Hpv virus diagram

There are over HPVs classified to date [ 1 , 2 ]. Therefore, HPVs are categorized into genotypes. This group contains 64 HPVs that mainly infect mucosal epithelia. 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 ]. 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 ].

Nowadays, over women die from cervical cancer per annum worldwide with over 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 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 ]. 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. 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.

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. 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. 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. 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.

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 ].

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. HPV infection of the oropharynx is thought to be due to changes in oral sexual practices [ 33 ]. HPV has been detected at highest levels in cancers of the tonsil, tongue base, and pharynx Table 1 [ 34 ]. 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 ]. 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 ].

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 majority of such cancers occur in immunosuppressed individuals and in patients with the inherited recessive genetic disorder EV epidermodysplasia verruciformis [ 41 , 42 ].

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 ]. 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 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 2 B [ 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 copies of the L1 protein organized into 72 pentameric capsomeres that probably have one copy of L2 at the center [ 46 ].

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. 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. 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 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 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 [ 66 — 68 ], 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 ].

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. Upon nuclear entry into the dividing cells of the basal layer or ectocervix viral early transcription is initiated. This makes sense because the first goal of the incoming virus is to carry out initial replication of its genome. Moreover, early expression of the viral transcription factor E2 would allow correct regulation of the viral early promoter to direct expression of the E6 and E7 regulatory proteins that ensure continued survival of HPV-infected cells [ 75 ].

E2 possesses one DNA-binding and one protein-binding domain linked by a flexible hinge region [ 76 ]. Three of these sites are located adjacent to the origin of replication and are required for E1-activated viral replication [ 77 ].

E2 binds E1, which then binds as a dimer of hexamers to the viral origin of replication and recruits the cellular DNA replication machinery [ 78 , 79 ].

Initial replication of an incoming HPV genome generates approximately 50— episomal copies per nucleus [ 80 ]. This constitutes the first phase of viral DNA replication and genome maintenance.

In infected basal cells, circular viral genomes are replicated in concert with replication of cellular DNA and equally partitioned into daughter cells through tethering of virus genomes to host cell chromosomes via E2 bound to the viral LCR and chromatin-binding proteins [ 77 ]. Brd4, via E2, is the most studied anchor for HPV genomes to cellular chromosomes [ 82 ].

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

In this way, HPV is capable of maintaining infection of epithelial cells over a significant period of time. Division of an infected basal epithelial cell can produce a transit amplifying cell that is capable of differentiating and moving into the upper epithelial layers [ 91 ].

These cells carry the viral genomes with them as they move through the upper epithelial layers. HPV has evolved to carry out its replication cycle in exquisite concert with epithelial differentiation and an orchestrated program of viral gene expression is carried out during epithelial differentiation Figure 3 [ 20 ]. These include the E6 and E7 viral oncoproteins [ 92 , 93 ].

Despite their designation as oncoproteins, their expression is essential for the normal replicative HPV life cycle. Early in situ hybridization studies indicated increased levels of the mRNA encoding these proteins in the lower to mid-upper epithelial layers [ 94 — 96 ].

However, expression of biomarkers that respond to E6 and E7 was found to decrease in the upper epithelial layers [ 97 ]. Therefore, biological activity of these proteins may be most important in the early phase of viral replication in basal epithelial cells. For example, E6 has been shown to be required for episomal genome maintenance [ 98 — ]. E7 expression, early in infection, activates the G 1 to S-phase checkpoint in keratinocytes that would normally undergo terminal differentiation, thus expanding the compartment of epithelial cells active in DNA replication [ 93 ].

This is an important step to accomplish the second, productive, phase of viral genome replication in cells of the mid to upper epithelial layers that would normally exit the cell cycle.

E7 activates the cell cycle of infected, differentiating cells by binding and releasing, or degrading, pRb and other pocket proteins, p and p, from a transcriptional repression complex containing the E2F transcription factor [ — ]. E2F becomes free to activate transcription of a number of cell cycle-related genes such as cyclins A and E, thus stimulating G 1 to S-phase transition [ 75 ].

E7 can also interact with and abrogate E2F inhibitory transcription complex activity leading to stimulation of promoter activity of growth control genes [ ].

This suggests the potential of E7 to make very significant transcriptional changes in infected cells. However, the expression level of the protein, and where it is expressed in the different layers of the infected epithelium, will have some impact on these activities. Therefore, activities of either protein will be affected by the other and it is clear that they often act co-operatively, for example in avoiding immune detection [ 87 ]. Normally, cells respond to any unscheduled cell proliferation event by inducing apoptosis.

Therefore, HPV E7 activity might be expected to induce cell death. To avoid this, HR-HPVs express the E6 protein, which binds the ubiquitin ligase, E6AP E6-associated protein and p53, a key regulator of apoptosis and targets it for degradation [ 75 , ].

E6 proteins can also cause a conformation change in p53 through binding. This inhibits its transcriptional transactivation properties [ , ].

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

HPV16 E6 has been shown to bind to, but not degrade, paxillin, a protein that plays essential roles in the structural organization of the cell [ ].

It is possible that this interaction could result in restructuring the infected cells to facilitate viral egress. Bak has been found to be most active in the upper layers of the skin where HPV replication occurs [ ]. It is thought that in uninfected cells, E6AP regulates the levels of Bak. This prevents Bak-mediated permeabilization of the mitochondrial and ER membranes, therefore avoiding the activation of the caspase cascade and apoptosis.

Therefore, this is another route to inhibition of apoptosis and it has been proposed that this pathway specifically links to the DNA damage response [ , ]. PDZ domain-containing proteins can bind to and stabilize low levels of E6 expressed during an infection leading to enhanced episome maintenance [ ]. The fact that this E6 motif is missing in low risk E6 proteins suggests that it may be associated with tumor-promoting properties of the HR-HPVs [ ].

The E6 PBM also allows a regulatory interaction with SNX27 sorting nexin 27 , a protein that controls endosomal transport, nutrient acquisition, and cell proliferation [ ]. E6 control of these pathways via SNX27 could have importance in keratinocyte metabolism during viral infection. E7 control of miR has been shown to be important for viral genome amplification. In fact, E6 and E7 control of many cellular transcription factors has the potential to alter expression of many RNA polymerase II-transcribed miRNAs that could be involved in the viral replication cycle.

Importantly, miRNAs can modulate viral gene expression. The subsequent loss of these viral replication factors results in a reduction in viral genome amplification and late gene expression [ ]. The late phase of the viral life cycle involves vegetative viral DNA replication and subsequently, virion formation.

Increased expression of the viral E1 and E2 proteins is required to accomplish this phase. The late stage of the life cycle is marked by activation due to changes in cell signaling of the viral major late promoter HPV P; HPV P that is situated in the E7 gene region Figures 2 A and 4 A [ , ].

This results in increased expression, not only of E1 and E2, but also of E4 and E5 [ 13 ]. Late stage DNA replication, probably using a rolling circle mechanism, yields many thousands of progeny viral genomes [ ].

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

A Linear diagram of the HPV16 genome showing the eight ORFs colored boxes the three characterized promoters forward facing arrows and the early and late polyadenylation sites thick black vertical lines. Green colored boxes indicate the E6 and E7 coding regions. Blue colored boxes represent the L1 and L2 capsid encoding genes. This leads to overexpression from the P97 promoter of the viral oncoproteins.

This can cause increased stability in the E6 E7 bicistronic mRNA leading to increased expression levels of the oncoproteins. Integration may also cause insertional mutagenesis of the host gene, which could have oncogenic effects. It also spreads through close skin-to-skin touching during sex.

A person with HPV can pass the infection to someone even when they have no signs or symptoms. If you are sexually active, you can get HPV, even if you have had sex with only one person.

You also can develop symptoms years after having sex with someone who has the infection. This makes it hard to know when you first got it. In most cases 9 out of 10 , HPV goes away on its own within two years without health problems. But when HPV does not go away, it can cause health problems like genital warts and cancer. Genital warts usually appear as a small bump or group of bumps in the genital area. They can be small or large, raised or flat, or shaped like a cauliflower.

A healthcare provider can usually diagnose warts by looking at the genital area. HPV can cause cervical and other cancers , including cancer of the vulva, vagina, penis, or anus. It can also cause cancer in the back of the throat called oropharyngeal cancer. This can include the base of the tongue and tonsils. Cancer often takes years, even decades, to develop after a person gets HPV.

Genital warts and cancers result from different types of HPV. There is no way to know who will develop cancer or other health problems from HPV. They may also be more likely to develop health problems from HPV.

Get vaccinated. The HPV vaccine is safe and effective. It can protect against diseases including cancers caused by HPV when given in the recommended age groups. Get screened for cervical cancer. Routine screening for women aged 21 to 65 years old can prevent cervical cancer. 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. Keywords: cervical cancer; epithelial differentiation; human papillomavirus; infection; tumour progression. Abstract HPVs human papillomaviruses infect epithelial cells and their replication cycle is intimately linked to epithelial differentiation.