message-specific RNA probes
.
Virology
172
,
331
340
97
Middleton
K.
,
Peh
W.
,
Southern
S.A.
,
Griffin
H.M.
,
Sotlar
K.
,
Nakahara
T.
et al
(
2003
)
Organisation of the human papillomavirus productive cycle during neoplastic progression provides a basis for the selection of diagnostic markers
.
J. Virol.
77
,
10186
10201
98
Thomas
J.T.
,
Hubert
W.G.
,
Ruesch
M.N.
and
Laimins
L.A.
(
1999
)
Human papillomavirus type 31 oncoproteins E6 and E7 are required for the maintenance of episomes during the viral life cycle in normal human keratinocytes
.
Proc. Natl. Acad. Sci. U.S.A.
96
,
8449
8454
99
Wang
H.-K.
,
Duffy
A.A.
,
Broker
T.R.
and
Chow
L.T.
(
2009
)
Robust production and passaging of infectious HPV in squamous epithelium of primary human keratinocytes
.
Genes Dev.
23
,
181
194
100
Park
R.B.
and
Androphy
E.J.
(
2002
)
Genetic analysis of high-risk E6 in episomal maintenance of human papillomavirus genomes in primary human keratinocytes
.
J. Virol.
76
,
11359
11364
101
Dyson
N.
,
Howley
P.M.
,
Münger
K.
and
Harlow
E.
(
1989
)
The human papillomavirus -16 E7 oncoprotein is able to bind to the retinoblastoma gene product
.
Science
243
,
934
937
102
Jones
D.L.
,
Alani
R.M.
and
Munger
K.
(
1997
)
The human papillomavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21Cip1-mediated inhibition of cdk2
.
Genes Dev.
11
,
2101
2111
103
Huh
K.
,
Zhou
X.
,
Hayakawa
H.
,
Cho
J.-Y.
,
Libermann
T.A.
,
Jin
J.
et al
(
2007
)
Human papillomavirus type 16 E7 oncoprotein associates with the cullin 2 ubiquitin ligase complex, which contributes to degradation of the retinoblastoma tumor suppressor
.
J. Virol.
81
,
9737
9747
104
Zhang
B.
,
Chen
W.
and
Roman
A.
(
2006
)
The E7 proteins of low- and high-risk human papillomaviruses share the ability to target the pRB family member p130 for degradation
.
Proc. Natl. Acad. Sci. U.S.A.
103
,
437
442
105
Helt
A.-M.
and
Galloway
D.A.
(
2001
)
Destabilization of the retinoblastoma tumor suppressor by human papillomavirus type 16 E7 is not sufficient to overcome cell cycle arrest in human keratinocytes
.
J. Virol.
75
,
6737
6747
106
Hwang
S.G.
,
Lee
D.
,
Kim
J.
,
Seo
T.
and
Choe
J.
(
2002
)
Human papillomavirus type 16 E7 binds to E2F1 and activates E2F1-driven transcription in a retinoblastoma protein-independent manner
.
J. Biol. Chem.
277
,
2923
2930
107
Songock
W.K.
,
Kim
S.-m.
and
Bodily
J.M.
(
2017
)
The human papillomavirus E7 oncoprotein as a regulator of transcription
.
Virus Res.
231
,
56
75
108
Martinez-Zapien
D.
,
Ruiz
F.X.
,
Poirson
J.
,
Mitschler
A.
,
Ramirez
J.
,
Forster
A.
et al
(
2016
)
Structure of the E6/E6AP/p53 complex required for HPV-mediated degradation of p53
.
Nature
529
,
541
545
109
Patel
D.
,
Huang
S.
,
Baglia
L.
and
McCance
D.J.
(
1999
)
The E6 protein of human papillomavirus type 16 binds to and inhibits co-activation by CBP and p300
.
EMBO J.
18
,
5061
5072
110
Zimmermann
H.
,
Degenkolbe
R.
,
Bernard
H.-U.
and
O’Connor
M.J.
(
1999
)
The human papillomavirus type 16 E6 oncoprotein can down-regulate p53 activity by targeting the transcriptional coactivator CBP/p300
.
J. Virol.
73
,
6209
6219
111
Lechner
M.S.
and
Laimins
L.A.
(
1994
)
Inhibition of p53 DNA binding by human papillomavirus E6 proteins
.
J. Virol.
68
,
4262
4273
112
Thomas
M.
,
Massimi
P.
,
Jenkins
J.
and
Banks
L.
(
1995
)
HPV-18 E6 mediated inhibition of p53 DNA binding activity is independent of E6 induced degradation
.
Oncogene
10
,
261
268
113
Mantovani
F.
and
Banks
L.
(
2001
)
The human papillomavirus E6 protein and its contribution to malignant progression
.
Oncogene
20
,
7874
7887
114
White
E.A.
,
Kramer
R.E.
,
Tan
M.J.A.
,
Hayes
S.D.
,
Harper
J.W.
and
Howley
P.M.
(
2012
)
Comprehensive analysis of host cellular interactions with human papillomavirus E6 proteins identifies new E6 binding partners and reflects viral diversity
.
J. Virol.
86
,
13174
13186
115
Howie
H.L.
,
Koop
J.I.
,
Weese
J.
,
Robinson
K.
,
Wipf
G.
,
Kim
L.
et al
(
2011
)
Beta-HPV 5 and 8 E6 promote p300 degradation by blocking AKT/p300 association
.
PLoS Pathog.
7
,
e1002211
116
Brimer
N.
,
Lyons
C.
,
Wallberg
A.E.
and
Vande Pol
S.B.
(
2012
)
Cutaneous papillomavirus E6 oncoproteins associate with MAML1 to repress transactivation and NOTCH signaling
.
Oncogene
31
,
4639
4646
117
Tan
M.J.A.
,
White
E.A.
,
Sowa
M.E.
,
Harper
J.W.
,
Aster
J.C.
and
Howley
P.M.
(
2012
)
Cutaneous β-human papillomavirus E6 proteins bind Mastermind-like coactivators and repress Notch signaling
.
Proc. Natl. Acad. Sci. U.S.A.
109
,
E1473
E1480
118
Boxman
I.L.
,
Mulder
L.H.
,
Noya
F.
,
de Waard
V.
,
Gibbs
S.
,
Broker
T.R.
et al
(
2001
)
Transduction of the E6 and E7 genes of epidermodysplasia-verruciformis-associated human papillomaviruses alters human keratinocyte growth and differentiation in organotypic cultures
.
J. Invest. Dermatol.
117
,
1397
1404
119
Woodworth
C.D.
,
Cheng
S.
,
Simpson
S.
,
Hamacher
L.
,
Chow
L.T.
,
Broker
T.R.
et al
(
1992
)
Recombinant retroviruses encoding human papillomavirus type 18 E6 and E7 genes stimulate proliferation and delay differentiation of human keratinocytes early after infection
.
Oncogene
7
,
619
626
120
Lu
Z.
,
Hu
X.
,
Li
Y.
,
Zheng
L.
,
Zhou
Y.
,
Jiang
H.
et al
(
2004
)
Human papillomavirus 16 E6 oncoprotein interferences with insulin signaling pathway by binding to tuberin
.
J. Biol. Chem.
279
,
35664
35670
121
Tong
X.
and
Howley
P.M.
(
1997
)
The bovine papillomavirus E6 oncoprotein interacts with paxillin and disrupts the actin cytoskeleton
.
Proc. Natl. Acad. Sci. U.S.A.
94
,
4412
4417
122
Thomas
M.
and
Banks
L.
(
1998
)
Inhibition of Bak-induced apoptosis by HPV-18 E6
.
Oncogene
17
,
2943
2954
123
Underbrink
M.P.
,
Howie
H.L.
,
Bedard
K.M.
,
Koop
J.I.
and
Galloway
D.A.
(
2008
)
E6 proteins from multiple human betapapillomavirus types degrade Bak and protect keratinocytes from apoptosis after UVB irradiation
.
J. Virol.
82
,
10408
10417
124
Jackson
S.
,
Harwood
C.
,
Thomas
M.
,
Banks
L.
and
Storey
A.
(
2000
)
Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins
.
Genes Dev.
14
,
3065
3073
125
Leverrier
S.
,
Bergamaschi
D.
,
Ghali
L.
,
Ola
A.
,
Warnes
G.
,
Akgül
B.
et al
(
2007
)
Role of HPV E6 proteins in preventing UVB-induced release of pro-apoptotic factors from the mitochondria
.
Apoptosis
12
,
549
560
126
James
C.
and
Roberts
S.
(
2016
)
Viral interactions with PDZ domain-containing proteins—an oncogenic trait?
Pathogens
,
127
Delury
C.P.
,
Marsh
E.K.
,
James
C.D.
,
Boon
S.S.
,
Banks
L.
,
Knight
G.L.
et al
(
2013
)
The role of protein kinase A regulation of the E6 PDZ-binding domain during the differentiation-dependent life cycle of human papillomavirus type 18
.
J. Virol.
87
,
9463
9472
128
Lee
C.
and
Laimins
L.A.
(
2004
)
Role of the PDZ domain-binding motif of the oncoprotein E6 in the pathogenesis of human papillomavirus type 31
.
J. Virol.
78
,
12366
12377
129
Nicolaides
L.
,
Davy
C.
,
Raj
K.
,
Kranjec
C.
,
Banks
L.
and
Doorbar
J.
(
2011
)
Stabilization of HPV16 E6 protein by PDZ proteins, and potential implications for genome maintenance
.
Virology
414
,
137
145
130
James
M.A.
,
Lee
J.H.
and
Klingelhutz
A.J.
(
2006
)
Human papillomavirus type 16 E6 activates NF-κB, induces cIAP-2 expression, and protects against apoptosis in a PDZ binding motif-dependent manner
.
J. Virol.
80
,
5301
5307
131
Doorslaer
K.
,
DeSalle
R.
,
Einstein
M.H.
and
Burk
R.D.
(
2015
)
Degradation of human PDZ-proteins by human alphapapillomaviruses represents an evolutionary adaptation to a novel cellular niche
.
PLoS Path
11
,
e1004980
132
Ganti
K.
,
Massimi
P.
,
Manzo-Merino
J.
,
Tomaić
V.
,
Pim
D.
,
Playford
M.P.
et al
(
2016
)
Interaction of the human papillomavirus E6 oncoprotein with sorting nexin 27 modulates endocytic cargo transport pathways
.
PLoS Pathog.
12
,
e1005854
133
Ronco
L.V.
,
Karpova
A.Y.
,
Vidal
M.
and
Howley
P.M.
(
1998
)
Human papillomavirus 16 E6 oncoprotein binds to interferon regulatory factor-3 and inhibits its transcriptional activity
.
Genes Dev.
12
,
2061
2072
134
Li
S.
,
Labrecque
S.
,
Gauzzi
M.C.
,
Cuddihy
A.R.
,
Wong
A.H.T.
,
Pellegrini
S.
et al
(
1999
)
The human papillomavirus (HPV)-18 E6 oncoprotein physically associates with Tyk2 and impairs Jak-STAT activation by interferon-alpha
.
Oncogene
18
,
5727
5737
135
Hasan
U.A.
,
Bates
E.
,
Takeshita
F.
,
Biliato
A.
,
Accardi
R.
,
Bouvard
V.
et al
(
2007
)
TLR9 expression and function is abolished by the cervical cancer-associated human papillomavirus type 16
.
J. Immunol.
178
,
3186
3197
136
Pacini
L.
,
Savini
C.
,
Ghittoni
R.
,
Saidj
D.
,
Lamartine
J.
,
Hasan
U.A.
et al
(
2015
)
Downregulation of toll-like receptor 9 expression by beta human papillomavirus 38 and implications for cell cycle control
.
J. Virol.
89
,
11396
11405
137
Reiser
J.
,
Hurst
J.
,
Voges
M.
,
Krauss
P.
,
Münch
P.
,
Iftner
T.
et al
(
2011
)
High-risk human papillomaviruses repress constitutive kappa interferon transcription via E6 to prevent pathogen recognition receptor and antiviral-gene expression
.
J. Virol.
85
,
11372
11380
138
Rincon-Orozco
B.
,
Halec
G.
,
Rosenberger
S.
,
Muschik
D.
,
Nindl
I.
,
Bachmann
A.
et al
(
2009
)
Epigenetic silencing of interferon-κ in human papillomavirus type 16–positive cells
.
Cancer Res.
69
,
8718
8725
139
Niebler
M.
,
Qian
X.
,
Höfler
D.
,
Kogosov
V.
,
Kaewprag
J.
,
Kaufmann
A.M.
et al
(
2013
)
Post-translational control of IL-1β via the human papillomavirus type 16 E6 oncoprotein: A novel mechanism of innate immune escape mediated by the E3-ubiquitin ligase E6-AP and p53
.
PLoS Pathog.
9
,
e1003536
140
Cai
X.
,
Li
G.
,
Laimins
L.A.
and
Cullen
B.R.
(
2006
)
Human papillomavirus genotype 31 does not express detectable microRNA levels during latent or productive virus replication
.
J. Virol.
80
,
10890
10893
141
Wang
X.
,
Wang
H.-K.
,
McCoy
J.P.
,
Banerjee
N.S.
,
Rader
J.S.
,
Broker
T.R.
et al
(
2009
)
Oncogenic HPV infection interrupts the expression of tumor-suppressive miR-34a through viral oncoprotein E6
.
RNA
15
,
637
647
142
Melar-New
M.
and
Laimins
L.A.
(
2010
)
Human papillomaviruses modulate expression of microRNA 203 upon epithelial differentiation to control levels of p63 proteins
.
J. Virol.
84
,
5212
5221
143
Gunasekharan
V.
and
Laimins
L.A.
(
2013
)
Human papillomaviruses modulate microRNA 145 expression to directly control genome amplification
.
J. Virol.
87
,
6037
6043
144
Bodily
J.M.
and
Meyers
C.
(
2005
)
Genetic analysis of the human papillomavirus type 31 differentiation-dependent late promoter
.
J. Virol.
79
,
3309
3321
145
Spink
K.M.
and
Laimins
L.A.
(
2005
)
Induction of the human papillomavirus type 31 late promoter requires differentiation but not DNA amplification
.
J. Virol.
79
,
4918
4926
146
Flores
E.R.
and
Lambert
P.F.
(
1997
)
Evidence for a switch in the mode of human papillomavirus type 16 DNA replication during the viral life cycle
.
J. Virol.
71
,
7167
7179
147
Nakahara
T.
,
Nishimura
A.
,
Tanaka
M.
,
Ueno
T.
,
Ishimoto
A.
and
Sakai
H.
(
2002
)
Modulation of the cell division cycle by human papillomavirus type 18 E4
.
J. Virol.
76
,
10914
10920
148
Wilson
R.
,
Ryan
G.B.
,
Knight
G.L.
,
Laimins
L.A.
and
Roberts
S.
(
2007
)
The full-length E1∧E4 protein of human papillomavirus type 18 modulates differentiation-dependent viral DNA amplification and late gene expression
.
Virology
362
,
453
460
149
Nakahara
T.
,
Peh
W.L.
,
Doorbar
J.
,
Lee
D.
and
Lambert
P.F.
(
2005
)
Human papillomavirus type 16 E1∧E4 contributes to multiple facets of the papillomavirus life cycle
.
J. Virol.
79
,
13150
13165
150
Fang
L.
,
Budgeon
L.R.
,
Doorbar
J.
,
Briggs
E.R.
and
Howett
M.K.
(
2006
)
The human papillomavirus type 11 E1∧E4 protein is not essential for viral genome amplification
.
Virology
351
,
271
279
151
Davy
C.
,
McIntosh
P.
,
Jackson
D.J.
,
Sorathia
R.
,
Miell
M.
,
Wang
Q.
et al
(
2009
)
A novel interaction between the human papillomavirus type 16 E2 and E1∧E4 proteins leads to stabilization of E2
.
Virology
394
,
266
275
152
Davy
C.E.
,
Jackson
D.J.
,
Wang
Q.
,
Raj
K.
,
Masterson
P.J.
,
Fenner
N.F.
et al
(
2002
)
Identification of a G2 arrest domain in the E1∧E4 protein of human papillomavirus type 16
.
J. Virol.
76
,
9806
9818
153
Davy
C.E.
,
Jackson
D.J.
,
Raj
K.
,
Peh
W.L.
,
Southern
S.A.
,
Das
P.
et al
(
2005
)
Human papillomavirus type 16 E1∧E4-induced G2 arrest is associated with cytoplasmic retention of active Cdk1/cyclin B1 complexes
.
J. Virol.
79
,
3998
4011
154
Egawa
N.
,
Wang
Q.
,
Griffin
H.M.
,
Murakami
I.
,
Jackson
D.
,
Mahmood
R.
et al
(
2017
)
HPV16 and 18 genome amplification show different E4-dependence, with 16E4 enhancing E1 nuclear accumulation and replicative efficiency via its cell cycle arrest and kinase activation functions
.
PLoS Pathog.
13
,
e1006282
155
DiMaio
D.
and
Petti
L.M.
(
2013
)
The E5 proteins
.
Virology
445
,
99
114
156
Crusius
K.
,
Auvinen
E.
and
Alonso
A.
(
1997
)
Enhancement of EGF- and PMA-mediated MAP kinase activation in cells expressing the human papillomavirus type 16 E5 protein
.
Oncogene
15
,
1437
1444
157
Fehrmann
F.
,
Klumpp
D.J.
and
Laimins
L.A.
(
2003
)
Human papillomavirus type 31 E5 protein supports cell cycle progression and activates late viral functions upon epithelial differentiation
.
J. Virol.
77
,
2819
2831
158
Genther
S.M.
,
Sterlings
S.
,
Duensing
S.
,
Munger
K.
,
Sattler
C.
and
Lambert
P.F.
(
2003
)
Quantitative role of the human papillomavirus type 16 E5 gene during the productive stage of the viral life cycle
.
J. Virol.
77
,
2832
2842
159
Knight
G.L.
,
Grainger
J.R.
,
Gallimore
P.H.
and
Roberts
S.
(
2004
)
Cooperation between different forms of the human papillomavirus type 1 E4 protein to block cell cycle progression and cellular DNA synthesis
.
J. Virol.
78
,
13920
13933
160
Prescott
E.L.
,
Brimacombe
C.L.
,
Hartley
M.
,
Bell
I.
,
Graham
S.
and
Roberts
S.
(
2014
)
Human papillomavirus type 1 E1∧E4 protein is a potent inhibitor of the serine-arginine (SR) protein kinase SRPK1 and inhibits phosphorylation of host SR proteins and of the viral transcription and replication regulator E2
.
J. Virol.
88
,
12599
12611
161
Doorbar
J.
,
Elston
R.C.
,
Napthine
S.
,
Raj
K.
,
Medcalf
E.
,
Jackson
D.
et al
(
2000
)
The E1∧E4 protein of human papillomavirus type 16 associates with a putative RNA helicase through sequences in its C terminus
.
J. Virol.
74
,
10081
10095
162
Wang
Q.
,
Griffin
H.M.
,
Southern
S.
,
Jackson
D.
,
Martin
A.
,
McIntosh
P.
et al
(
2004
)
Functional analysis of the human papillomavirus type 16E1∧E4 protein provides a mechanism for in vivo and in vitro keratin filament reorganization
.
J. Virol.
78
,
821
833
163
Bryan
J.
and
Brown
D.R.
(
2000
)
Association of the human papillomavirus type 11 E1∧E4 protein with cornified cell envelopes derived from infected genital epithelium
.
Virology
277
,
262
269
164
Doorbar
J.
,
Ely
S.
,
Sterling
J.
,
McLean
C.
and
Crawford
L.
(
1991
)
Specific interaction between HPV16 E1∧E4 and cytokeratins results in collapse of the epithelial cell intermediate filament network
.
Nature
352
,
824
827
165
Ashrafi
G.H.
,
Haghshenas
M.
,
Marchetti
B.
and
Campo
M.S.
(
2006
)
E5 protein of human papillomavirus 16 downregulates HLA class I and interacts with the heavy chain via its first hydrophobic domain
.
Int. J. Cancer
119
,
2105
2112
166
Wetherill
L.F.
,
Holmes
K.K.
,
Verow
M.
,
Müller
M.
,
Howell
G.
,
Harris
M.
et al
(
2012
)
High-risk human papillomavirus E5 oncoprotein displays channel-forming activity sensitive to small-molecule inhibitors
.
J. Virol.
86
,
5341
5351
167
Blackford
A.N.
and
Jackson
S.P.
(
2017
)
ATM, ATR, and DNA-PK: The trinity at the heart of the DNA damage response
.
Mol. Cell
66
,
801
817
168
Anacker
D.C.
and
Moody
C.A.
(
2017
)
Modulation of the DNA damage response during the life cycle of human papillomaviruses
.
Virus Res.
231
,
41
49
169
Moody
C.A.
and
Laimins
L.A.
(
2009
)
Human papillomaviruses activate the ATM DNA damage pathway for viral genome amplification upon differentiation
.
PLoS Pathog.
5
,
e1000605
170
Sakakibara
N.
,
Chen
D.
,
Jang
M.K.
,
Kang
D.W.
,
Luecke
H.F.
,
Wu
S.-Y.
et al
(
2013
)
Brd4 is displaced from HPV replication factories as they expand and amplify viral DNA
.
PLoS Pathog.
9
,
e1003777
171
Banerjee
N.S.
,
Wang
H.-K.
,
Broker
T.R.
and
Chow
L.T.
(
2011
)
Human papillomavirus (HPV) E7 induces prolonged G2 following S phase reentry in differentiated human keratinocytes
.
J. Biol. Chem.
286
,
15473
15482
172
Johnson
B.A.
,
Aloor
H.L.
and
Moody
C.A.
(
2017
)
The Rb binding domain of HPV31 E7 is required to maintain high levels of DNA repair factors in infected cells
.
Virology
500
,
22
34
173
Fradet-Turcotte
A.
,
Bergeron-Labrecque
F.
,
Moody
C.A.
,
Lehoux
M.
,
Laimins
L.A.
and
Archambault
J.
(
2011
)
Nuclear accumulation of the papillomavirus E1 helicase blocks S-phase progression and triggers an ATM-dependent DNA damage response
.
J. Virol.
85
,
8996
9012
174
Reinson
T.
,
Toots
M.
,
Kadaja
M.
,
Pipitch
R.
,
Allik
M.
and
Ustav
E.
(
2013
)
Engagement of the ATR-dependent DNA damage response at the human papillomavirus 18 replication centers during the initial amplification
.
J. Virol.
87
,
951
964
175
Sakakibara
N.
,
Mitra
R.
and
McBride
A.A.
(
2011
)
The papillomavirus E1 helicase activates a cellular DNA damage response in viral replication foci
.
J. Virol.
85
,
8981
8995
176
Stanley
M.A.
(
2012
)
Epithelial cell responses to infection with human papillomavirus
.
Clin. Microbiol. Rev.
25
,
215
222
177
Johansson
C.
and
Schwartz
S.
(
2013
)
Regulation of human papillomavirus gene expression by splicing and polyadenylation
.
Nat. Rev. Microbiol.
11
,
239
251
178
Cumming
S.A.
,
Chuen-Im
T.
,
Zhang
J.
and
Graham
S.V.
(
2009
)
The RNA stability regulator HuR regulates L1 protein expression in vivo in differentiating cervical epithelial cells
.
Virology
383
,
142
149
179
Chuen-Im
T.
,
Zhang
J.
,
Milligan
S.G.
,
McPhillips
M.G.
and
Graham
S.V.
(
2008
)
The alternative splicing factor hnRNP A1 is up-regulated during virus-infected epithelial cell differentiation and binds the human papillomavirus type 16 late regulatory element
.
Virus Res.
131
,
189
198
180
McPhillips
M.G.
,
Veerapraditsin
T.
,
Cumming
S.A.
,
Karali
D.
,
Milligan
S.G.
,
Boner
W.
et al
(
2004
)
SF2/ASF binds the human papillomavirus type 16 late RNA control element and is regulated during epithelial differentiation
.
J. Virol.
78
,
10598
10605
181
Cumming
S.A.
,
McPhillips
M.G.
,
Veerapraditsin
T.
,
Milligan
S.G.
and
Graham
S.V.
(
2003
)
Activity of the human papillomavirus type 16 late negative regulatory element is partly due to four weak consensus 5΄ splice sites that bind a U1 snRNP-like complex
.
J. Virol.
77
,
5167
5177
182
Fay
J.
,
Kelehan
P.
,
Lambkin
H.
and
Schwartz
S.
(
2009
)
Increased expression of cellular RNA-binding proteins in HPV-induced neoplasia and cervical cancer
.
J. Med. Virol.
81
,
897
907
183
Becker
K.A.
,
Florin
L.
,
Sapp
C.
and
Sapp
M.
(
2003
)
Dissection of human papillomavirus type 33 L2 domains involved in nuclear domains (ND) 10 homing and reorganization
.
Virology
314
,
161
167
184
Nelson
L.M.
,
Rose
R.C.
and
Moroianu
J.
(
2002
)
Nuclear import strategies of high risk HPV16 L1 major capsid protein
.
J. Biol. Chem.
277
,
23958
23964
185
Day
P.M.
,
Roden
R.B.S.
,
Lowy
D.R.
and
Schiller
J.T.
(
1998
)
The papillomavirus minor capsid protein, L2, induces localisation of the major capsid protein, L1, and the viral transcription/replication protein, E2, to PML oncogenic domains
.
J. Virol.
72
,
142
150
186
Florin
L.
,
Sapp
C.
,
Streeck
R.E.
and
Sapp
M.
(
2002
)
Assembly and translocation of papillomavirus capsid proteins
.
J. Virol.
76
,
10009
10014
187
Buck
C.B.
,
Thompson
C.D.
,
Pang
Y.-Y.S.
,
Lowy
D.R.
and
Schiller
J.T.
(
2005
)
Maturation of papillomavirus capsids
.
J. Virol.
79
,
2839
2846
188
Stauffer
Y.
,
Raj
K.
,
Masternak
K.
and
Beard
P.
(
1998
)
Infectious human papillomavirus type 18 pseudovirions
.
J. Mol. Biol.
283
,
529
536
189
Schmitt
M.
,
Dalstein
V.
,
Waterboer
T.
,
Clavel
C.
,
Gissmann
L.
and
Pawlita
M.
(
2011
)
The HPV16 transcriptome in cervical lesions of different grades
.
Mol. Cell. Probes
25
,
260
265
190
Yuan
C.-H.
,
Filippova
M.
and
Duerksen-Hughes
P.
(
2012
)
Modulation of apoptotic pathways by human papillomaviruses (HPV): mechanisms and implications for therapy
.
Viruses
4
,
3831
191
Wongworawat
Y.
,
Filippova
M.
,
Williams
V.M.
,
Filippov
V.
and
Duerksen-Hughes
P.J.
(
2016
)
Chronic oxidative stress increases the integration frequency of foreign DNA and human papillomavirus 16 in human keratinocytes
.
Am. J. Cancer Res.
6
,
764
780
192
Okoye
A.
,
Cordano
P.
,
Taylor
E.R.
,
Morgan
I.M.
,
Everett
R.
and
Campo
M.S.
(
2005
)
Human papillomavirus 16 L2 inhibits the transcriptional activation function, but not the DNA replication function, of HPV-16 E2
.
Virus Res.
108
,
1
14
193
Gammoh
N.
,
Grm
H.S.
,
Massimi
P.
and
Banks
L.
(
2006
)
Regulation of human papillomavirus type 16 E7 activity through direct protein interaction with the E2 transcriptional activator
.
J. Virol.
80
,
1787
1797
194
Smal
C.
,
Wetzler
D.E.
,
Dantur
K.I.
,
Chemes
L.B.
,
Garcia-Alai
M.M.
,
Dellarole
M.
et al
(
2009
)
The human papillomavirus E7−E2 interaction mechanism in vitro reveals a finely tuned system for modulating available E7 and E2 proteins
.
Biochemistry
48
,
11939
11949
195
Grm
H.S.
,
Massimi
P.
,
Gammoh
N.
and
Banks
L.
(
2005
)
Crosstalk between the human papillomavirus E2 transcriptional activator and the E6 oncoprotein
.
Oncogene
24
,
5149
5164
196
Hellberg
D.
(
2012
)
Sex steroids and cervical cancer
.
Anticancer Res.
32
,
3045
3054
197
Zhu
H.
,
Shen
Z.
,
Luo
H.
,
Zhang
W.
and
Zhu
X.
(
2016
)
Chlamydia trachomatis infection-associated risk of cervical cancer: a meta-analysis
.
Medicine (Baltimore)
95
,
e3077
198
Guidry
J.T.
and
Scott
R.S.
(
2017
)
The interaction between human papillomavirus and other viruses
.
Virus Res.
231
,
139
147
199
Kyrgiou
M.
,
Mitra
A.
and
Moscicki
A.-B.
(
2017
)
Does the vaginal microbiota play a role in the development of cervical cancer?
Transl. Res.
179
,
168
182
200
Groves
I.J.
and
Coleman
N.
(
2015
)
Pathogenesis of human papillomavirus-associated mucosal disease
.
J. Pathol.
235
,
527
538
201
Pett
M.
and
Coleman
N.
(
2007
)
Integration of high-risk human papillomvirus: a key event in cervical carcinogenesis?
J. Pathol.
212
,
356
367
202
Goodwin
E.C.
,
Naeger
L.K.
,
Breiding
D.E.
,
Androphy
E.J.
and
DiMaio
D.
(
1998
)
Transactivation-competent bovine papillomavirus E2 protein is specifically required for efficient repression of human papillomavirus oncogene expression and for acute growth inhibition of cervical carcinoma cell lines
.
J. Virol.
72
,
3925
3934
203
Francis
D.A.
,
Schmid
S.I.
and
Howley
P.M.
(
2000
)
Repression of the integrated papillomavirus E6/E7 promoter is required for growth suppression of cervical cancer cells
.
J. Virol.
74
,
2679
2686
204
Dooley
K.E.
,
Warburton
A.
and
McBride
A.A.
(
2016
)
Tandemly integrated HPV16 can form a Brd4-dependent super-enhancer-like element that drives transcription of viral oncogenes
.
mBio
7
,
e01446
16
205
Jeon
S.
and
Lambert
P.F.
(
1995
)
Integration of human papillomavirus type 16 DNA into the human genome leads to increased stability of E6 and E7 mRNAs: implications for cervical carcinogenesis
.
Proc. Natl. Acad. Sci. U.S.A.
92
,
1654
1658
206
Kyo
S.
,
Klumpp
D.J.
,
Inoue
M.
,
Kanaya
T.
and
Laimins
L.A.
(
1997
)
Expression of AP1 during cellular differentiation determines human papillomavirus E6/E7 expression in stratified epithelial cells
.
J. Gen. Virol.
78
,
401
411
207
Scarpini
C.G.
,
Groves
I.J.
,
Pett
M.R.
,
Ward
D.
and
Coleman
N.
(
2014
)
Virus transcript levels and cell growth rates after naturally occurring HPV16 integration events in basal cervical keratinocytes
.
J. Pathol.
233
,
281
293
208
Jang
M.K.
,
Shen
K.
and
McBride
A.A.
(
2014
)
Papillomavirus genomes associate with Brd4 to replicate at fragile sites in the host genome
.
PLoS Pathog.
10
,
e1004117
209
Howie
H.L.
,
Katzenellenbogen
R.A.
and
Galloway
D.A.
(
2009
)
Papillomavirus E6 proteins
.
Virology
384
,
324
334
210
Iftner
T.
,
Elbel
M.
,
Schopp
B.
,
Hiller
T.
,
Loizou
J.I.
,
Caldecott
K.W.
et al
(
2002
)
Interference of papillomavirus E6 protein with single‐strand break repair by interaction with XRCC1
.
EMBO J.
21
,
4741
4748
211
Korzeniewski
N.
,
Spardy
N.
,
Duensing
A.
and
Duensing
S.
(
2011
)
Genomic instability and cancer: Lessons learned from human papillomaviruses
.
Cancer Lett.
305
,
113
122
212
Nguyen
C.L.
and
Münger
K.
(
2009
)
Human papillomavirus E7 protein deregulates mitosis via an association with nuclear mitotic apparatus protein 1
.
J. Virol.
83
,
1700
1707
213
Nguyen
C.L.
,
Eichwald
C.
,
Nibert
M.L.
and
Münger
K.
(
2007
)
Human papillomavirus type 16 E7 oncoprotein associates with the centrosomal component γ-tubulin
.
J. Virol.
81
,
13533
13543
214
Nguyen
C.L.
,
McLaughlin-Drubin
M.E.
and
Münger
K.
(
2008
)
Delocalization of the microtubule motor dynein from mitotic spindles by the human papillomavirus E7 oncoprotein is not sufficient for induction of multipolar mitoses
.
Cancer Res.
68
,
8715
8722
215
Duensing
S.
,
Duensing
A.
,
Crum
C.P.
and
Münger
K.
(
2001
)
Human papillomavirus type 16 E7 oncoprotein-induced abnormal centrosome synthesis is an early event in the evolving malignant phenotype
.
Cancer Res.
61
,
2356
2360
216
Patel
D.
and
McCance
D.J.
(
2010
)
Compromised spindle assembly checkpoint due to altered expression of Ubch10 and Cdc20 in human papillomavirus type 16 E6- and E7-expressing keratinocytes
.
J. Virol.
84
,
10956
10964
217
Nakagawa
S.
and
Huibregtse
J.M.
(
2000
)
Human scribble (Vartul) is targeted for ubiquitin-mediated degradation by the high-risk papillomavirus E6 proteins and the E6AP ubiquitin-protein ligase
.
Mol. Cell. Biol.
20
,
8244
8253
218
Javier
R.T.
(
2008
)
Cell polarity proteins: common targets for tumorigenic human viruses
.
Oncogene
27
,
7031
7046
219
MacDonald
A.I.
,
Sun
P.
,
Hernandez-Lopez
H.
,
Aasen
T.
,
Hodgins
M.B.
,
Edward
M.
et al
(
2012
)
A functional interaction between the MAGUK protein hDlg and the gap junction protein connexin 43 in cervical tumour cells
.
Biochem. J.
446
,
9
21
220
Sun
P.
,
Dong
L.
,
MacDonald
A.
,
Akbari
S.
,
Edward
M.
,
Hodgins
M.
et al
(
2015
)
HPV16 E6 controls the gap junction protein Cx43 in cervical tumour cells
.
Viruses
7
,
2871
221
Glausinger
B.A.
,
Lee
S.S.
,
Thomas
M.
,
Banks
L.
and
Javier
R.T.
(
2000
)
Interactions of the PDZ-protein MAGI-1 with adenovirus E4-ORF1 and high-risk papillomavirus E6 oncoproteins
.
Oncogene
19
,
5270
5280
222
Thomas
M.
,
Glausinger
B.
,
Pim
D.
,
Javier
R.
and
Banks
L.
(
2001
)
HPV E6 and MAGUK protein interactions: determination of the molecular basis for specific protein recognition and degradation
.
Oncogene
20
,
5431
5439
223
McLaughlin-Drubin
M.E.
,
Huh
K.-W.
and
Münger
K.
(
2008
)
Human papillomavirus type 16 E7 oncoprotein associates with E2F6
.
J. Virol.
82
,
8695
8705
224
Huh
K.-W.
,
DeMasi
J.
,
Ogawa
H.
,
Nakatani
Y.
,
Howley
P.M.
and
Münger
K.
(
2005
)
Association of the human papillomavirus type 16 E7 oncoprotein with the 600-kDa retinoblastoma protein-associated factor, p600
.
Proc. Natl. Acad. Sci. U.S.A.
102
,
11492
11497
225
Stöppler
H.
,
Hartmann
D.-P.
,
Sherman
L.
and
Schlegel
R.
(
1997
)
The human papillomavirus type 16 E6 and E7 oncoproteins dissociate cellular telomerase activity from the maintenance of telomere length
.
J. Biol. Chem.
272
,
13332
13337
226
Zheng
Z.-M.
and
Wang
X.
(
2011
)
Regulation of cellular miRNA expression by human papillomaviruses
.
Biochim. Biophys. Acta
1809
,
668
677
227
Suprynowicz
F.A.
,
Campo
M.S.
and
Schlegel
R.
(
2006
)
Biological activities of papillomvirus E5 proteins
. In
Papillomavirus Research: from Natural History to Vaccines and Beyond
(
Campo
M.S.
, ed.), pp.
97
114
,
Caister Academic Press
,
Norfolk, England
228
Bouvard
V.
,
Matlashewski
G.
,
Gu
Z.-M.
,
Storey
A.
and
Banks
L.
(
1994
)
The human papillomavirus type 16 E5 gene cooperates with the E7 gene to stimulate proliferation of primary cells and increases viral gene expression
.
Virology
203
,
73
80
229
Valle
G.F.
and
Banks
L.
(
1995
)
The human papillomavirus (HPV)-6 and HPV-16 E5 proteins co-operate with HPV-16 E7 in the transformation of primary rodent fibroblasts
.
J. Gen. Virol.
76
,
1239
1245
230
Stöppler
M.C.
,
Straight
S.W.
,
Tsao
G.
,
Schlegel
R.
and
McCance
D.J.
(
1996
)
The E5 gene of HPV-16 enhances keratinocyte immortalization by full-length DNA
.
Virology
223
,
251
254
231
Conrad
M.
,
Bubb
V.J.
and
Schlegel
R.
(
1993
)
The human papillomavirus type 6 and 16 E5 proteins are membrane-associated proteins which associate with the 16-kilodalton pore-forming protein
.
J. Virol.
67
,
6170
6178
232
Schapiro
F.
,
Sparkowski
J.
,
Adduci
A.
,
Suprynowicz
F.
,
Schlegel
R.
and
Grinstein
S.
(
2000
)
Golgi alkalinization by the papillomavirus E5 oncoprotein
.
J. Cell Biol.
148
,
305
316
233
Straight
S.W.
,
Herman
B.
and
McCance
D.J.
(
1995
)
The E5 oncoprotein of human papillomavirus type 16 inhibits the acidification of endosomes in human keratinocytes
.
J. Virol.
69
,
3185
3192
234
Belleudi
F.
,
Leone
L.
,
Purpura
V.
,
Cannella
F.
,
Scrofani
C.
and
Torrisi
M.R.
(
2011
)
HPV16 E5 affects the KGFR/FGFR2b-mediated epithelial growth through alteration of the receptor expression, signaling and endocytic traffic
.
Oncogene
30
,
4963
4976
235
Barbaresi
S.
,
Cortese
M.S.
,
Quinn
J.
,
Ashrafi
G.H.
,
Graham
S.V.
and
Campo
M.S.
(
2010
)
Effects of human papillomavirus type 16 E5 deletion mutants on epithelial morphology: functional characterization of each transmembrane domain
.
J. Gen. Virol.
91
,
521
530
236
Genther Williams
S.M.
,
Disbrow
G.L.
,
Schlegel
R.
,
Lee
D.
,
Threadgill
D.W.
and
Lambert
P.F.
(
2005
)
Requirement of epidermal growth factor receptor for hyperplasia induced by E5, a high-risk human papillomavirus oncogene
.
Cancer Res.
65
,
6534
6542
237
Maufort
J.P.
,
Genther Williams
S.M.
,
Pitot
H.C.
and
Lambert
P.F.
(
2007
)
Human papillomavirus 16 E5 oncogene contributes to two stages of skin carcinogenesis
.
Cancer Res.
67
,
6106
6112
238
Crusius
K.
,
Auvinen
E.
,
Steuer
B.
,
Gaissert
H.
and
Alonso
A.
(
1998
)
The human papillomavirus type 16 E5-protein modulates ligand-dependent activation of the EGF receptor family in the human epithelial cell line HaCaT
.
Exp. Cell Res.
241
,
76
83
This is an open access article published by Portland Press Limited on behalf of the Biochemical Society and distributed under the Creative Commons Attribution License 4.0 (CC BY).