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REVIEW ARTICLE
Human polyomaviruses and cancer: an overview
José Carlos Mann Prado, Telma Alves Monezi, Aline Teixeira Amorim, Vanesca Lino, Andressa Paladino, Enrique Boccardo
Corresponding author
eboccardo@usp.br

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Departamento de Microbiologia, Instituto de Ciencias Biomedicas, Universidade de Sao Paulo, Sao Paulo, SP, BR
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of the genomes of BKPyV&#44; JCK&#44; MCPyV and TSPvV&#46; The early and late regions &#40;gray&#41; are transcribed from opposite strands of the genome&#46; The early region is transcribed in the counterclockwise direction and harbors the genes coding for the different T antigen isoforms as indicated&#46; The late region expresses the structural genes &#40;VPs&#41; and the agnoprotein ORF &#40;when present&#41;&#46; BKPyV&#44; JCV and MCPyV express a microRNA from the opposite strand of the early region&#46; The noncoding control region &#40;NCCR&#41; contains the origin of genome replication and the promoters for the regulation of transcription&#46; For details&#44; see text&#46;</p>"
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    "textoCompleto" => "<span class="elsevierStyleSections"><span id="cesec10" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle10">INTRODUCTION</span><p id="para10" class="elsevierStylePara elsevierViewall">Polyomaviruses &#40;PyVs&#41; are icosahedral&#44; nonenveloped viruses that are approximately 45 nm in size&#46; The capsid is composed of 72 pentameric capsomers and surrounds a circular&#44; double-stranded viral DNA genome that is approximately 5&#44;5 kbp&#46; Inside the virion&#44; the DNA is associated with the cellular histones H2A&#44; H2B&#44; H3 and H4&#44; forming the viral minichromosome&#46; In addition&#44; inside the cell&#44; the minichromosome is found to be associated with histone H1 <a class="elsevierStyleCrossRef" href="#bib1">1</a>&#46; These viruses are relatively resistant to treatment with formalin and are not affected by organic solvents <a class="elsevierStyleCrossRef" href="#bib2">2</a>&#46;</p><p id="para20" class="elsevierStylePara elsevierViewall">Currently&#44; the International Committee on Taxonomy of Viruses &#40;ICTV&#41; has divided the <span class="elsevierStyleItalic">Polyomaviridae</span> family into 5 genera&#58; <span class="elsevierStyleItalic">Alphapolyomavirus&#44;</span> with 37 species that infect animals and humans&#44; including human PyVs &#40;HPyVs&#41; 5&#44; 8&#44; 9&#44; 12 and 13&#59; <span class="elsevierStyleItalic">Betapolyomavirus</span>&#44; with 29 species that infect animals and humans&#44; including HPyVs 1 and 4&#59; <span class="elsevierStyleItalic">Deltapolyomavirus</span> with only HPyVs 6&#44; 7&#44; 10 and 11&#59; <span class="elsevierStyleItalic">Gammapolyomavirus</span>&#44; with seven animal virus species&#44; including PyVs that infect birds&#59; and&#44; finally&#44; an unassigned genus that contain three species of animal PyVs <a class="elsevierStyleCrossRef" href="#bib3">3</a>&#44;<a class="elsevierStyleCrossRef" href="#bib4">4</a>&#46;</p><span id="cesec20" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle20">Biology of polyomaviruses</span><p id="para30" class="elsevierStylePara elsevierViewall">The genomes of PyVs can be divided into three regions&#58; the control region&#59; the early region&#44; which encodes early proteins&#59; and the late region&#44; which encodes late proteins with structural function&#46; The control region contains the origin of replication and the promoters that regulate the expression of early and late genes&#46; However&#44; this region does not encode any protein or functional RNA&#46; This region is involved in the regulation of the viral life cycle by modulating replication and transcription&#46; Both strands of the PyV DNA code for proteins&#46; Early genes are expressed from one strand immediately after infection&#46; On the other hand&#44; late genes are expressed from the opposite strand after viral genome replication&#46; The mRNA transcribed from both early and late regions exist in at least two isoforms due to alternative processing&#46; In addition&#44; the expression of a viral microRNA has been observed in the John Cunningham polyomavirus &#40;JCPyV&#41;&#44; BK polyomavirus &#40;BKPyV&#41; and Merkel cell polyomavirus &#40;MCPyV&#41; <a class="elsevierStyleCrossRef" href="#bib5">5</a>&#44;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#46; This microRNA is encoded by the DNA strand complementary to the large T antigen &#40;see below&#41; and&#44; at least in MCPyV&#44; this RNA seems to regulate the expression of this viral protein <a class="elsevierStyleCrossRef" href="#bib5">5</a>&#46;</p><p id="para40" class="elsevierStylePara elsevierViewall">The proteins encoded by the early genes are involved in the regulation of viral transcription and genome replication&#46; These proteins are known as &#8220;T antigens&#8221; and received this name because they were recognized by antibodies from rodents bearing tumors <a class="elsevierStyleCrossRef" href="#bib7">7</a>&#46; Different T antigen isoforms exist and are named depending on the viral species from which they originate&#46; The transforming potential of the viral group is directly related to the expression of T antigens and was initially established in studies using simian virus 40 &#40;SV40&#41; <a class="elsevierStyleCrossRef" href="#bib8">8</a>&#46; The large T &#40;LT&#41; antigen is a nuclear protein that is approximately 700 amino acids&#46; However&#44; alterations in its phosphorylation pattern may change the location of this protein within the cell <a class="elsevierStyleCrossRef" href="#bib9">9</a>&#44;<a class="elsevierStyleCrossRef" href="#bib10">10</a>&#46; The LT antigen regulates both viral transcription and genome replication <a class="elsevierStyleCrossRef" href="#bib11">11</a>&#46; In addition&#44; the LT antigen as well as the other T antigen isoforms expressed in human and animal PyVs are pleiotropic proteins that affect the function and expression of several cellular proteins involved in the regulation of cell proliferation &#40;see below&#41;&#46; The neutralization of the functions of these proteins is critical for the induction of the entry of the host cell into the cell cycle&#44; making the DNA replication machinery available and allowing viral genome replication <a class="elsevierStyleCrossRefs" href="#bib12">12-15</a>&#46;</p><p id="para50" class="elsevierStylePara elsevierViewall">The late region harbors the genes that encode structural proteins found in the viral capsid&#44; such as VP1 and VP2&#46; Some species also express the structural proteins VP3 and VP4&#46; VP2 and VP3 are important for viral entry into the host cell&#46; However&#44; the role of VP4 during the viral life cycle remains a matter of debate&#46; Previous studies have suggested that VP4 acts as a viroporin to disrupt the nuclear envelope and mediate viral release <a class="elsevierStyleCrossRefs" href="#bib16">16-19</a>&#46; However&#44; in a recent study&#44; Henriksen et al&#46; showed that human renal proximal tubule epithelial cells transfected with BKPyV genomes carrying start codon substitutions in VP4&#44; predicted to abolish the production of this protein&#44; released comparable amounts of viral particles in the supernatant as cells transfected with WT genomes <a class="elsevierStyleCrossRef" href="#bib20">20</a>&#46; It is clear that additional studies are needed to determine the role of VP4 in PyV biology&#46; In addition&#44; some PyVs&#44; including JCPyV&#44; BKPyV and SV40&#44; present an open reading frame &#40;ORF&#41; that encodes a regulatory cytoplasmic protein named agnoprotein <a class="elsevierStyleCrossRef" href="#bib21">21</a>&#46; The involvement of agnoprotein in viral release has been suggested in species that express this protein&#44; including SV40&#44; JCPyV and BKPyV <a class="elsevierStyleCrossRef" href="#bib22">22</a>&#46;</p><p id="para60" class="elsevierStylePara elsevierViewall">Studies conducted during the past two decades have shown that the expression of VP1 in different systems leads to the production of structures called virus-like particles &#40;VLPs&#41;&#44; which are similar to the viral capsid <a class="elsevierStyleCrossRefs" href="#bib23">23-27</a>&#46; After being expressed&#44; the structural proteins accumulate in the cellular nucleus&#44; contributing to the mounting of the virion&#46; These proteins are found in different amounts in viral capsids&#44; with VP1 being the major protein in the formation of pentamers&#46; The carboxy end of VP1 extends outside the pentamer and interacts with surrounding pentamers&#46; These interactions&#44; mediated by VP1 together with Ca<span class="elsevierStyleSup">2&#43;</span> and disulfide bonds&#44; contribute to the stabilization of the capsomers and capsid structure <a class="elsevierStyleCrossRef" href="#bib2">2</a>&#46;</p><p id="para70" class="elsevierStylePara elsevierViewall">The mechanism of viral entry into the host cell seems to depend on the virus and cell type under study&#46; For instance&#44; cell internalization via caveolin- or clathrin-dependent endocytosis&#44; as well as entry via other mechanisms&#44; has been previously described <a class="elsevierStyleCrossRef" href="#bib28">28</a>&#44;<a class="elsevierStyleCrossRef" href="#bib29">29</a>&#46; Once in the cytoplasm&#44; the viral capsid suffers alterations that expose the nuclear localization signals present in proteins VP2 and VP3 and mediate nuclear import&#46; After reaching the nucleus&#44; the capsid is completely dismounted&#44; and the viral genome is exposed and maintained in the episomal form&#46; Next&#44; the early region is transcribed to produce an mRNA molecule that&#44; after processing&#44; will generate the large T antigen and its other isoforms&#46; The LT antigen protein will first mediate viral genome replication&#46; This event may also be regulated by epigenetic mechanisms due to the association of viral DNA with cellular histones <a class="elsevierStyleCrossRef" href="#bib30">30</a>&#46; Only after genome amplification will the LT antigen promote the transcription of the late region to express the structural proteins&#46; Infective virions are mounted in the nucleus&#44; and the release of these virions may depend on the occurrence of cell lysis <a class="elsevierStyleCrossRef" href="#bib2">2</a>&#44;<a class="elsevierStyleCrossRef" href="#bib31">31</a>&#46;</p><p id="para80" class="elsevierStylePara elsevierViewall">The majority of PyV infections are asymptomatic&#59; however&#44; these infections may cause alterations in cell cultures and induce tumors in immunocompromised laboratory animals&#44; including newborn mice&#46; The transforming potential of PyVs has been demonstrated <span class="elsevierStyleItalic">in vitro</span> using cells from different organisms <a class="elsevierStyleCrossRef" href="#bib32">32</a>&#46; Early studies conducted in immunocompromised animals injected with murine polyomavirus &#40;MuPyV&#41;-infected cells showed the formation of multiple &#40;<span class="elsevierStyleItalic">poly</span>&#41; tumors &#40;<span class="elsevierStyleItalic">omas</span>&#41; and served to name the group <a class="elsevierStyleCrossRef" href="#bib7">7</a>&#46;</p></span><span id="cesec30" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle30">Human polyomaviruses</span><p id="para90" class="elsevierStylePara elsevierViewall">The discovery and characterization of HPyVs occurred in different technological contexts&#46; In 1971&#44; two isolates were described&#44; and for decades&#44; these species remained the only members of the family that infected humans <a class="elsevierStyleCrossRef" href="#bib33">33</a>&#44;<a class="elsevierStyleCrossRef" href="#bib34">34</a>&#46; It was not until 2007&#44; and only after major advances in DNA sequencing technologies&#44; that other twelve PyVs were identified in human samples&#44; increasing the total number of HPyVs to fourteen <a class="elsevierStyleCrossRef" href="#bib14">14</a>&#44;&#46; The timeline of HPyV discovery is summarized in <a class="elsevierStyleCrossRef" href="#fig1-cln_73p1">Figure 1</a>&#46;</p><elsevierMultimedia ident="fig1-cln_73p1"></elsevierMultimedia><p id="para100" class="elsevierStylePara elsevierViewall">Serological studies have shown that exposure to most HPyVs occurs early in life and that infection prevalence in adults may be high <a class="elsevierStyleCrossRef" href="#bib45">45</a>&#46; Interestingly&#44; immunocompromised individuals exhibit higher viral loads of these agents suggesting that immunocompromised individuals are more susceptible to reactivation of these viruses <a class="elsevierStyleCrossRef" href="#bib14">14</a>&#44;<a class="elsevierStyleCrossRefs" href="#bib46">46-49</a>&#46; Among the PyVs that affect humans and are associated with important diseases in immunocompromised individuals&#44; the most relevant are JCPyV&#44; BKPyV&#44; MCPyV and Trichodysplasia spinulosa PyV &#40;TSPyV&#41;&#46; These PyVs are ubiquitous and are highly prevalent in the normal human population&#46; In general&#44; infection by these agents is asymptomatic in healthy individuals&#44; with prevalence values as high as 80&#37; in adults&#44; as determined by serological studies <a class="elsevierStyleCrossRef" href="#bib27">27</a>&#44;<a class="elsevierStyleCrossRef" href="#bib50">50</a>&#46; On the other hand&#44; in immunocompromised persons&#44; infection with BKPyV is associated with the development of nephropathies and hemorrhagic cystitis&#44; while infection with JCPyV is associated with progressive multifocal leukoencephalopathy &#40;PML&#41;&#46; In addition&#44; MCPyV is associated with the development of Merkel cell carcinoma &#40;MCC&#41; and is considered a group 2A carcinogen &#40;probably carcinogenic to humans&#41; by the International Agency for Research on Cancer <a class="elsevierStyleCrossRef" href="#bib51">51</a>&#46;</p><p id="para110" class="elsevierStylePara elsevierViewall">It is accepted that PyV-associated tumors develop after the interruption of the viral life cycle&#46; This may be caused by accidental viral integration into de cellular genome&#46; In the case of MCPyV and BKPyV&#44; viral cycle interruption may be caused by rupture of the VP1 gene <a class="elsevierStyleCrossRef" href="#bib52">52</a>&#44;<a class="elsevierStyleCrossRef" href="#bib53">53</a> or by loss of the carboxy-terminal domain of the LT antigen due to nonsense mutations&#46; This domain of the LT antigen is needed for the normal cycle to promote viral genome replication <a class="elsevierStyleCrossRef" href="#bib52">52</a>&#44;<a class="elsevierStyleCrossRef" href="#bib37">37</a>&#46; Therefore&#44; viral replication is interrupted while truncated versions of the LT antigen and its isoforms are expressed <a class="elsevierStyleCrossRef" href="#bib52">52</a>&#46;</p><p id="para120" class="elsevierStylePara elsevierViewall">The presence of the LT antigen is a universal characteristic of the members of the <span class="elsevierStyleItalic">Polyomaviridae</span> family&#46; LT antigens share high identity between the members of the PyV genus&#44; which allows recognition by cross-hybridization in western blots performed with a few specific antibodies <a class="elsevierStyleCrossRef" href="#bib54">54</a>&#46; The N-terminal region of this protein contains a DnaJ domain&#44; which contributes to viral replication and mediates the binding of the cellular chaperone HSc70&#46; This protein also contains an LXCXE motif that binds the members of the retinoblastoma protein family pRb&#44; p107 and p130&#46; Together DnaJ and LXCXE disturb the pRb&#47;E2F complexes&#44; promoting the progression of the cell cycle <a class="elsevierStyleCrossRef" href="#bib11">11</a>&#46; The C-terminal domain of the LT antigen harbors a conserved threonine residue that&#44; when phosphorylated&#44; competes with cyclin E1 and Myc to bind to FBXW7&#46; The protein FBXW7 &#40;F-box&#41; is part of the ubiquitin ligase complex formed by Skp1&#47;culin&#47;F-box &#40;SCF&#41;&#46; As such&#44; LT prevents the degradation of cyclin E1 and Myc and contributes to cell growth and proliferation <a class="elsevierStyleCrossRef" href="#bib31">31</a>&#46;</p><p id="para130" class="elsevierStylePara elsevierViewall">The LT antigen also presents a nuclear localization sequence &#40;NLS&#41;&#44; an origin-binding domain &#40;OBD&#41; and a helicase domain&#46; The OBD and the helicase domain are critical for viral genome replication <a class="elsevierStyleCrossRef" href="#bib55">55</a>&#46; Finally&#44; LT antigens from many&#44; but not all&#44; HPyVs exhibit a p53-binding domain <a class="elsevierStyleCrossRef" href="#bib56">56</a>&#44;<a class="elsevierStyleCrossRef" href="#bib57">57</a>&#46; The colocalization of p53 and the LT antigen has been demonstrated in the cytoplasm of cultured cells of BKPyV-positive neuroblastoma and prostate cancer <a class="elsevierStyleCrossRef" href="#bib58">58</a>&#44;<a class="elsevierStyleCrossRef" href="#bib59">59</a>&#46; It is believed that this interaction may block the expression of p53-regulated genes in response to DNA damage <a class="elsevierStyleCrossRef" href="#bib57">57</a>&#46; Another cellular target of early PyV proteins is the phosphatase PP2A <a class="elsevierStyleCrossRef" href="#bib60">60</a>&#46; This protein is inactivated by T antigens from SV40&#44; JCPyV and MCPyV <a class="elsevierStyleCrossRef" href="#bib59">59</a>&#46; PP2A is a critical regulator of the mitogen-activated protein kinase &#40;MAPK&#41; signaling cascade and has many functions&#46; This protein contributes to the control of cellular metabolism by regulating the activities of different enzymes involved in glycolysis&#44; lipid metabolism and catecholamine synthesis <a class="elsevierStyleCrossRef" href="#bib61">61</a>&#46; In addition&#44; this protein regulates various critical processes&#44; such as cell cycle progression&#44; DNA replication and transcription&#44; protein translation&#44; signal transduction&#44; cytoskeletal dynamics&#44; cell mobility and apoptosis&#46; As such&#44; PP2A plays an important role in cell transformation and cancer <a class="elsevierStyleCrossRefs" href="#bib62">62-65</a>&#46;</p><p id="para140" class="elsevierStylePara elsevierViewall">Most HPyVs have the potential to cause nonneoplastic diseases in the context of immunosuppression <a class="elsevierStyleCrossRef" href="#bib54">54</a>&#46; However&#44; this association has only been confirmed for a few of these viruses&#46; Among the 4 PyVs associated with diseases in immunosuppressed humans&#44; two are associated with proliferative diseases of the skin&#46; MCPyV is associated with MCC&#44; while TSPyV is the etiological factor for Trichodysplasia spinulosa &#40;TS&#41;&#46; The two other viruses are JCPyV&#44; which is associated with PML&#44; and BKPyV&#44; which is a leading cause of chronic dysfunction in renal transplant patients&#44; urethral stenosis and nephropathy&#46; The main characteristics of these viruses will be presented in the next sections&#46; Moreover&#44; the cell transforming potential exhibited by different HPyV proteins <span class="elsevierStyleItalic">in vitro</span> raises the intriguing possibility that some of these agents&#44; in addition to MCPyV&#44; may be associated with specific human cancers&#46; Therefore&#44; several studies conducted by different groups around the world have addressed the presence of all HPyVs in different human tumors&#46; <a class="elsevierStyleCrossRef" href="#t1-cln_73p1">Table 1</a> presents a comprehensive summary of the main results obtained&#46;</p><elsevierMultimedia ident="t1-cln_73p1"></elsevierMultimedia></span><span id="cesec40" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle40">Merkel cell polyomavirus and Merkel cell carcinoma</span><p id="para150" class="elsevierStylePara elsevierViewall">In 2008&#44; the identification of the fifth HPyV&#44; detected in samples of MCC&#44; was reported&#44; and this virus was named MCPyV&#46; The authors performed digital transcriptome subtraction &#40;DTS&#41; in MCC samples and identified one sequence that exhibited no similarity with human transcripts&#46; In-depth analysis of the transcript using nucleotide databases showed that this sequence was related to the T antigen sequence from simian lymphotropic polyomavirus &#40;LPyV&#41; and BKPyV&#46; The viral genome&#44; which was detected in 80&#37; of the MCC samples&#44; was amplified by <span class="elsevierStyleItalic">primer walking</span> and sequenced&#46; The study also showed that in most of the MCPyV-positive tumors&#44; the viral DNA exhibited a clonal integration pattern within the cell genome&#46; The same integration pattern detected in primary tumors was observed in the derived metastases&#44; supporting the notion that viral integration preceded the clonal expansion of tumor <a class="elsevierStyleCrossRef" href="#bib37">37</a>&#46;</p><p id="para160" class="elsevierStylePara elsevierViewall">MCC&#44; a rare and aggressive neoplasia&#44; was described in 1972 by Toker as a trabecular carcinoma of the skin <a class="elsevierStyleCrossRef" href="#bib66">66</a>&#46; Data from the Netherlands show an incidence rate of 0&#44;35 cases per 100&#46;000 per year &#40;0&#44;35&#47;100&#46;000&#41;&#44; while the incidence in the USA is 0&#44;24&#47;100&#46;000 <a class="elsevierStyleCrossRef" href="#bib67">67</a>&#44;<a class="elsevierStyleCrossRef" href="#bib68">68</a>&#46; On the other hand&#44; in Queensland &#40;Australia&#41;&#44; where most habitants are Caucasian&#44; the incidence increases to 1&#44;6&#47;100&#46;000 <a class="elsevierStyleCrossRef" href="#bib69">69</a>&#46; This tumor is more prevalent in men &#40;61&#37; of the cases&#41; than in women&#44; particularly in white individuals older than 65 years <a class="elsevierStyleCrossRefs" href="#bib68">68-70</a>&#46; This pathology is well described by the acronym AEIOU&#58; &#8220;<span class="elsevierStyleUnderline">A</span>symptomatic&#47;lack of tenderness&#44; <span class="elsevierStyleUnderline">E</span>xpanding rapidly&#44; <span class="elsevierStyleUnderline">I</span>mmune suppression&#44; <span class="elsevierStyleUnderline">O</span>lder than age 50&#44; and <span class="elsevierStyleUnderline">U</span>V-exposed site on a person with fair skin&#8221; <a class="elsevierStyleCrossRef" href="#bib71">71</a>&#46; MCC occurs as fast-growing reddish-blue nodules located mainly over soft tissues&#44; sometimes with telangiectasia&#44; in areas exposed to intense solar radiation&#46; The occurrence of MCC varies from 41&#37; to 50&#37; in the head and neck&#44; 32&#37; to 38&#37; in the limbs and 12&#37; to 14&#37; in the trunk of the body <a class="elsevierStyleCrossRef" href="#bib72">72</a>&#46; In addition&#44; MCC can be detected in anatomic areas with low UV exposure&#44; such as genitalia and mucosa <a class="elsevierStyleCrossRef" href="#bib71">71</a>&#46; Interestingly&#44; a retrospective study conducted in the USA showed that MCC cases in black people occur mainly at the extremities of the inferior limbs <a class="elsevierStyleCrossRef" href="#bib73">73</a>&#46; The ultimate diagnosis of MCC is given by histopathological analysis of biopsies&#46; This tumor presents small ovoid cells with hyperchromatic nuclei&#44; which are characteristic of neuroendocrine tumors&#46; The tumor architecture may be trabecular&#44; nodular or diffuse <a class="elsevierStyleCrossRef" href="#bib74">74</a>&#46; The best immunohistochemical markers for this pathology are neurofilaments and cytokeratin 20 <a class="elsevierStyleCrossRef" href="#bib75">75</a>&#46;</p><span id="cesec50" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle50">Merkel cell polyomavirus biology and epidemiology</span><p id="para170" class="elsevierStylePara elsevierViewall">The MCPyV genome comprises 5387 bp &#40;isolate MCC350&#44; EU375803&#41; and exhibits the characteristic organization of the family &#40;<a class="elsevierStyleCrossRef" href="#fig2-cln_73p1">Figure 2</a>&#41;&#46; The early region of this virus expresses the large T &#40;LT&#41;&#44; small &#40;sT&#41;&#44; and 57kT antigens <a class="elsevierStyleCrossRef" href="#bib76">76</a>&#46; In addition&#44; in 2013&#44; the existence of a fourth ORF&#44; expressed from an alternative transcription initiation site located in the second exon of the gene coding for the LT antigen was described&#46; The protein coded by this gene is called alternate frame of the large T ORF &#40;ALTO&#41;&#59; this protein is expressed in replicating infected cells and remains in the cytosol&#46; The role of this protein in the viral cycle and associated diseases has not been determined&#46; Intriguingly&#44; the ORF that encodes this protein has been found to be mutated in tumor tissues&#44; suggesting that this protein may play a role in viral pathogenesis <a class="elsevierStyleCrossRef" href="#bib77">77</a>&#46; The importance of the LT antigen in the pathology mediated by this virus is highlighted by the fact that silencing of this antigen in MCPyV-positive MCC-derived cells inhibits cell growth and induces senescence <a class="elsevierStyleCrossRef" href="#bib78">78</a>&#46; Several studies have demonstrated that MCPyV genomes present in tumors exhibit mutations in the 3&#39; region of the gene encoding the LT antigen&#44; mainly at the region upstream of the helicase domain and downstream of the gene encoding the sT antigen <a class="elsevierStyleCrossRef" href="#bib53">53</a>&#44;<a class="elsevierStyleCrossRefs" href="#bib79">79-81</a>&#46; The accumulation of mutations in this portion of the LT antigen is important in the process of carcinogenesis since these mutations downregulate viral replication and viral load&#44; allowing immune evasion while retaining the ability to promote unscheduled cell proliferation&#46; This phenomenon is possible because the mutated form of the LT antigen always preserves the domains that are involved in interactions with cellular factors&#44; including the domain that targets pRb <a class="elsevierStyleCrossRef" href="#bib82">82</a>&#46; The sT antigen&#44; a 186-amino-acid protein&#44; harbors the site for PP2A binding&#46; This site is conserved among PyVs and plays a role in cellular transformation <a class="elsevierStyleCrossRef" href="#bib60">60</a>&#46; In addition&#44; the sT antigen promotes LT-antigen-dependent MCV genome replication by sequestering the F-box and WD repeat domain containing 7 &#40;FBXW7&#41; component of the Skp&#44; Cullin&#44; F-box &#40;SCF&#41;-containing ubiquitin ligase responsible for LT antigen degradation by the proteasome <a class="elsevierStyleCrossRef" href="#bib76">76</a>&#44;<a class="elsevierStyleCrossRef" href="#bib83">83</a>&#46; The amino acids at position 91 to 95 of the sT antigen are required for this function and define the large T stabilization domain &#40;LSD&#41;&#46; Mutation of the LSD in the sT antigen leads to downregulation of the LT antigen and prevents viral genome replication&#46; Mutations in this domain also prevent rodent cell transformation and induction of cellular oncoproteins&#44; including c-Myc and cyclin E&#44; by the sT antigen <a class="elsevierStyleCrossRef" href="#bib84">84</a>&#46; Moreover&#44; <span class="elsevierStyleItalic">in vitro</span> and <span class="elsevierStyleItalic">in vivo</span> observations indicate that LSD integrity is required for sT mediated induction of supernumerary centrosomes&#44; appearance of aneuploid cells&#44; accumulation of chromosomal breaks and micronuclei <a class="elsevierStyleCrossRef" href="#bib85">85</a>&#46; Importantly&#44; sustained expression of the sT antigen in MCPyV is required for tumor cell proliferation&#44; which has been linked to sT-antigen-mediated stabilization of the eukaryotic translation initiation factor 4E-binding protein 1 &#40;4E-BP1&#41;&#44; which leads to increased cap-dependent translation in infected cells <a class="elsevierStyleCrossRef" href="#bib86">86</a>&#46; Moreover&#44; a recent study conducted using an <span class="elsevierStyleItalic">in vivo</span> model of MCC showed that expression of the sT antigen with an intact LSD domain was critical for tumor initiation&#46; On the other hand&#44; coexpression of LT did not affect the frequency of tumor establishment <a class="elsevierStyleCrossRef" href="#bib87">87</a>&#46; Finally&#44; the MCPyV sT antigen is more frequently detected in human MCC tumors than the LT antigen&#46; These observations suggest a critical role for the sT antigen in MCPyV-mediated carcinogenesis&#46; As previously mentioned&#44; MCPyV integration into the genome of the host cell&#44; which interrupts normal viral cycle regulation&#44; is a critical step in MCC development <a class="elsevierStyleCrossRef" href="#bib76">76</a>&#46; To date&#44; there has been no report of MCCs harboring MCPyV DNA in the episomal state&#46; Importantly&#44; a truncated form of the LT antigen or its complete smaller isoforms continue to be expressed&#44; altering cell homeostasis <a class="elsevierStyleCrossRefs" href="#bib88">88-91</a>&#46;</p><elsevierMultimedia ident="fig2-cln_73p1"></elsevierMultimedia><p id="para180" class="elsevierStylePara elsevierViewall">Finally&#44; the MCPyV early region expresses a microRNA with no identified cellular target but complementary to the 3&#39; portion of the LT antigen&#44; suggesting the involvement of this microRNA in the regulation of the expression of the viral protein <a class="elsevierStyleCrossRef" href="#bib5">5</a>&#46;</p><p id="para190" class="elsevierStylePara elsevierViewall">The late region harbors the genes that encode the structural proteins VP1&#44; VP2 and VP3&#46; Interestingly&#44; VP3 is not detected in MCPyV-infected cells or in MCPyV virions&#46; Moreover&#44; alteration of the initiation codon of the VP3 ORF does not alter the infectivity of MCPyV in cell culture&#46; These observations indicate that VP3 may be expressed under only certain conditions <a class="elsevierStyleCrossRef" href="#bib92">92</a>&#46;</p><p id="para200" class="elsevierStylePara elsevierViewall">The study of MCPyV prevalence in the human population suggests that this virus is part the skin microbiota <a class="elsevierStyleCrossRef" href="#bib38">38</a>&#46; Exposure to this agent occurs early in life&#44; as demonstrated by serological surveys&#44; which showed that 20&#37; to 40&#37; of children less than five years old test positive for antibodies against this virus&#46; In addition&#44; positivity increases to 80&#37; in individuals more than 50 years old <a class="elsevierStyleCrossRef" href="#bib27">27</a>&#44;<a class="elsevierStyleCrossRef" href="#bib50">50</a>&#44;<a class="elsevierStyleCrossRefs" href="#bib93">93-97</a>&#46; Transmission may occur via direct contact with the skin or saliva <a class="elsevierStyleCrossRef" href="#bib98">98</a>&#46; In addition&#44; airborne as well as fecal-oral routes of transmission have been proposed <a class="elsevierStyleCrossRefs" href="#bib99">99-101</a>&#46; A prospective study conducted with bisexual and homosexual adults who were controlled at six month intervals showed that primary infection is asymptomatic in most of the cases&#46; Analysis of clinical variables such as fever&#44; presence of sprouts&#44; diarrhea or loss of weight&#44; as well as cytological tests involving the counting of erythrocytes and lymphocytes &#40;including CD4 and CD8 populations&#41; were unable to differentiate control individuals from those that had seroconverted <a class="elsevierStyleCrossRef" href="#bib97">97</a>&#46; As described above&#44; MCPyV is considered to be a part of the skin microbiota&#46; However&#44; detection of viral DNA is very frequent in patients with MCC&#44; even at sites that are distant from the lesion <a class="elsevierStyleCrossRef" href="#bib80">80</a>&#44;<a class="elsevierStyleCrossRef" href="#bib102">102</a>&#46; Viral DNA has been detected in blood&#44; eyebrows&#44; nasal swabs and aspirates&#44; and adrenal glands <a class="elsevierStyleCrossRef" href="#bib80">80</a>&#44;<a class="elsevierStyleCrossRef" href="#bib99">99</a>&#44;<a class="elsevierStyleCrossRefs" href="#bib101">101-104</a>&#46; The presence of this virus has been analyzed in other tissues and was not detected in samples from the central nervous system <a class="elsevierStyleCrossRef" href="#bib105">105</a>&#46; However&#44; analysis of viral presence in lymphoid tissues led to unconclusive results <a class="elsevierStyleCrossRefs" href="#bib106">106-108</a>&#46;</p></span><span id="cesec60" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle60">Pathogenesis of Merkel cell polyomavirus</span><p id="para210" class="elsevierStylePara elsevierViewall">Merkel cells are located at the basal layer of the epithelia of the skin and oral mucosa and are in direct contact with the tactile neural discs&#44; to which these cells transmit mechanical information&#46; Merkel cells are associated with afferent demyelinated neurons of the dermis <a class="elsevierStyleCrossRef" href="#bib109">109</a>&#46; In the skin&#44; these cells are part of the somatic sensorial system and are classified as exteroreceptors&#46; However&#44; in the epithelium of the mouth&#44; the format and function of these cells increase in complexity <a class="elsevierStyleCrossRef" href="#bib110">110</a>&#46; Although MCC is diagnosed by the detection of specific markers&#44; namely&#44; cytokeratin 20 and CD56&#44; the origin of Merkel cells remains a matter of debate <a class="elsevierStyleCrossRef" href="#bib111">111</a>&#46; Considering the analysis of the expression of different cellular markers&#44; several hypotheses have been proposed&#44; including epithelial stem cells and pre-pro-B lymphocytes being the precursors of Merkel cells <a class="elsevierStyleCrossRefs" href="#bib112">112-116</a>&#46; However&#44; independent of the anatomic locations of these cells&#44; when observed by electron microscopy&#44; Merkel cell tumors exhibit neuroendocrine granules&#44; suggesting the neuroendocrine origin of these malignancies <a class="elsevierStyleCrossRef" href="#bib117">117</a>&#46; Results from a recent study suggest that dermal fibroblasts may be the primary cells infected by MCPyV <a class="elsevierStyleCrossRef" href="#bib118">118</a>&#46; Interestingly&#44; analysis of MCPyV expression and replication in dermal fibroblasts from different species demostrated that only human and chimpanzee cells were permissive for the production of infectious MCPyV <a class="elsevierStyleCrossRef" href="#bib119">119</a>&#46; However&#44; no viral DNA or protein has been detected in the dermis adjacent to MCPyV-positive MCCs <a class="elsevierStyleCrossRef" href="#bib120">120</a>&#46;</p><p id="para220" class="elsevierStylePara elsevierViewall">Immunosuppression is another important factor in MCC development and progression&#46; In fact&#44; immunocompromised individuals exhibit a higher &#40;16-fold&#41; relative risk for MCC than the normal population <a class="elsevierStyleCrossRef" href="#bib70">70</a>&#46; Immunosuppression allows the establishment of persistent infections&#44; even in the presence of immunogenic viral antigens <a class="elsevierStyleCrossRef" href="#bib121">121</a>&#46; In addition&#44; similar to other tumor viruses&#44; including human papillomaviruses&#44; Kaposi&#39;s sarcoma herpesvirus and human T lymphotropic virus type-I&#44; MCPyV exhibits a series of immune evasion mechanisms&#46; For instance&#44; it has been observed that the LT antigen inhibits the activity of the transcription factor C&#47;EBP&#946;&#44; which downregulates the expression of Toll-like receptor 9 <a class="elsevierStyleCrossRef" href="#bib122">122</a>&#46; This fact makes the cell unable to detect unmethylated double-stranded DNA in its cytoplasm <a class="elsevierStyleCrossRef" href="#bib123">123</a>&#46; Moreover&#44; the sT antigen binds NF-&#954;B &#40;NEMO&#47;IKK-&#947;&#41;&#44; altering an important pathway involved in innate immunity <a class="elsevierStyleCrossRef" href="#bib124">124</a>&#46; In addition&#44; MCPyV-positive MCCs present lower levels of MHC I than MCPyV-negative tumors&#46; Usually&#44; cells lacking MHC I expression are eliminated by natural killers &#40;NK&#41; cells&#46; Importantly&#44; MCPyV reduces the expression of the NK-activating receptor group 2&#44; member D &#40;NKG2D&#41;&#44; allowing the survival of tumor cells expressing low levels of MHC I <a class="elsevierStyleCrossRef" href="#bib125">125</a>&#46; However&#44; MHC I expression may be induced in MCPyV-positive cells in response to IFN-&#947;&#44; which may prove relevant for MCC treatment <a class="elsevierStyleCrossRef" href="#bib126">126</a>&#46;</p><p id="para230" class="elsevierStylePara elsevierViewall">Studies conducted in different populations have shown that patients diagnosed with MCC are at higher risk of developing second neoplasias <a class="elsevierStyleCrossRef" href="#bib66">66</a>&#44;<a class="elsevierStyleCrossRefs" href="#bib127">127&#8211;129</a>&#46; Among these neoplasias&#44; malignant skin tumors are the most frequent&#44; highlighting the effect of UV radiation in the genesis of these different types of tumors <a class="elsevierStyleCrossRef" href="#bib127">127</a>&#44;<a class="elsevierStyleCrossRef" href="#bib130">130</a>&#46; In addition&#44; lymphoid leukemia is also common in MCC patients <a class="elsevierStyleCrossRef" href="#bib131">131</a>&#46; Importantly&#44; in many cases&#44; the second neoplasia is an independent primary MCC <a class="elsevierStyleCrossRefs" href="#bib132">132-138</a>&#46;</p><p id="para240" class="elsevierStylePara elsevierViewall">Finally&#44; the presence of MCPyV has been analyzed in different human tumors&#46; The results from several studies addressing this issue are summarized in <a class="elsevierStyleCrossRef" href="#t1-cln_73p1">Table 1</a>&#46;</p></span></span><span id="cesec70" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle70">John Cunningham polyomavirus</span><p id="para250" class="elsevierStylePara elsevierViewall">The human polyomavirus JCPyV is genetically related to BKPyV and SV40&#46; The first report of this virus was made by Zurhein and Chou more than fifty years ago <a class="elsevierStyleCrossRef" href="#bib139">139</a>&#46; Using electron microscopy&#44; these authors observed the presence of particles similar to papovavirus in oligodendrocytes present in demyelinated areas of the brains of patients with PML <a class="elsevierStyleCrossRef" href="#bib139">139</a>&#46; The virus was then isolated after the inoculation of brain extracts from a patient with PML &#40;patient John Cunningham&#41; in primary human fetal glial cells <a class="elsevierStyleCrossRef" href="#bib33">33</a>&#46;</p><p id="para260" class="elsevierStylePara elsevierViewall">Different studies have shown that 40-60&#37; of all adults exhibit IgG antibodies against the JCPyV VP1 protein <a class="elsevierStyleCrossRef" href="#bib31">31</a>&#44;<a class="elsevierStyleCrossRef" href="#bib51">51</a>&#46; Initial subclinical infections occur during childhood&#44; and the virus establishes lifelong infections in specific sites&#44; such as the proximal kidney tubule&#46; On rare occasions&#44; the virus may be reactivated&#46; This phenomenon is more frequent in immunosuppressed individuals&#44; such as patients with AIDS or recipients of organ transplants&#44; than in non-immunocompromised individuals <a class="elsevierStyleCrossRef" href="#bib31">31</a>&#46; Viral reactivation may lead to the development of PML&#44; a fatal demyelinating disorder of the central nervous system caused by the destruction of oligodendrocytes as a consequence of the lytic viral cycle <a class="elsevierStyleCrossRef" href="#bib11">11</a>&#44;<a class="elsevierStyleCrossRef" href="#bib140">140</a>&#46; In addition&#44; this virus has been associated with renal diseases in immunosuppressed individuals and organ transplant recipients <a class="elsevierStyleCrossRefs" href="#bib141">141-144</a>&#46;</p><span id="cesec80" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle80">Viral biology and epidemiology</span><p id="para270" class="elsevierStylePara elsevierViewall">The 5130-bp genome of JCPyV &#40;J02226&#41; presents the same general characteristics that are typical of PyVs&#44; as described above <a class="elsevierStyleCrossRef" href="#bib1">1</a> &#40;<a class="elsevierStyleCrossRef" href="#fig2-cln_73p1">Figure 2</a>&#41;&#46; This virus expresses three structural proteins&#44; namely&#44; VP1&#44; VP2 and VP3&#44; from its late region&#44; with VP1 being the major capsid protein <a class="elsevierStyleCrossRef" href="#bib145">145</a>&#46; In addition&#44; this virus expresses three regulatory proteins&#46; The LT and sT antigens are expressed from the early region&#44; while the gene coding for agnoprotein is located in the late region&#46; Three splicing variants have been reported for the LT antigen&#44; namely&#44; T&#8242;135&#44; T&#8242;136&#44; and T&#8242;<span class="elsevierStyleInf">165</span>&#44; which are expressed in infected cells during the lytic cycle <a class="elsevierStyleCrossRef" href="#bib146">146</a>&#44;<a class="elsevierStyleCrossRef" href="#bib147">147</a>&#46; In addition&#44; JCPyV expresses a microRNA that may be involved in regulation of the LT antigen&#44; as reported for MCPyV <a class="elsevierStyleCrossRef" href="#bib5">5</a>&#46;</p><p id="para280" class="elsevierStylePara elsevierViewall">The JCPyV LT antigen shares structural and functional homology with LT antigens from other PyVs&#46; Similar to LT antigens from other PyVs the JCPyV LT antigen and its splicing variants are multifunctional proteins that interact with viral and host DNA and proteins affecting their functions&#46; As previously mentioned&#44; LT antigens are important for the induction of DNA replication in infected cells&#44; allowing the virus to usurp the DNA replication machinery to amplify its genome <a class="elsevierStyleCrossRef" href="#bib10">10</a>&#44;<a class="elsevierStyleCrossRef" href="#bib11">11</a>&#46; This occurrence fosters viral multiplication in permissive cells and viral transmission&#46; However&#44; JCPyV infection of nonpermissive cells may lead to cellular transformation <a class="elsevierStyleCrossRef" href="#bib57">57</a>&#46; Expression of the LT antigen may be regulated by the expression of a viral microRNA complementary to the 3&#39; region of the early mRNA&#46; In addition&#44; this microRNA targets the cellular mRNA that expresses UL16-binding protein 3 &#40;ULBP3&#41; <a class="elsevierStyleCrossRef" href="#bib6">6</a>&#44; probably leading to inhibition of the antiviral response of NK cells <a class="elsevierStyleCrossRef" href="#bib148">148</a>&#46;</p><p id="para290" class="elsevierStylePara elsevierViewall">Other viral proteins are involved in the control of the cell cycle and viral replication&#46; JCPyV also expresses an sT antigen&#46; As described above for TSPyV and JCPyV&#44; the sT antigen binds the phosphatase PP2A&#44; promoting cell proliferation <a class="elsevierStyleCrossRef" href="#bib149">149</a>&#46; In addition&#44; sT targets members of the pRb family&#44; further affecting cell cycle control <a class="elsevierStyleCrossRef" href="#bib150">150</a>&#46; The JCPyV agnoprotein has been described as a multifunctional factor <a class="elsevierStyleCrossRef" href="#bib151">151</a>&#46; Functional elimination of this protein by deletion or mutation leads to a dramatic downregulation of viral genome replication and transcription <a class="elsevierStyleCrossRef" href="#bib22">22</a>&#46; However&#44; the effect of this protein on host cell homeostasis is not clearly understood&#46; The agnoprotein of JCPyV may bind several cellular factors&#44; including p53&#44; YB-1&#44; Ku70&#44; FEZ1&#44; HP1&#945;&#44; PP2A&#44; AP-3&#44; PCNA&#44; and &#945;-SNAP&#46; In addition&#44; this protein can bind LT&#44; sT and VP1 and regulate the viral cycle <a class="elsevierStyleCrossRef" href="#bib22">22</a>&#44;<a class="elsevierStyleCrossRef" href="#bib152">152</a>&#46; JCPyV variants carrying deletions in the gene coding for the agnoprotein have been linked to the development of severe encephalopathy&#44; which is of clinical relevance <a class="elsevierStyleCrossRef" href="#bib153">153</a>&#46;</p><p id="para300" class="elsevierStylePara elsevierViewall">JCPyV inoculation in animal models&#44; including rodents and nonhuman primates&#44; that are not permissive to the replication of this virus resulted in the formation of tumors&#46; Since then&#44; the tumorigenic potential of this virus in humans and the association of this virus with the development of some human malignancies has been a matter of debate <a class="elsevierStyleCrossRef" href="#bib154">154</a> &#40;<a class="elsevierStyleCrossRef" href="#t1-cln_73p1">Table 1</a>&#41;&#46; To date&#44; no conclusive prospective studies supporting a causal association between JCPyV infection and cancer development in humans have been conducted&#46; Several case-control studies&#44; sometimes nested within cohort studies&#44; have been conducted to establish the association between JCPyV seropositivity and specific human tumor types&#44; including colorectal cancer <a class="elsevierStyleCrossRefs" href="#bib155">155-161</a>&#44; lymphoma <a class="elsevierStyleCrossRef" href="#bib162">162</a>&#44;<a class="elsevierStyleCrossRef" href="#bib163">163</a>&#44; central nervous system tumors <a class="elsevierStyleCrossRef" href="#bib164">164</a><a class="elsevierStyleCrossRefs" href="#bib165">165&#8211;166</a>&#44; esophageal carcinoma <a class="elsevierStyleCrossRef" href="#bib167">167</a>&#44; carcinoma of the bladder <a class="elsevierStyleCrossRef" href="#bib168">168</a>&#44; and prostate cancer <a class="elsevierStyleCrossRef" href="#bib169">169</a>&#46; These results should be interpreted with caution since anti-JCPyV antibodies may persist for decades&#44; indicating previous exposure to the agent but not viral reactivation&#46; On the other hand&#44; detection of JCPyV by qPCR in the urine indicates active replication and has been applied for the detection of the virus in cases of colorectal and bladder carcinomas <a class="elsevierStyleCrossRef" href="#bib170">170</a>&#44;<a class="elsevierStyleCrossRef" href="#bib171">171</a>&#46;</p><p id="para310" class="elsevierStylePara elsevierViewall">To date&#44; the oncogenic potential of this virus has not been clearly established&#46; Moreover&#44; although JCPyV DNA has been detected in a varying percentage of gastrointestinal tumors&#44; the IARC classifies this virus as a group 2B carcinogen&#44; indicating that JCPV is possibly carcinogenic to humans <a class="elsevierStyleCrossRef" href="#bib51">51</a>&#44;<a class="elsevierStyleCrossRef" href="#bib161">161</a>&#46;</p><p id="para320" class="elsevierStylePara elsevierViewall">It is well established that immunosuppressed individuals exhibit an increased risk of cancer&#46; Few studies have addressed the prevalence of JCPyV in tumors of immunosuppressed patients&#46; In a recent study&#44; Bolting et al&#46; observed a higher prevalence of JCPyV DNA in the normal mucosa of the gastrointestinal tracts of patients who received immunosuppressant therapy than in immunocompetent control individuals &#40;23&#44;7&#37; vs&#46; 6&#44;3&#37;&#59; p &#61; 0&#44;02&#41; <a class="elsevierStyleCrossRef" href="#bib172">172</a>&#46; Importantly&#44; organ transplant recipients exhibited a relative risk of 10&#46;4 &#40;prevalence 35&#44;3&#37;&#41; for carrying viral DNA&#46; Altogether&#44; these results suggest that persistent viral infection in immunosuppressed individuals may be a risk factor for tumor development&#46; Further studies are needed to confirm this hypothesis&#46; Another study compared the prevalence of JCPyV between the normal colonic epithelium and adenomatous polyps from liver transplant recipients &#40;LTRs&#41; and normal and adenoma tissue samples from control patients <a class="elsevierStyleCrossRef" href="#bib173">173</a>&#46; The authors observed that LTRs exhibited higher prevalence of JCPyV DNA in the normal colonic mucosa than the control patients &#40;67&#37; vs&#46; 24&#37;&#44; p &#61; 0&#46;025&#41;&#46; In addition&#44; the JCPyV LT antigen protein was detected at a higher proportion in adenomas from LTRs than in those from immunocompetent patients &#40;50&#37; vs&#46; 5&#37;&#44; p &#60; 0&#46;001&#41; <a class="elsevierStyleCrossRef" href="#bib173">173</a>&#46; These results suggest that JCPyV may be reactivated under immunosuppressive conditions&#46;</p><p id="para330" class="elsevierStylePara elsevierViewall">Altogether&#44; the data discussed above underscore the need for further molecular and epidemiological studies to gain insights into the mechanisms of JCPyV pathogenesis&#46; Molecular studies conducted to better characterize the impact of viral proteins in cellular processes will be needed to determine the mechanisms of JCPyV-mediated cell transformation&#46; In addition&#44; epidemiological&#44; prospective and multicentric studies will be necessary to determine the existence of causality between JCPyV and specific human cancers&#46;</p></span></span><span id="cesec90" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle90">BK polyomavirus</span><p id="para340" class="elsevierStylePara elsevierViewall">Ninety percent of adults worldwide have been exposed to BKPyV&#46; As is the case for the other PyVs discussed in this review&#44; initial BKPyV infection occurs during childhood <a class="elsevierStyleCrossRef" href="#bib174">174</a>&#46; The virus seems to be transmitted via multiple routes&#44; including respiratory&#44; urine-oral&#44; feco-oral&#44; and transplacental and via transplantation of infected organs <a class="elsevierStyleCrossRefs" href="#bib174">174-179</a>&#46;</p><p id="para350" class="elsevierStylePara elsevierViewall">Four BKPyV genotypes&#44; namely&#44; I&#44; II&#44; III and IV have been described based on variations in the nucleotide sequence of the gene coding the structural protein VP1 and constitute different serotypes <a class="elsevierStyleCrossRef" href="#bib49">49</a>&#44;<a class="elsevierStyleCrossRef" href="#bib180">180</a> &#40;<a class="elsevierStyleCrossRef" href="#fig2-cln_73p1">Figure 2</a>&#41;&#46; BKPyV expresses two minor structural proteins&#44; namely&#44; VP2 and VP3&#44; which participate in nuclear entry upon infection and virion mounting <a class="elsevierStyleCrossRef" href="#bib181">181</a>&#46; In addition&#44; BKPyV expresses a microRNA with similar functional characteristics as those described for JCPyV <a class="elsevierStyleCrossRef" href="#bib5">5</a>&#44;<a class="elsevierStyleCrossRef" href="#bib6">6</a>&#44;<a class="elsevierStyleCrossRef" href="#bib148">148</a>&#46; Finally&#44; the BKPyV late region expresses an agnoprotein important for the productive life cycle of the virus <a class="elsevierStyleCrossRef" href="#bib182">182</a>&#44;<a class="elsevierStyleCrossRef" href="#bib183">183</a>&#46; Agnoprotein has been shown to interact with the N-ethylmaleimide-sensitive factor attachment protein alpha &#40;&#945;-SNAP&#41;&#44; affecting the secretion of fusion reporter proteins and supporting a role for this viral protein in the regulation of exocytosis <a class="elsevierStyleCrossRef" href="#bib184">184</a>&#46; In addition&#44; agnoprotein also targets the proliferating cell nuclear antigen &#40;PCNA&#41;&#44; downregulating DNA synthesis and cell proliferation <span class="elsevierStyleItalic">in vitro</span><a class="elsevierStyleCrossRef" href="#bib185">185</a>&#46; This observation suggests that agnoprotein may inhibit viral DNA synthesis at late stages of the viral cycle to allow virion mounting&#46; The early region of the BKPyV genome expresses LT and sT antigens&#46; Recently&#44; the expression of a truncated form of the T antigen &#40;trT&#41; has been reported <a class="elsevierStyleCrossRef" href="#bib186">186</a>&#46;</p><p id="para360" class="elsevierStylePara elsevierViewall">After primary infection&#44; the virus may establish persistent infection in uroepithelial cells&#44; oligodendrocytes and mononuclear cells from the blood <a class="elsevierStyleCrossRef" href="#bib49">49</a>&#44;<a class="elsevierStyleCrossRef" href="#bib174">174</a>&#46; In a great majority of the cases&#44; the infection is asymptomatic&#44; and the virus can be detected in the urine of 0&#44;5&#37; to 20&#37; of the healthy population <a class="elsevierStyleCrossRef" href="#bib178">178</a>&#44;<a class="elsevierStyleCrossRef" href="#bib187">187</a>&#46; However&#44; BKPyV can be reactivated in organ transplant recipients due to the immunosuppressant therapy used in these patients&#46; Viral reactivation is associated with increased viral load and destruction of infected tissues <a class="elsevierStyleCrossRef" href="#bib49">49</a>&#46; In fact&#44; BKPyV is one of the leading causes of kidney transplant failure&#44; and the prevalence of this virus in kidney transplant recipients is high &#40;10&#37; to 60&#37;&#41;&#46; In addition&#44; this virus is associated with ureteric stenosis and nephropathy <a class="elsevierStyleCrossRef" href="#bib178">178</a>&#44;<a class="elsevierStyleCrossRef" href="#bib179">179</a>&#46; Viral reactivation has also been associated with old age&#44; pregnancy&#44; diabetes mellitus&#44; congenic immunodeficiency and AIDS <a class="elsevierStyleCrossRef" href="#bib179">179</a>&#46; Finally&#44; BKPyV has also been detected in HIV-associated salivary gland disease &#40;HIVSGD&#41;&#44; suggesting that this virus may also exhibit tropism for this organ <a class="elsevierStyleCrossRef" href="#bib188">188</a>&#46;</p><p id="para370" class="elsevierStylePara elsevierViewall">As observed for other PyVs&#44; the complete BKPyV genome or fragments containing the early genes are able to transform several cell types from different animals in cell culture systems&#46; However&#44; transformation of human cells by BKPyV is inefficient <a class="elsevierStyleCrossRef" href="#bib189">189</a>&#46; The LT antigen seems to be the main transformation-associated protein in BKPyV&#46; This protein transforms rodent cells and immortalizes human cells in the presence of activated oncogenes such <span class="elsevierStyleItalic">ras</span> and <span class="elsevierStyleItalic">myc</span><a class="elsevierStyleCrossRef" href="#bib189">189</a>&#44;<a class="elsevierStyleCrossRef" href="#bib190">190</a>&#46; <span class="elsevierStyleItalic">In vitro</span> studies have shown that the LT antigen from BKPyV binds p53 as well as members of the pRb family <a class="elsevierStyleCrossRef" href="#bib183">183</a>&#46;</p><p id="para380" class="elsevierStylePara elsevierViewall">BKPyV DNA has been detected in several human cancers&#44; including carcinomas of the lung&#44; pancreas&#44; liver&#44; urogenital tract&#44; head and neck <a class="elsevierStyleCrossRef" href="#bib191">191</a>&#44;<a class="elsevierStyleCrossRef" href="#bib192">192</a>&#46; In addition&#44; this virus has been detected in rhabdomyosarcoma&#44; Kaposi&#39;s sarcoma and brain tumors <a class="elsevierStyleCrossRef" href="#bib192">192</a>&#46; The results from these and other studies are presented in <a class="elsevierStyleCrossRef" href="#t1-cln_73p1">Table 1</a>&#46; In addition&#44; a recent study showed that patients with bladder cancer exhibit higher median antibody titers against this virus than matched controls&#46; Moreover&#44; it was observed that the risk of bladder cancer was significantly increased in individuals exhibiting high antibody titers against BKPyV and MCPyV <a class="elsevierStyleCrossRef" href="#bib168">168</a>&#46;</p><p id="para390" class="elsevierStylePara elsevierViewall">As in the case of JCPyV&#44; BKPyV is considered a possible human carcinogen &#40;2B&#41; by the IARC&#46; Therefore&#44; comprehensive prospective epidemiological studies are needed in order to prove or refute the role of BKPyV in human cancers&#46;</p></span><span id="cesec100" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle100">Concluding remarks</span><p id="para400" class="elsevierStylePara elsevierViewall">The proven cell transforming ability of different members of the <span class="elsevierStyleItalic">Polyomaviridae</span> family has promoted to studies to determine the existence of an association between different HPyVs and cancer development&#46; The first HPyVs were described more than 45 years ago&#46; However&#44; recent technological advances have led to the swift identification of several PyVs in human samples&#46; Epidemiological and molecular data has established MCPyV as a <span class="elsevierStyleItalic">bona fide</span> tumor virus&#46; Moreover&#44; BKPyV and JCPyV are possibly involved in the etiology of specific human malignancies&#46;</p><p id="para410" class="elsevierStylePara elsevierViewall">In fact&#44; there is a possibility that other HPyVs may be related with different malignancies in humans&#46; Multiple studies conducted during the last decade have addressed the presence of almost all the known HPyVs in human tumors &#40;<a class="elsevierStyleCrossRef" href="#t1-cln_73p1">Table 1</a>&#41;&#46; For instance&#44; TS lesions associated with TSPyV infection that affect individuals who receive immunosuppressing therapies are characterized by the expansion of the inner root sheath epithelium&#44; high expression of the proliferation marker Ki-67&#44; presence of eosinophil granules and the trichohyalin protein in the hyperproliferative cells of the internal root of the hair bulb <a class="elsevierStyleCrossRef" href="#bib193">193</a>&#44;<a class="elsevierStyleCrossRef" href="#bib194">194</a>&#46; Importantly&#44; TSPyV sT antigen expression has been linked to the deregulation of cellular pathways involved in the control of cell proliferation and apoptosis <a class="elsevierStyleCrossRef" href="#bib195">195</a>&#46; TSPyV sT and middle T &#40;mT&#41; antigens share the first 196 amino acids&#44; and this region harbors a PP2A-binding motif <a class="elsevierStyleCrossRef" href="#bib196">196</a>&#46; To date&#44; the role of the mT antigen in the regulation of cell proliferation by TSPyV is unknown&#59; however&#44; the role has been well established for MuPyV <a class="elsevierStyleCrossRef" href="#bib197">197</a>&#44;<a class="elsevierStyleCrossRef" href="#bib198">198</a>&#46; A recent study has shown that the TSPyV mT antigen interacts with PP2A via a Zn<span class="elsevierStyleSup">2&#43;</span>-binding domain motif and that this interaction is required for the activation of the pro-proliferative MEK&#47;ERK&#47;MNK1 signaling axis <a class="elsevierStyleCrossRef" href="#bib199">199</a>&#46; As described above&#44; the PP2A-MAPK-regulated pathway is critical for the control of apoptosis and cell proliferation&#46; Therefore&#44; dysregulation of this pathway may lead to uncontrolled cell growth <a class="elsevierStyleCrossRef" href="#bib200">200</a>&#44;<a class="elsevierStyleCrossRef" href="#bib201">201</a>&#46;</p><p id="para420" class="elsevierStylePara elsevierViewall">HPyV6&#44; as well as MCPyV&#44; was detected in human skin health samples as part of the microbiome <a class="elsevierStyleCrossRef" href="#bib38">38</a>&#44;<a class="elsevierStyleCrossRef" href="#bib202">202</a>&#46; Many studies have been conducted to analyze the existence of an association between HPyV6 and lesions of the skin <a class="elsevierStyleCrossRef" href="#bib46">46</a>&#44;<a class="elsevierStyleCrossRef" href="#bib203">203</a>&#44;<a class="elsevierStyleCrossRef" href="#bib204">204</a> and other tissues <a class="elsevierStyleCrossRef" href="#bib47">47</a>&#44;<a class="elsevierStyleCrossRef" href="#bib205">205</a>&#46; To date&#44; these efforts have not led to conclusive results&#46; Interestingly&#44; a recent study detected HPyV6 DNA and the VP1 core protein in samples from patients with melanoma treated with BRAF inhibitors <a class="elsevierStyleCrossRef" href="#bib206">206</a>&#46; However&#44; and intriguingly&#44; all the samples also tested positive for HPyV7 and HPV&#46; Nonetheless&#44; the HPyV6 DNA load detected suggests that this virus may contribute to epithelial cell proliferation in these patients&#46; The HPyV6 sT antigen contains a PP2A binding domain that may be involved in the activation of MAPK signaling cascade and c-Jun <a class="elsevierStyleCrossRef" href="#bib237">237</a>&#46;</p><p id="para430" class="elsevierStylePara elsevierViewall">Some HPyVs have been linked to specific severe pathologies&#44; mainly in immunosuppressed individuals&#46; The growing number of individuals infected with HIV or being treated with immunosuppressant drugs raises the concern that new conditions associated with known or yet-to-be-discovered HPyVs may arise&#46; Therefore&#44; further studies are needed to better characterize these agents and their biology&#44; epidemiology and associations with malignancies in human populations&#46;</p></span></span><span id="cesec110" class="elsevierStyleSection elsevierViewall"><span class="elsevierStyleSectionTitle" id="cestitle110">AUTHOR CONTRIBUTIONS</span><p id="para440" class="elsevierStylePara elsevierViewall">Prado JC prepared the text describing the general characteristics of PyVs&#44; details on Merkel cell PyVs and Table 1&#46; Monezi TA prepared the text describing the general characteristics of TSPyV and its association with human pathologies&#46; She also prepared the illustrations in Figures 1 and 2 and helped prepare Table 1&#46; Amorim AT prepared the text describing the general characteristics of JCPyV and its association with human pathologies&#46; Lino V prepared the text describing the general characteristics of BKPyV and its association with human pathologies&#46; Paladino A revised the entire text and helped prepare Table 1&#46; Boccardo E prepared&#44; revised and corrected the entire text&#46;</p></span></span>"
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              "titulo" => "Biology of polyomaviruses"
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              "titulo" => "Human polyomaviruses"
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              "titulo" => "Merkel cell polyomavirus and Merkel cell carcinoma"
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                  "titulo" => "Merkel cell polyomavirus biology and epidemiology"
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                  "titulo" => "Pathogenesis of Merkel cell polyomavirus"
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              "titulo" => "John Cunningham polyomavirus"
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              "titulo" => "BK polyomavirus"
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              "titulo" => "Concluding remarks"
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          "titulo" => "AUTHOR CONTRIBUTIONS"
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        "resumen" => "<span id="ceabs10" class="elsevierStyleSection elsevierViewall"><p id="spara160" class="elsevierStyleSimplePara elsevierViewall">The name of the family <span class="elsevierStyleItalic">Polyomaviridae</span>&#44; derives from the early observation that cells infected with murine polyomavirus induced multiple &#40;<span class="elsevierStyleItalic">poly</span>&#41; tumors &#40;<span class="elsevierStyleItalic">omas</span>&#41; in immunocompromised mice&#46; Subsequent studies showed that many members of this family exhibit the capacity of mediating cell transformation and tumorigenesis in different experimental models&#46; The transformation process mediated by these viruses is driven by viral pleiotropic regulatory proteins called T &#40;tumor&#41; antigens&#46; Similar to other viral oncoproteins T antigens target cellular regulatory factors to favor cell proliferation&#44; immune evasion and downregulation of apoptosis&#46; The first two human polyomaviruses were isolated over 45 years ago&#46; However&#44; recent advances in the DNA sequencing technologies led to the rapid identification of additional twelve new polyomaviruses in different human samples&#46; Many of these viruses establish chronic infections and have been associated with conditions in immunosuppressed individuals&#44; particularly in organ transplant recipients&#46; This has been associated to viral reactivation due to the immunosuppressant therapy applied to these patients&#46; Four polyomaviruses namely&#44; Merkel cell polyomavirus &#40;MCPyV&#41;&#44; Trichodysplasia spinulosa polyomavirus &#40;TSPyV&#41;&#44; John Cunningham Polyomavirus &#40;JCPyV&#41; and BK polyomavirus &#40;BKPyV&#41; have been associated with the development of specific malignant tumors&#46; However&#44; present evidence only supports the role of MCPyV as a carcinogen to humans&#46; In the present review we present a summarized discussion on the current knowledge concerning the role of MCPyV&#44; TSPyV&#44; JCPyV and BKPyV in human cancers&#46;</p></span>"
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        "nota" => "<p class="elsevierStyleNotepara" id="cenpara10">No potential conflict of interest was reported&#46;</p> <p class="elsevierStyleNotepara" id="cenpara20">Commemorative Edition&#58; 10 years of ICESP</p>"
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          "en" => "<p id="spara10" class="elsevierStyleSimplePara elsevierViewall">Timeline of the discovery of human polyomaviruses&#46; The timeline shows the name of the virus&#44; the year of discovery and the type of sample from which the virus was isolated&#46; For complete references&#44; see the text&#46; BKV or BKPyV&#44; human polyomavirus BK or human polyomavirus 1&#59; JCV or JCPyV&#44; John Cunningham or JC polyomavirus or human polyomavirus 2&#59; KIPyV&#44; Karolinska Institute polyomavirus or human polyomavirus 3&#59; WUPyV&#44; Washington University polyomavirus or human polyomavirus 4&#59; MCPyV&#44; Merkel cell polyomavirus or human polyomavirus 5&#59; HPyV6&#44; human polyomavirus 6&#59; HPyV7&#44; human polyomavirus 7&#59; TSPyV&#44; Trichodysplasia spinulosa polyomavirus or human polyomavirus 8&#59; HPyV9&#44; human polyomavirus 9&#59; MWPyV&#44; Malawi polyomavirus or human polyomavirus 10&#59; STLPyV Saint Louis polyomavirus or human polyomavirus 11&#59; HPyV12&#44; human polyomavirus 12&#59; NJPyV&#44; New Jersey polyomavirus or human polyomavirus 13&#59; LIPyV&#44; Lyon IARC polyomavirus or human polyomavirus 14&#46;</p>"
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          "en" => "<p id="spara20" class="elsevierStyleSimplePara elsevierViewall">Schematic representation of the genomes of BKPyV&#44; JCK&#44; MCPyV and TSPvV&#46; The early and late regions &#40;gray&#41; are transcribed from opposite strands of the genome&#46; The early region is transcribed in the counterclockwise direction and harbors the genes coding for the different T antigen isoforms as indicated&#46; The late region expresses the structural genes &#40;VPs&#41; and the agnoprotein ORF &#40;when present&#41;&#46; BKPyV&#44; JCV and MCPyV express a microRNA from the opposite strand of the early region&#46; The noncoding control region &#40;NCCR&#41; contains the origin of genome replication and the promoters for the regulation of transcription&#46; For details&#44; see text&#46;</p>"
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es en pt

¿Es usted profesional sanitario apto para prescribir o dispensar medicamentos?

Are you a health professional able to prescribe or dispense drugs?

Você é um profissional de saúde habilitado a prescrever ou dispensar medicamentos