Investing papilloma classification of animals
Alternatively its replication is limited and continuously controlled by the remaining subsets of the immune system. In this model a major epitope for mE6 was defined as residues 90—99, while a weaker mE7 epitope was mapped to residues 69—77 Fig 5 and S5 Fig. However, no mE7 response was detected Fig 5C suggesting that the E6 response is dominant.
Interestingly, our results are analogous to other findings that papillomavirus E6 being the dominant antigen in natural host responses in different species such as rabbits and humans [ 49 , 50 ]. Indeed several studies in animals and patients have suggested that E1 and E2 are potential rejection antigens [ 51 ].
Taken together, our results suggest that it may be beneficial to vaccinate against more than a single viral antigen to elicit therapeutic responses in a greater proportion of patients, but responses to a single epitope can dominate. This supports their capacity to find, infiltrate, proliferate and control disease, although low levels of virus remained detectable in certain areas of the tail sections at 10 weeks after treatment of mice with a high disease burden Fig 7C.
It is not clear if with further time, these viral reservoirs would have been eliminated. These observations Figs 6D and 7E suggest that that neither mucosal vaccination nor local application of adjuvant is required for effective homing, although they might be beneficial. Of relevance to clinical trial design, our therapeutic investigations using MusPV1 show that a substantial length of time is required to clear established papilloma and that even following lesion regression, viral reservoirs may remain Fig 7A—7C.
Consistent with the notion that greater disease burden is associated with a poorer outcome of immunotherapy, the therapeutic response was more effective against persistent infection in the absence of established disease Fig 6. Given the increasing use of HPV testing for screening, our results suggest the potential for therapeutic vaccination against persistent infection to prevent the onset of high grade neoplasia.
This is consistent with our adoptive T cell study to treat MusPV1-associated papillomas, although this approach is not appropriate for the treatment of premalignant disease in patients. Our studies were consistent with others showing common inbred strains of mice fully control MusPV1 infection [ 31 , 32 ]. However, for the first time, we show that challenge of the outbred SKH-1 mouse strain leads to the diverse outcomes, as seen in HPV-infected patients Fig 1 ; a subset of the outbred SKH-1 mice appear genetically susceptible and will develop persistent infections, whereas the remainder will clear their infections in time or do not develop clinically-apparent lesions.
An understanding of the genetic factors in mice driving these different outcomes might be applied to identify those patients who will clear an HPV infection without intervention, and those needing active treatment. Furthermore, while challenge of inbred mice with syngeneic tumor models, e.
TC-1 and C3, provides critical mechanistic information, studies in outbred SKH-1 mice with MusPV1 may exhibit a range of clinical outcomes that could be more predictive of clinical studies of vaccines and other immunologic interventions. The tractability of mouse genetics will greatly facilitate further mechanistic analyses. All plasmid constructs were confirmed by DNA sequencing. Primers were assessed for specificity and sensitivity S3 Fig.
Tissues were disrupted using a frozen mortar and pestle and homogenized with QIAshredders Qiagen. Triplicate reactions were performed for each primer-probe set. Production of MusPV1 Virions and Experimental Challenge Generation of infectious mouse papilloma virions and propagation of the virus using nude mice were performed as described in [ 53 ].
Briefly, formalin-fixed, paraffin-embedded tissues sections FFPE mouse tail sections were pretreated with heat and protease prior to hybridization with probe. To ensure RNA integrity and assay procedure, adjacent sections were also hybridized with a probe to the endogenous housekeeping gene ubiquitin. After washing, an HRP-based amplification system was then used to detect the target probes followed by color development with DAB.
Briefly, FFPE sections were deparaffinized in xylene, followed by dehydration in graded ethanol. Endogenous peroxidase was blocked, by treatment of slides with Dual Endogenous Enzyme-Blocking Reagent Dako for 5 min at room temperature. These 20mers were then pooled into libraries of 5 peptides covering for E6 amino acids 1—40, 25—65, 50—90, 75— and —, and for E7 1—40, 25—65, 50—90, and 75— Subsequently, a pair of electrode needles was inserted into the muscle area surrounding the DNA injection site.
After 48 h, these cells were incubated with splenocytes from either vaccinated or infected mice in the presence of Golgi plug for 12 h, and then collected for cell staining and flow cytometry analysis. The cells were collected for cell staining and flow cytometry analysis.
Upon nuclear entry, viral DNA replication is initiated by the binding of E2 on specific sites located on the LCR, which is required for the recruitment and binding of E1 helicase to the viral origin of replication After this initial step, which aimed to generate a low copy number of genomes, the maintenance phase is initiated Figure 3 [reviewed in ].
This phase consists of creating the conditions to maintain a constant number of viral genomes in the nuclei of undifferentiated basal cells as an extrachromosomal genome to create a persistent infection. The transactivation domain at the N-terminal part of E2, with the bromodomain protein Brd4, interacts with the host mitotic chromosomes. Brd4 interacts with the E2 transactivation domain of most PVs Life cycle of HPV. After this initial step, the maintenance phase is initiated.
Upon cell differentiation in stratified epithelium, vegetative or productive viral replication is initiated, with the subsequent production of progeny virions. Here, the oncoproteins E6 and E7 expressed at relatively low levels in differentiated cells play a key role by inactivating tumor suppressor proteins.
The activation in differentiated epithelial cells of the late promoter, located in the E7 region, leads to the production of the high levels of E1 and E2 viral proteins required to ensure viral DNA replication. E4 and E5 contribute to efficient productive replication.
The capsid proteins L1 and L2 are expressed from the late promoter, and are involved in the encapsidation of newly replicated genomes, resulting in virion release in the superficial layers during desquamation. E4 also plays a role at this step of the viral life cycle, by interacting with the keratin network.
The right side of the schematic representation illustrates that a minority of HPV infections become persistent, thus increasing the risk of keratinocyte transformation, through integration of viral DNA into the human genome, which leads to the loss of E2 repression function and subsequent E6 and E7 upregulation.
Upon cell differentiation in stratified epithelium, vegetative or productive viral replication is initiated, with the subsequent production of progeny virions , , [reviewed in ] Figure 3. Uninfected cells leave the basal layer for terminal differentiation, are withdrawn from the cell cycle, and stop the replication of the DNA.
Because the amplification of the viral genome requires cellular conditions that enable cell proliferation and thus DNA replication, the virus has developed strategies to prevent cell-cycle arrest and apoptosis signals. Here, the oncoproteins E6 and E7 expressed at relatively low levels in differentiated cells play a key role by inactivating tumor suppressor proteins e.
E4 and E5 contribute to efficient productive replication , The capsid proteins L1 and L2 are expressed from the late promoter, and are involved in the encapsidation of newly replicated genomes, resulting in virion release in the superficial layers during desquamation Figure 3. E4 also plays a role at this step of the viral life cycle, by interacting with the keratin network A more complete description of the function of each of the viral proteins is provided in Table 1.
Main features and functions of the early and late gene products from alpha and beta HPV types. Epigenetic regulation of HPV transcription plays an important role in the virus life cycle. HPV regulatory epigenetic mechanisms have recently been partly elucidated by Pentland et al. This event leads to attenuated expression of oncoproteins in undifferentiated cells. This is coherent with reduced recruitment of polycomb repressor complex 2 PCR2 , enrichment of RNA pol II binding, and a consequent increase in the transcriptional activity of the viral early promoter.
Pentland et al. During cell differentiation, a drop in YY1 expression levels leads to loss of chromatin loop formation and to increased expression of the oncoproteins consecutive to epigenetic depression of the viral genome Transforming Activities of PVs Studies performed on mucosal HR HPV types, such as HPV16 and 18, showed that both oncoproteins E6 and E7 play a key role in cervical cancer by altering pathways involved in the host immune response to establish a persistent infection and promote cellular transformation.
The E6 amino acids and E7 amino acids oncoproteins play a central role in carcinogenesis by interacting with a large number of cellular proteins involved in key cellular events, such as the cell cycle and apoptosis control. Continuous expression of the E6 and E7 oncoproteins is essential to initiate and to maintain the cellular transformation process. Indeed, the use of different strategies to inhibit the function of E6 and E7 in HPV-positive cancer cells resulted in cell growth arrest by apoptosis or senescence , The main targets of the E6 and E7 oncoproteins are p53 and pRb, respectively; p53 regulates DNA damage response and apoptosis, and pRb tightly controls the cell cycle.
Moreover, the absence of cutaneous E6 and E7 transcripts in skin tumors suggests an alternative mechanism for promoting cancer development hit-and-run mechanism. Among them, the E6-associated protein E6AP is an E3 ubiquitin ligase that targets proteins for ubiquitination and degradation by the proteasome In normal cells, p53 plays a key role to safeguard the integrity of the cellular genome, avoiding the proliferation of cells with damaged DNA.
For example, E6 of HPV23 interferes with the ability of the homeodomain-interacting protein kinase 2 HIPK2 to phosphorylate p53 on serine 46 to activate its apoptotic function upon UVB irradiation This event leads to the displacement of p53 from CBP and to the inhibition of pdependent p53 acetylation HPV5 and 8 E6s inhibit the association of AKT with the p C-terminus that is needed to ensure p stability, thus leading to its proteasomal degradation The degradation of p results in decreased protein levels of ATR, a PI3 kinase family member, which plays a key role in UV radiation damage signaling.
The reduced ATR level results in decreased phosphorylation and subsequent attenuated accumulation of p53 in cells in response to UVB radiation exposure. Both events lead to increased persistence of thymine dimers and UVB radiation-induced double-strand breaks in these cells More recently, Hufbauer et al. E6 has additional cellular targets that play an important role in apoptosis e. The anti-apoptotic protein Bak, a member of the Bcl-2 family of proteins, plays an important role in regulating the apoptotic process by forming pores with Bax to permeabilize the outer mitochondrial membrane.
Bak has been shown to be targeted for degradation by different HPVs from the alpha and beta genera, an event that contributes to preventing UV radiation-induced apoptosis. The ability of the E6 proteins of beta HPVs e. Holloway et al. The degradation of Bak by E6 prevents the release of proapoptotic factors including apoptosis-inducing factor AIF from the mitochondria into the nucleus, an event that prevents cells from undergoing UV radiation-induced apoptosis Viarisio et al.
Phosphorylation at this site negatively regulates the PDZ domain-binding activity. Different PDZ domain-containing proteins have been identified as targets of E6 of HR HPV types: DLG1, a human homolog of Drosophila discs large 1, and hScrib, a homolog of the Drosophila scribble protein — , which play an important role in the polarity of the epithelial cells and have been identified as tumor suppressors ; the molecular scaffolds membrane-associated guanylate kinase homology proteins, such as MAGI-1 , which is involved in the modulation of epithelial cell adhesion and tight junction integrity, acts as a tumor suppressor through the stabilization of PTEN , ; and another HPV16 PDZ domain-containing protein, CAL, which is involved in the regulation of intracellular vesicular trafficking In addition to playing a role in many cellular processes, the PBM of E6 proteins also regulates the HPV life cycle; mutations of this motif were shown to lead to lower levels of episomal HPV genome and cell growth This event plays a key role in hampering differentiation of HPV8-expressing keratinocytes and provides a further example of how skin and mucosal HPV types evolved different mechanisms to alter normal cell homeostasis and induce cellular transformation.
Using a proteomic approach, Thomas et al. Of note, whereas PDZ substrates such as DLG1 are common targets of the E6 proteins irrespective of their oncogenic potential, the ability of E6 PBMs to interact with hScrib, a component of the Scribble polarity complex, is correlated with the transforming ability of the studied HPV types Telomerase activity also plays an important role during cervical carcinogenesis, because it increases with the grade of the cervical lesions The ability to activate the promoter of hTERT human telomerase reverse transcriptase , the catalytic subunit of the telomerase, by different HPVs was assessed using a luciferase-based assay.
Moreover, E6 recruits histone acetyltransferase HAT at the hTERT promoter, which facilitates the access of transcriptional activators to key regulatory sites through the opening of the chromatin Together, these events lead to extending the life span of primary human keratinocytes, and to their immortalization.
The latter interaction is required to inhibit Notch1, a key player in skin differentiation and in the activation of transcription of the cell-cycle inhibitor p Interaction of beta HPV E6 with the Notch pathway appears to be important to promote the transformation process of the infected keratinocytes , The different affinities of E6s of different genera for specific cellular targets could be a consequence of their tropism and co-evolution with different type of tissues Moreover, HPV E7 comprises two nuclear localization sequences NLSs and one nuclear export sequence NES , which enable E7 to be located in both the nuclear and cytoplasmic compartments, where E7 has different functions Moreover, the interaction between BPV-1 E7 and p inhibits apoptosis, contributing to viral-induced transformation The ability of HPV16 E7 to bind to p correlates with its capacity to transform cells Phosphorylation at these sites contributes to modulating some of the E7 functions.
Interestingly, an additional phosphorylation site at serine position 29 exists in a natural E7 variant N29S and leads to increased levels of phosphorylation by CKII, which increases the interaction of E7 with TBP and pRb, and its transforming activity in primary rodent cells This motif is essential for the interaction with pRb and related pocket proteins p and p Residues in the CR3 domain of E7 also seem to be required for its interaction with pRb HR HPV E7 oncoproteins are able to target pRb and other members of the retinoblastoma family for proteasome-mediated degradation.
This event requires the recruitment of the cullin-2 ubiquitin ligase complex, which binds to the CR1 region The latter products are required for the activation of the cyclin-dependent kinase CDK complexes, which force the entry of HPV-infected cells into the S phase This event leads to unscheduled growth and accumulation of genomic instability. The ability of E7 to interact with pRb is not sufficient for HPV-induced transformation, which, as mentioned above, requires the interaction of E7 with additional cellular proteins These proteins are important negative regulators of the cell cycle, and they are believed to also act as tumor suppressors.
However, unlike pRb, their role as tumor suppressors is still controversial, because related genetic alterations are not frequent in human cancers. In another study, the same group used a transgenic mouse model expressing the E7 oncoprotein of HPV8 in the epidermis to investigate the molecular basis for HPV-induced invasion of skin keratinocytes.
HPV8 E7 expression in mouse skin led to a reduction of E-cadherin and a subsequent upregulation of N-cadherin, an event that causes epithelial—mesenchymal transition. E7-positive keratinocytes also showed increased fibronectin expression and secretion. E7 of beta-HPVs may play an important role in promoting an invasive phenotype in keratinocytes and may provide additional evidence to support a role of cutaneous HPVs in skin carcinogenesis.
Using in vitro colony formation and tumor sphere assays, Hufbauer et al. E7 expression also led to a reduction of the epithelial differentiation marker calgranulin B. Together, these results highlight a possible role of beta HPVs in skin carcinogenesis by increasing the number of stem cell-like cells present during early carcinogenesis and delaying cell differentiation.
Lanfredini et al. In that study, using HPV8 transgenic HPV8tg mice that express the entire HPV8 early region, the authors identified KSCs from the upper part of the junctional zone as the site from which the expansion to the interfollicular epidermis takes place during the initial step of skin carcinogenesis.
This population of stem cells express leucine-rich repeats and immunoglobulin-like domains protein 1 Lrig-1 and are characterized by nuclear staining for the stemness marker p Of note, the skin lesions of patients with EV show strong p63 immunostaining associated with very low levels of miR In addition to features cited above, E7 can also deregulate the cell cycle by binding and abrogating the inhibitory effect of CDK inhibitors like p21Cip1 and p27Kip1.
This interaction abolishes their inhibitory effect on the cell cycle and highlights a different mechanism by which E7 favors cell proliferation — E6 and E7 of HPV38 and 49, which can efficiently immortalize human primary keratinocytes, do not have the ability to target pRb for degradation when expressed in these cells Studies from our laboratory have shown that different beta HPV types e. The latter studies highlight that cutaneous HPVs have evolved different mechanisms than HR mucosal HPVs, to target key cellular proteins pRb and p53 and promote cellular transformation.
Transforming Activities of E5 Although the transforming activities of E6 and E7 oncoproteins are well characterized, the role of the E5 oncoprotein is still poorly understood E5 is a hydrophobic membrane-associated protein that localizes to the endoplasmic reticulum, Golgi apparatus, and plasma membrane , E5 forms a hexameric viroporin complex, which modulates ion homeostasis E5 viroporin is required for the hyperactivation of mitotic signaling, and it plays a key role during the life cycle of HR HPV types.
Recombinant HPV16 E5 membrane channel activity is sensitive to compounds such as adamantine and rimantadine. Inhibition of E5 viroporin activity in primary human keratinocytes harboring HPV18 genome leads to decreased ERK-MAPK phosphorylation and cyclin B1 levels, and to an increase in the expression of differentiation marker E5 viroporin activity is therefore critical for maintaining mitogenic signaling and delaying expression of differentiation marker during the productive stages of the HPV18 life cycle; therefore, targeting viroporin could pave the way for an effective antiviral strategy.
E5 is involved in the transformation of primary human keratinocytes by potentiating epidermal growth factor receptor EGFR signaling Via stimulation of EGFR, HPV16 E5 induces Met, a growth factor receptor involved in tumor cell motility and cancer metastasis; moreover, Met signaling is required for proper differentiation-dependent viral gene expression HPV16 E5 protein enhances, in cooperation with EGFR signaling, the down-regulation of tumor suppressor p27Kip1 levels, which promotes cell-cycle progression The level of another CDK inhibitor, p21, is reduced in cells that over-express E5 Both events lead to an increase in cell proliferation and in the percentage of cells in the S phase.
HPV16 E5 also contributes to carcinogenesis by inhibiting apoptosis by multiple molecular strategies. The same study showed that miRa expression affects cell proliferation, cell growth, and apoptosis, thus confirming the role of HPV16 E5 in cervical cancer development Another anti-apoptotic strategy consists of decreasing pro-apoptotic Bak and Bax levels, and increasing the expression of the anti-apoptotic Bcl HPV16 E5 inhibits apoptosis of cervical cancer cells by stimulating the ubiquitin-proteasome-mediated degradation of Bax protein All these data indicate that expression of E5 contributes to HPV-driven cellular transformation.
However, unlike E6 and E7, E5 is not required for the maintenance of the oncogenic phenotype, because the E5 ORF is frequently disrupted during HPV integration, thus rather highlighting a role of E5 at the initial step of carcinogenesis HPV types from different genera beta, gamma, and mu lack the E5 ORF, suggesting that the corresponding functions are performed by other viral proteins.
Most of the patients with EV who are susceptible to persistent beta HPV infections carry mutations in these genes. Conclusive Remarks, Challenges, and Open Questions In the past decades, epidemiological and biological studies have clearly demonstrated the role of mucosal HR HPV types in human carcinogenesis.
While co-evolving with the human host, HPVs have developed strategies to evade the immune system and create the optimal conditions to persist in the host for many years. During HPV chronic infection, the E6 and E7 oncoproteins interact with different cellular proteins to prevent apoptosis, counteract the cellular senescence program, and promote unscheduled cell growth. The expression of the oncoproteins is kept under the tight control of E2. Loss of E2 repressive functions, by viral integration or by other mechanisms, which are discussed in this review, leads to constitutive high expression of E6 and E7, a key event in HPV-mediated transformation Figure 3.
Although the mechanisms leading to cervical cancer have been well-characterized, there is still a gap in the understanding of the pathogenesis of other HPV-related malignancies, e. The proportion of HPV-driven oropharyngeal cancers has been increasing over the past decades in many parts of the world, mainly in Europe and North America — The natural history of HPV infection in the oral cavity and oropharynx is poorly studied and needs further investigation.
Of note, recent studies identified HPV16 E6 antibody as a good diagnostic and prognostic marker of oropharyngeal cancer. HPV16 E6 seropositivity was detected more than 10 years before the diagnosis , Moreover, although the available prophylactic vaccines have demonstrated their effectiveness in the context of prevention of anogenital cancers , very limited epidemiological data are available on the efficacy of the HPV vaccine on oral HPV infection This deserves further investigation.
Prophylactic vaccines show a good efficiency in covering targeted HPVs, but they are inefficient in existing infections. Therefore, therapeutic vaccines are needed to fill this gap. Several studies have reported the development of promising therapeutic vaccines. Their use in the near future could be expected; however, their cost could be high. This limitation could be overcome by the use of inexpensive technologies i.
One of the most recurrent questions regarding the prophylactic vaccine is whether HPV vaccination will result in the occupation of a newly vacant ecological niche by non-targeted HPV types. However, as reported in recent studies, a few types i. The bacterial microbiome composition may also play a role in the outcome of mucosal HPV infection. A chronic mycoplasma infection was shown to promote cervical dysplasia induced by HPV Therefore, identifying the bacterial microbiome could allow the identification of patients at high risk for developing cervical cancer.
Our knowledge of the biology of beta and gamma HPV types is still uncomplete. There are also important gaps in the understanding of the life cycle of cutaneous HPV types, which also deserve further research. Since that meeting, strong epidemiological and experimental data in favor of a role of cutaneous HPV types as cofactors in skin carcinogenesis have been published, as described in this review.
Indeed, recent findings from our group and others have shown that unlike the expression of oncoproteins of HR HPV types, cutaneous HPV E6 and E7 expression appears to be required only at the initial step of skin carcinogenesis by exacerbating the deleterious effects of UV radiation
COLLEGE BOWL BETTING SPREADS
Plants are all multicellular and consist of complex cells. In addition, plants are autotrophs, organisms that make their own food. With over , species, the plant kingdom is the second largest kingdom. Plant species range from the tiny green mosses to giant trees. Without plants, life on Earth would not exist! Plants feed almost all the heterotrophs organisms that eat other organisms on Earth. Animals The animal kingdom is the largest kingdom with over 1 million known species.
All animals consist of many complex cells. They are also heterotrophs. Members of the animal kingdom are found in the most diverse environments in the world. To their surprise they discovered unicellular one cell organisms in the samples. These organisms are today classified in the kingdom, Archaebacteria. Archaebacteria are found in extreme environments such as hot boiling water and thermal vents under conditions with no oxygen or highly acid environments.
Eubacteria Like archaebacteria, eubacteria are complex and single celled. They are the kinds found everywhere and are the ones people are most familiar with. Eubacteria are classified in their own kingdom because their chemical makeup is different. Most eubacteria are helpful. Some produce vitamins and foods like yogurt. However, some eubacteria such as Streptococci can give you strep throat! Mucosal human papillomaviruses encode four different E5 proteins whose chemistry and phylogeny correlate with malignant or benign growth.
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PubMed Abstract Google Scholar. Rous P, Beard JW. Front Oncol. Published online May 8. Author information Article notes Copyright and License information Disclaimer. This article was submitted to Molecular and Cellular Oncology, a section of the journal Frontiers in Oncology. Received Jan 10; Accepted Apr The use, distribution or reproduction in other forums is permitted, provided the original author s and the copyright owner s are credited and that the original publication in this journal is cited, in accordance with accepted academic practice.
No use, distribution or reproduction is permitted which does not comply with these terms. This article has been cited by other articles in PMC. Abstract Papillomaviridae is a family of small non-enveloped icosahedral viruses with double-stranded circular DNA. Keywords: Papillomavirus, infection and cancer, transformation, anogenital cancer, skin cancer. Introduction Papillomaviridae is a family of small non-enveloped icosahedral viruses with double-stranded circular DNA, which range in length from 5, bp for Sparus aurata papillomavirus 1 SaPV1 to 8, bp for canine papillomavirus type 1 CPV1.
Open in a separate window. Figure 1. Entry and Life Cycle of HPV The viral particle reaches the basal layer of the epithelium via micro-wounds or micro-fissures, or via hair follicles 80 , , , to infect basal keratinocytes or stem epithelial cells. Figure 2. Figure 3. Table 1 Main features and functions of the early and late gene products from alpha and beta HPV types. Hampers the differentiation of HPV8-expressing keratinocytes by targeting the PDZ domain-containing protein syntenin 2.
Interacts with Notch pathway and promote the transformation process of the infected keratinocytes. Transforming Activities of PVs Studies performed on mucosal HR HPV types, such as HPV16 and 18, showed that both oncoproteins E6 and E7 play a key role in cervical cancer by altering pathways involved in the host immune response to establish a persistent infection and promote cellular transformation.
Transforming Activities of E5 Although the transforming activities of E6 and E7 oncoproteins are well characterized, the role of the E5 oncoprotein is still poorly understood Conclusive Remarks, Challenges, and Open Questions In the past decades, epidemiological and biological studies have clearly demonstrated the role of mucosal HR HPV types in human carcinogenesis.
Author Contributions The author confirms being the sole contributor of this work and has approved it for publication. Conflict of Interest Statement The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. Acknowledgments I would like to thank Dr.
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Rautava J, Syrjanen S. Biology of human papillomavirus infections in head and neck carcinogenesis. Head Neck Pathol. HPV virions can remain infectious for 2 weeks on senescent cells but require cell cycle re-activation to allow virus entry. Kallikrein-8 Proteolytically processes human papillomaviruses in the extracellular space to facilitate entry into host cells. Keratinocyte-secreted laminin 5 can function as a transient receptor for human papillomaviruses by binding virions and transferring them to adjacent cells.
Furin cleavage of l2 during papillomavirus infection: minimal dependence on cyclophilins. The N-terminal region of the human papillomavirus L2 protein contains overlapping binding sites for neutralizing, cross-neutralizing and non-neutralizing antibodies. Human papillomavirus type 16 entry: retrograde cell surface transport along actin-rich protrusions. Entry of human papillomavirus type 16 by actin-dependent, clathrin- and lipid raft-independent endocytosis.
Papillomaviruses and endocytic trafficking. Int J Mol Sci. Human papillomavirus major capsid protein L1 remains associated with the incoming viral genome throughout the entry process. Direct binding of retromer to human papillomavirus type 16 minor capsid protein L2 mediates endosome exit during viral infection.
Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling. Nat Cell Biol. Human papillomavirus L2 facilitates viral escape from late endosomes via sorting nexin Characterizing the spatio-temporal role of sorting nexin 17 in human papillomavirus trafficking. A Novel PDZ domain interaction mediates the binding between human papillomavirus 16 L2 and sorting nexin 27 and modulates virion trafficking. Human papillomavirus entry: hiding in a bubble.
Establishment of human papillomavirus infection requires cell cycle progression. Large scale RNAi reveals the requirement of nuclear envelope breakdown for nuclear import of human papillomaviruses. Classification plants papilloma investing of phoenix robot forex Investing papilloma classification of plants MAGI-1 interacts with beta-catenin and is associated with cell-cell adhesion structures.
The latter products are required for the activation of the cyclin-dependent kinase CDK complexes, which force the entry of HPV-infected cells into the S phase HPV8-E6 Interferes with Syntenin-2 expression through deregulation of differentiation, methylation and phosphatidylinositide-kinase dependent mechanisms.
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More than different human papillomaviruses HPVs have been listed so far.
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| Ethereal looks from scotland | The HPV curve emphasizes the high incidence of infection that develops soon after women initiate sexual activity and subsequent lower incidence because a high proportion of infections are self-limited. It will be important for the ongoing see more efficacy trials to analyze this parameter, as cross-protection against HPV types not in the vaccine investing enhance its overall utility. When DNA was delivered to skin, the gene expression was detected in Langerhans cells and dermal dendritic cells [ 61 ], suggesting the important role of animals cells for subsequent antigen presentation. The capsid proteins L1 and L2 are expressed from the late promoter, and are involved in the encapsidation of papilloma classification replicated genomes, resulting in virion release in the superficial layers during desquamation. These two vaccine types utilize the major structural protein present in different HPV types, L1 as a target antigen in a form of virus-like particle VLP. HPV-associated diseases. |
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| Van winkle twins bitcoins | From this moment, PVs' interaction with their host became more specific, resulting in a co-evolution. Similarly, SCC of the tonsil in cats also tends to metastasize early to the regional lymph nodes [ 86 ]. The virus is the causal agent of bovine papillomatosis BP Muro et al. These studies brought new questions to be answered: how can the co-factor act in synergism with the virus? The expression of the oncoproteins is kept under the tight control of E2. This local effect of EP has been thought to contribute to the magnitude and longivity of the responses to DNA vaccines in larger animals, such as rabbits and humans [ 71 ]. |
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Eubacteria are classified in their own kingdom because their chemical makeup is different. Most eubacteria are helpful. Some produce vitamins and foods like yogurt. However, some eubacteria such as Streptococci can give you strep throat! Fungi Mushrooms, mold and mildew are all examples of organisms in the kingdom fungi. Most fungi are multicellular and consists of many complex cells. Fungi are organisms that biologists once confused with plants, however, unlike plants, fungi cannot make their own food.
Most obtain their food from parts of plants that are decaying in the soil. Protists Slime molds and algae are protists. Sometimes they are called the odds and ends kingdom because its members are so different from one another. Protists include all microscopic organisms that are not bacteria, not animals, not plants and not fungi. Most protists are unicellular. You may be wondering why those protists are not classified in the Archaebacteria or Eubacteria kingdoms.
It is because, unlike bacteria, protists are complex cells. Animal Phylums Explained The most common way to classify animals is by their phyla, or major body plan. Here is a shortlist of the most common ones: Porifera — multi-celled simple sea creatures i.
Platyhelminthes — a group of soft-bodied, usually much flattened invertebrates i. Sea slugs, squids, snails, and scallops Arthropoda — invertebrate animals with an exoskeleton , a segmented body, and paired jointed appendages. Most insects and arachnids e. Using a proteomic approach, Thomas et al. Of note, whereas PDZ substrates such as DLG1 are common targets of the E6 proteins irrespective of their oncogenic potential, the ability of E6 PBMs to interact with hScrib, a component of the Scribble polarity complex, is correlated with the transforming ability of the studied HPV types Telomerase activity also plays an important role during cervical carcinogenesis, because it increases with the grade of the cervical lesions The ability to activate the promoter of hTERT human telomerase reverse transcriptase , the catalytic subunit of the telomerase, by different HPVs was assessed using a luciferase-based assay.
Moreover, E6 recruits histone acetyltransferase HAT at the hTERT promoter, which facilitates the access of transcriptional activators to key regulatory sites through the opening of the chromatin Together, these events lead to extending the life span of primary human keratinocytes, and to their immortalization.
The latter interaction is required to inhibit Notch1, a key player in skin differentiation and in the activation of transcription of the cell-cycle inhibitor p Interaction of beta HPV E6 with the Notch pathway appears to be important to promote the transformation process of the infected keratinocytes , The different affinities of E6s of different genera for specific cellular targets could be a consequence of their tropism and co-evolution with different type of tissues Moreover, HPV E7 comprises two nuclear localization sequences NLSs and one nuclear export sequence NES , which enable E7 to be located in both the nuclear and cytoplasmic compartments, where E7 has different functions Moreover, the interaction between BPV-1 E7 and p inhibits apoptosis, contributing to viral-induced transformation The ability of HPV16 E7 to bind to p correlates with its capacity to transform cells Phosphorylation at these sites contributes to modulating some of the E7 functions.
Interestingly, an additional phosphorylation site at serine position 29 exists in a natural E7 variant N29S and leads to increased levels of phosphorylation by CKII, which increases the interaction of E7 with TBP and pRb, and its transforming activity in primary rodent cells This motif is essential for the interaction with pRb and related pocket proteins p and p Residues in the CR3 domain of E7 also seem to be required for its interaction with pRb HR HPV E7 oncoproteins are able to target pRb and other members of the retinoblastoma family for proteasome-mediated degradation.
This event requires the recruitment of the cullin-2 ubiquitin ligase complex, which binds to the CR1 region The latter products are required for the activation of the cyclin-dependent kinase CDK complexes, which force the entry of HPV-infected cells into the S phase This event leads to unscheduled growth and accumulation of genomic instability.
The ability of E7 to interact with pRb is not sufficient for HPV-induced transformation, which, as mentioned above, requires the interaction of E7 with additional cellular proteins These proteins are important negative regulators of the cell cycle, and they are believed to also act as tumor suppressors. However, unlike pRb, their role as tumor suppressors is still controversial, because related genetic alterations are not frequent in human cancers.
In another study, the same group used a transgenic mouse model expressing the E7 oncoprotein of HPV8 in the epidermis to investigate the molecular basis for HPV-induced invasion of skin keratinocytes. HPV8 E7 expression in mouse skin led to a reduction of E-cadherin and a subsequent upregulation of N-cadherin, an event that causes epithelial—mesenchymal transition. E7-positive keratinocytes also showed increased fibronectin expression and secretion.
E7 of beta-HPVs may play an important role in promoting an invasive phenotype in keratinocytes and may provide additional evidence to support a role of cutaneous HPVs in skin carcinogenesis. Using in vitro colony formation and tumor sphere assays, Hufbauer et al. E7 expression also led to a reduction of the epithelial differentiation marker calgranulin B. Together, these results highlight a possible role of beta HPVs in skin carcinogenesis by increasing the number of stem cell-like cells present during early carcinogenesis and delaying cell differentiation.
Lanfredini et al. In that study, using HPV8 transgenic HPV8tg mice that express the entire HPV8 early region, the authors identified KSCs from the upper part of the junctional zone as the site from which the expansion to the interfollicular epidermis takes place during the initial step of skin carcinogenesis.
This population of stem cells express leucine-rich repeats and immunoglobulin-like domains protein 1 Lrig-1 and are characterized by nuclear staining for the stemness marker p Of note, the skin lesions of patients with EV show strong p63 immunostaining associated with very low levels of miR In addition to features cited above, E7 can also deregulate the cell cycle by binding and abrogating the inhibitory effect of CDK inhibitors like p21 Cip1 and p27 Kip1. This interaction abolishes their inhibitory effect on the cell cycle and highlights a different mechanism by which E7 favors cell proliferation — E6 and E7 of HPV38 and 49, which can efficiently immortalize human primary keratinocytes, do not have the ability to target pRb for degradation when expressed in these cells Studies from our laboratory have shown that different beta HPV types e.
The latter studies highlight that cutaneous HPVs have evolved different mechanisms than HR mucosal HPVs, to target key cellular proteins pRb and p53 and promote cellular transformation. Although the transforming activities of E6 and E7 oncoproteins are well characterized, the role of the E5 oncoprotein is still poorly understood E5 is a hydrophobic membrane-associated protein that localizes to the endoplasmic reticulum, Golgi apparatus, and plasma membrane , E5 forms a hexameric viroporin complex, which modulates ion homeostasis E5 viroporin is required for the hyperactivation of mitotic signaling, and it plays a key role during the life cycle of HR HPV types.
Recombinant HPV16 E5 membrane channel activity is sensitive to compounds such as adamantine and rimantadine. Inhibition of E5 viroporin activity in primary human keratinocytes harboring HPV18 genome leads to decreased ERK-MAPK phosphorylation and cyclin B1 levels, and to an increase in the expression of differentiation marker E5 viroporin activity is therefore critical for maintaining mitogenic signaling and delaying expression of differentiation marker during the productive stages of the HPV18 life cycle; therefore, targeting viroporin could pave the way for an effective antiviral strategy.
E5 is involved in the transformation of primary human keratinocytes by potentiating epidermal growth factor receptor EGFR signaling Via stimulation of EGFR, HPV16 E5 induces Met, a growth factor receptor involved in tumor cell motility and cancer metastasis; moreover, Met signaling is required for proper differentiation-dependent viral gene expression HPV16 E5 protein enhances, in cooperation with EGFR signaling, the down-regulation of tumor suppressor p27 Kip1 levels, which promotes cell-cycle progression The level of another CDK inhibitor, p21, is reduced in cells that over-express E5 Both events lead to an increase in cell proliferation and in the percentage of cells in the S phase.
HPV16 E5 also contributes to carcinogenesis by inhibiting apoptosis by multiple molecular strategies. The same study showed that miRa expression affects cell proliferation, cell growth, and apoptosis, thus confirming the role of HPV16 E5 in cervical cancer development Another anti-apoptotic strategy consists of decreasing pro-apoptotic Bak and Bax levels, and increasing the expression of the anti-apoptotic Bcl HPV16 E5 inhibits apoptosis of cervical cancer cells by stimulating the ubiquitin-proteasome-mediated degradation of Bax protein All these data indicate that expression of E5 contributes to HPV-driven cellular transformation.
However, unlike E6 and E7, E5 is not required for the maintenance of the oncogenic phenotype, because the E5 ORF is frequently disrupted during HPV integration, thus rather highlighting a role of E5 at the initial step of carcinogenesis HPV types from different genera beta, gamma, and mu lack the E5 ORF, suggesting that the corresponding functions are performed by other viral proteins.
Most of the patients with EV who are susceptible to persistent beta HPV infections carry mutations in these genes. In the past decades, epidemiological and biological studies have clearly demonstrated the role of mucosal HR HPV types in human carcinogenesis.
While co-evolving with the human host, HPVs have developed strategies to evade the immune system and create the optimal conditions to persist in the host for many years. During HPV chronic infection, the E6 and E7 oncoproteins interact with different cellular proteins to prevent apoptosis, counteract the cellular senescence program, and promote unscheduled cell growth. The expression of the oncoproteins is kept under the tight control of E2.
Loss of E2 repressive functions, by viral integration or by other mechanisms, which are discussed in this review, leads to constitutive high expression of E6 and E7, a key event in HPV-mediated transformation Figure 3. Although the mechanisms leading to cervical cancer have been well-characterized, there is still a gap in the understanding of the pathogenesis of other HPV-related malignancies, e.
The proportion of HPV-driven oropharyngeal cancers has been increasing over the past decades in many parts of the world, mainly in Europe and North America — The natural history of HPV infection in the oral cavity and oropharynx is poorly studied and needs further investigation. Of note, recent studies identified HPV16 E6 antibody as a good diagnostic and prognostic marker of oropharyngeal cancer.
HPV16 E6 seropositivity was detected more than 10 years before the diagnosis , Moreover, although the available prophylactic vaccines have demonstrated their effectiveness in the context of prevention of anogenital cancers , very limited epidemiological data are available on the efficacy of the HPV vaccine on oral HPV infection This deserves further investigation.
Prophylactic vaccines show a good efficiency in covering targeted HPVs, but they are inefficient in existing infections. Therefore, therapeutic vaccines are needed to fill this gap. Several studies have reported the development of promising therapeutic vaccines. Their use in the near future could be expected; however, their cost could be high.
This limitation could be overcome by the use of inexpensive technologies i. One of the most recurrent questions regarding the prophylactic vaccine is whether HPV vaccination will result in the occupation of a newly vacant ecological niche by non-targeted HPV types. However, as reported in recent studies, a few types i. The bacterial microbiome composition may also play a role in the outcome of mucosal HPV infection.
A chronic mycoplasma infection was shown to promote cervical dysplasia induced by HPV Therefore, identifying the bacterial microbiome could allow the identification of patients at high risk for developing cervical cancer. Our knowledge of the biology of beta and gamma HPV types is still uncomplete.
There are also important gaps in the understanding of the life cycle of cutaneous HPV types, which also deserve further research. Since that meeting, strong epidemiological and experimental data in favor of a role of cutaneous HPV types as cofactors in skin carcinogenesis have been published, as described in this review. Indeed, recent findings from our group and others have shown that unlike the expression of oncoproteins of HR HPV types, cutaneous HPV E6 and E7 expression appears to be required only at the initial step of skin carcinogenesis by exacerbating the deleterious effects of UV radiation Most importantly, both models provided further evidence for a hit-and-run mechanism.
However, additional studies are still necessary to validate this hypothesis in humans. In addition to these experimental data, a recent prospective study of two organ transplant recipient cohorts showed that having five or more different beta HPV types in eyebrow hair, and a high beta HPV viral load, was associated with cSCC carcinogenesis, providing strong evidence for a role of beta HPVs in this cancer, whereas no evidence was found for basal cell carcinoma The development of vaccination strategies that target cutaneous HPV infections would be of great benefit to these patients , Another open question regards the tropism of certain HPVs.
Our recent data highlighted that E6 and E7 of HPV49 share some features with HR mucosal types, and efficiently transform epithelial cells in in vitro and in vivo models , Beta and gamma HPV types have also been isolated from the nasopharynx and the nasal mucosa , Moreover, a recent study based on a prospective design reported that beta or gamma HPV types were associated with the incidence of HNC A large number of gamma HPV types have been isolated; however, their biological activities are poorly studied and deserve more investigation.
Finally, some of the known but not yet biologically characterized beta or gamma HPV types may display transforming activity and also deserve attention. In addition to these not-yet-studied types, one may also consider the large number of novel HPVs found in recent years, as well as the rapid evolution of viral detection and screening techniques and large data set analysis pipelines.
For all these reasons, we believe that in the coming years the field of HPV research will continue to be a source of surprises and excitement for the scientific community. The author confirms being the sole contributor of this work and has approved it for publication. TG wrote the manuscript and designed the figures. The author declares that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
I would like to thank Dr. Massimo Tommasino and Dr. Rosita Accardi for helpful discussions. I am grateful to Dr. Jessica Cox for editing, and to Ms. Nicole Suty for her help with preparation of this manuscript. The clinical importance of understanding the evolution of papillomaviruses. Trends Microbiol. Concurrence of iridovirus, polyomavirus, and a unique member of a new group of fish papillomaviruses in lymphocystis disease-affected gilthead sea bream.
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