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The Biology and Clinical Features of Cutaneous Polyomaviruses

Open ArchivePublished:November 20, 2018DOI:https://doi.org/10.1016/j.jid.2018.09.013
      Human polyomaviruses are double-stand DNA viruses with a conserved genomic structure, yet they present with diverse tissue tropisms and disease presentations. Merkel cell polyomavirus, trichodysplasia spinulosa polyomavirus, human polyomavirus 6 and 7, and Malawi polyomavirus are shed from the skin, and Merkel cell polyomavirus, trichodysplasia spinulosa polyomavirus, human polyomavirus 6 and 7 have been linked to specific skin diseases. We present an update on the genomic and clinical features of these cutaneous polyomaviruses.

      Abbreviations:

      HPyV (human polyomavirus), MCPyV (Merkel cell polyomavirus), MWPyV (Malawi polyomavirus), LT (large T antigen), ST (small T antigen), TSPyV (trichodysplasia spinulosa polyomavirus)
      The identification and study of human polyomaviruses (HPyVs) has expanded dramatically in the past decade. The BK and JC PyVs were the first HPyVs discovered and linked to nephropathy and progressive multifocal leukoencephalopathy in 1971 (
      • Gardner S.D.
      • Field A.M.
      • Coleman D.V.
      • Hulme B.
      New human papovavirus (B.K.) isolated from urine after renal transplantation.
      ,
      • Padgett B.L.
      • Walker D.L.
      • ZuRhein G.M.
      • Eckroade R.J.
      • Dessel B.H.
      Cultivation of papova-like virus from human brain with progressive multifocal leucoencephalopathy.
      ). Since 2007, starting with KI and WU PyVs, improved technologies have uncovered 10 more possible HPyVs (
      • Allander T.
      • Andreasson K.
      • Gupta S.
      • Bjerkner A.
      • Bogdanovic G.
      • Persson M.A.
      • et al.
      Identification of a third human polyomavirus.
      ,
      • Gaynor A.M.
      • Nissen M.D.
      • Whiley D.M.
      • Mackay I.M.
      • Lambert S.B.
      • Wu G.
      • et al.
      Identification of a novel polyomavirus from patients with acute respiratory tract infections.
      ,
      • Kamminga S.
      • van der Meijden E.
      • Wunderink H.F.
      • Touze A.
      • Zaaijer H.L.
      • Feltkamp M.C.W.
      Development and evaluation of a broad bead-based multiplex immunoassay to measure IgG seroreactivity against human polyomaviruses.
      ). Here, we discuss the PyVs shed from human skin, with a particular focus on those linked to disease, including trichodysplasia spinulosa polyomavirus (TSPyV), HpyV6, and HPyV7.

      Genomic Structure

      Although the overall genomic structure is conserved between cutaneous PyVs, some subtle differences exist (Table 1). Like canonical PyVs, cutaneous PyVs all possess genomes of ∼5,000 bp. The PyV genome is divided into early, late, and noncoding control regions. All cutaneous PyV early regions encode for large and small T antigens (LT and ST, respectively).
      Table 1Genomic features of cutaneous polyomaviruses
      PolyomavirusReference GenomeSize (bp)LT (AA)ST (AA)MT (AA)ALTO (AA)VP1/2/3 (AA)MicroRNACell Receptor
      MCPyVNC_010277.25,387817186248/250423/241/196PresentGanglioside GT1b/glycosaminoglycans
      TSPyVNC_014361.15,232697198332131376/313/195GM1/sialylactose
      HPyV6NC_14406.14,926669190387/336/215ND (non-ganglioside)
      HPyV7NC_14407.14,952671193380/329/290ND (non-ganglioside)
      MWPyV (HPyV10)NC_018102.14,927668199404/311/201ND
      — indicates no evidence for presence.
      Abbreviations: AA, amino acid; ALTO, alternative T open reading frame; HPyV, human polyomavirus; MCPyV, Merkel cell polyomavirus; MWPyV, Malawi polyomavirus; LT, large T antigen; MT, middle T antigen; ND, not determined; ST, small T antigen; TSPyV, trichodysplasia spinulosa polyomavirus.
      Early region transcription occurs first, before viral DNA replication. LT alone can replicate the PyV genome. Domains essential for DNA replication are conserved in all cutaneous PyVs, including the DnaJ domain (HPDKGG), Rb/p107/p130 binding motif (LXCXE), Zinc-binding (Zn-binding) motif, helicase, and nuclear localization sequence (Table 2) (
      • Borchert S.
      • Czech-Sioli M.
      • Neumann F.
      • Schmidt C.
      • Wimmer P.
      • Dobner T.
      • et al.
      High-affinity Rb binding, p53 inhibition, subcellular localization, and transformation by wild-type or tumor-derived shortened Merkel cell polyomavirus large T antigens.
      ,
      • DeCaprio J.A.
      • Garcea R.L.
      A cornucopia of human polyomaviruses.
      ,
      • Van Ghelue M.
      • Khan M.T.
      • Ehlers B.
      • Moens U.
      Genome analysis of the new human polyomaviruses.
      ). The LXCXE and DnaJ/Hsc70 binding motifs work together to bind Rb and disrupt its interaction with E2F to promote cell-cycle progression and viral replication (
      • Sullivan C.S.
      • Cantalupo P.
      • Pipas J.M.
      The molecular chaperone activity of simian virus 40 large T antigen is required to disrupt Rb-E2F family complexes by an ATP-dependent mechanism.
      ). The Zn-binding motif and helicase domains allow LT to oligomerize and bind viral DNA, unwind it, and recruit host cell DNA replication factors (
      • Zhou B.
      • Arnett D.R.
      • Yu X.
      • Brewster A.
      • Sowd G.A.
      • Xie C.L.
      • et al.
      Structural basis for the interaction of a hexameric replicative helicase with the regulatory subunit of human DNA polymerase alpha-primase.
      ). Some PyVs also use the helicase domain to bind and inhibit the p53 tumor suppressor. While HPyV6/7 and Malawi PyV (MWPyV) LTs bind directly to p53 (
      • Berrios C.
      • Jung J.
      • Primi B.
      • Wang M.
      • Pedamallu C.
      • Duke F.
      • et al.
      Malawi polyomavirus is a prevalent human virus that interacts with known tumor suppressors.
      ,
      • Rozenblatt-Rosen O.
      • Deo R.C.
      • Padi M.
      • Adelmant G.
      • Calderwood M.A.
      • Rolland T.
      • et al.
      Interpreting cancer genomes using systematic host network perturbations by tumour virus proteins.
      ), MCPyV LT inhibits p53 signaling without a direct interaction (
      • Borchert S.
      • Czech-Sioli M.
      • Neumann F.
      • Schmidt C.
      • Wimmer P.
      • Dobner T.
      • et al.
      High-affinity Rb binding, p53 inhibition, subcellular localization, and transformation by wild-type or tumor-derived shortened Merkel cell polyomavirus large T antigens.
      ,
      • Cheng J.
      • Rozenblatt-Rosen O.
      • Paulson K.G.
      • Nghiem P.
      • DeCaprio J.A.
      Merkel cell polyomavirus large T antigen has growth-promoting and inhibitory activities.
      ). TSPyV LT has also been shown to lack significant interaction with p53 (
      • An P.
      • Brodsky J.L.
      • Pipas J.M.
      The conserved core enzymatic activities and the distinct dynamics of polyomavirus large T antigens.
      ). Nonconserved domains in LTs show differences between the cutaneous PyVs (Table 2) (
      • Van Ghelue M.
      • Khan M.T.
      • Ehlers B.
      • Moens U.
      Genome analysis of the new human polyomaviruses.
      ). MCPyV LT is slightly larger due to an uncharacterized insertion between the DnaJ- and Rb-binding motifs. The LTs of TSPyV, HPyV6/7, and MWPyV, but not MCPyV, possess a motif (WXXWW) that binds the spindle checkpoint protein Bub1. This domain is required for the transforming, but not the immortalizing, properties of SV40 LT (
      • Cotsiki M.
      • Lock R.L.
      • Cheng Y.
      • Williams G.L.
      • Zhao J.
      • Perera D.
      • et al.
      Simian virus 40 large T antigen targets the spindle assembly checkpoint protein Bub1.
      ). SV40 LT also promotes transformation through a CUL7-binding motif (FNXEX) in its N-terminus, which is only conserved in TSPyV (
      • Ali S.H.
      • Kasper J.S.
      • Arai T.
      • DeCaprio J.A.
      Cul7/p185/p193 binding to simian virus 40 large T antigen has a role in cellular transformation.
      ).
      Table 2Locations of large T and small T motifs and ligands
      MotifLarge TSmall T
      DnaJWXXWWCUL7LXCXENLSOBDZinc Fingerp53 bindingLSDZinc Finger
      LigandHsc70Bub1CUL7Rb,p107,p130KPNADNADNAp53Fbxw7PP2A subunits
      SequenceHPDKGGWXXWWFNXEXLXCXEKRKUndefinedCX2X7HX3HUndefinedLKDYMC(1XX)→H(1XX)
      MCPyV42–47
      Not verified experimentally.
      Not verified experimentally.
      212–216299–307316–430473–488
      Indirect binding to p53.
      92–96109–130
      TSPyV42–4799–103106–110122–126174–182191–306
      Not verified experimentally.
      350–36593–97
      Not verified experimentally.
      113–132
      HPyV642–4793–97
      Not verified experimentally.
      109–113139–147154–273
      Not verified experimentally.
      317–330+
      Direct binding to p53.
      111–130
      Not verified experimentally.
      HPyV742–4794–98
      Not verified experimentally.
      109–113144–152159–278
      Not verified experimentally.
      322–335+
      Direct binding to p53.
      111–130
      Not verified experimentally.
      MWPyV42–4790–94
      Not verified experimentally.
      105–109149–157163–280
      Not verified experimentally.
      324–339+
      Direct binding to p53.
      110–130
      Not verified experimentally.
      SV4042–4791–9598–102103–-107124–132139–256302–317351–450, 533–626102–122
      Abbreviations: HPyV, human polyomavirus; LSD, large T antigen stabilization domain; MCPyV, Merkel cell polyomavirus; MWPyV, Malawi polyomavirus; NLS, nuclear localizing sequence; OBD, origin binding domain.
      —, no evidence for presence.
      1 Not verified experimentally.
      2 Indirect binding to p53.
      3 Direct binding to p53.
      The ST is generated through alternative splicing and shares the LT DnaJ domain. The C-terminal half of ST possesses two conserved Zn-binding motifs that bind to PP2A isoforms promoting viral DNA replication through multiple mechanisms. The PP2A-binding region of SV40 ST promotes cell-cycle progression (
      • Schuchner S.
      • Wintersberger E.
      Binding of polyomavirus small T antigen to protein phosphatase 2A is required for elimination of p27 and support of S-phase induction in concert with large T antigen.
      ) and inhibits LT degradation (
      • Scheidtmann K.H.
      • Mumby M.C.
      • Rundell K.
      • Walter G.
      Dephosphorylation of simian virus 40 large-T antigen and p53 protein by protein phosphatase 2A: inhibition by small-t antigen.
      ), but these activities have not been tested in cutaneous STs. The PP2A binding regions appear to be conserved among cutaneous PyVs (Table 2). MCPyV ST stabilizes LT through a distinct LT stabilization domain motif that is conserved in TSPyV, but not in HPyV6/7 or MWPyV (Table 2) (
      • Kwun H.J.
      • Shuda M.
      • Feng H.
      • Camacho C.J.
      • Moore P.S.
      • Chang Y.
      Merkel cell polyomavirus small T antigen controls viral replication and oncoprotein expression by targeting the cellular ubiquitin ligase SCFFbw7.
      ). While MCPyV ST can transform primary fibroblasts (
      • Shuda M.
      • Kwun H.J.
      • Feng H.
      • Chang Y.
      • Moore P.S.
      Human Merkel cell polyomavirus small T antigen is an oncoprotein targeting the 4E-BP1 translation regulator.
      ), the transforming properties of other cutaneous STs is unknown.
      Some PyVs possess an alternative open reading frame overlapping with LT that encodes for additional protein(s). The TSPyV early region encodes for both middle T antigen and alternative T antigen (
      • Carter J.J.
      • Daugherty M.D.
      • Qi X.
      • Bheda-Malge A.
      • Wipf G.C.
      • Robinson K.
      • et al.
      Identification of an overprinting gene in Merkel cell polyomavirus provides evolutionary insight into the birth of viral genes.
      ,
      • van der Meijden E.
      • Kazem S.
      • Dargel C.A.
      • van Vuren N.
      • Hensbergen P.J.
      • Feltkamp M.C.
      Characterization of T antigens, including middle T and alternative T, expressed by the human polyomavirus associated with trichodysplasia spinulosa.
      ); the MCPyV early region only encodes for alternative T antigen (
      • van der Meijden E.
      • Kazem S.
      • Dargel C.A.
      • van Vuren N.
      • Hensbergen P.J.
      • Feltkamp M.C.
      Characterization of T antigens, including middle T and alternative T, expressed by the human polyomavirus associated with trichodysplasia spinulosa.
      ), while HPyV6/7 and MWPyV encode for neither (Table 1). While the well-characterized mouse PyV middle T antigen is a phosphorylated membrane protein that alters signaling pathways and promotes transformation, the functions of middle T antigen/alternative T antigen of cutaneous PyVs require further characterization (
      • van der Meijden E.
      • Feltkamp M.
      The human polyomavirus middle and alternative T-antigens; thoughts on roles and relevance to cancer.
      ).
      MCPyV is the only cutaneous PyV known to encode for a microRNA (Table 1). Like SV40, MCPyV microRNA inhibits LT expression, possibly as a means to limit replication and promote episomal persistence (
      • Seo G.J.
      • Chen C.J.
      • Sullivan C.S.
      Merkel cell polyomavirus encodes a microRNA with the ability to autoregulate viral gene expression.
      ). More recent reports also suggest that the MCPyV microRNA may also attenuate the host immune response (
      • Akhbari P.
      • Tobin D.
      • Poterlowicz K.
      • Roberts W.
      • Boyne J.R.
      MCV-miR-M1 targets the host-cell immune response resulting in the attenuation of neutrophil chemotaxis.
      ).
      The PyV late genes encode for the capsomere proteins, which surround the viral genome and promote attachment and entry into host cells. Many PyV capsids bind gangliosides terminating in sialic acid as their primary attachment receptor through a structurally conserved groove (
      • Stehle T.
      • Yan Y.
      • Benjamin T.L.
      • Harrison S.C.
      Structure of murine polyomavirus complexed with an oligosaccharide receptor fragment.
      ). While MCPyV can bind to ganglioside GT1b (
      • Erickson K.D.
      • Garcea R.L.
      • Tsai B.
      Ganglioside GT1b is a putative host cell receptor for the Merkel cell polyomavirus.
      ), glycosaminoglycans have been implicated as the primary entry receptor (Table 1) (
      • Schowalter R.M.
      • Reinhold W.C.
      • Buck C.B.
      Entry tropism of BK and Merkel cell polyomaviruses in cell culture.
      ). More recent structural studies have also demonstrated that the proposed sialic acid binding site is occluded in HPyV6/7, suggesting alternative receptors for cutaneous PyVs (
      • Stroh L.J.
      • Neu U.
      • Blaum B.S.
      • Buch M.H.
      • Garcea R.L.
      • Stehle T.
      Structure analysis of the major capsid proteins of human polyomaviruses 6 and 7 reveals an obstructed sialic acid binding site.
      ).

      Merkel Cell Polyomavirus

      MCPyV and its associated disease, Merkel cell carcinoma, have been reviewed extensively elsewhere. Serologic studies indicate that exposure to MCPyV is widespread (
      • DeCaprio J.A.
      Merkel cell polyomavirus and Merkel cell carcinoma.
      ,
      • van der Meijden E.
      • Kazem S.
      • Burgers M.M.
      • Janssens R.
      • Bouwes Bavinck J.N.
      • de Melker H.
      • et al.
      Seroprevalence of trichodysplasia spinulosa-associated polyomavirus.
      ). Viral DNA is present in 2.6% of healthy blood donors (
      • Mazzoni E.
      • Rotondo J.C.
      • Marracino L.
      • Selvatici R.
      • Bononi I.
      • Torreggiani E.
      • et al.
      Detection of Merkel cell polyomavirus DNA in serum samples of healthy blood donors.
      ). Primary exposure to MCPyV begins in childhood after a period of immunity from maternal antibodies (
      • Martel-Jantin C.
      • Pedergnana V.
      • Nicol J.T.
      • Leblond V.
      • Tregouet D.A.
      • Tortevoye P.
      • et al.
      Merkel cell polyomavirus infection occurs during early childhood and is transmitted between siblings.
      ,
      • Nicol J.T.
      • Robinot R.
      • Carpentier A.
      • Carandina G.
      • Mazzoni E.
      • Tognon M.
      • et al.
      Age-specific seroprevalences of merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus.
      ). Seroprevalence rates rise from early childhood until adulthood, in which 60–96.2% of adult populations are estimated to have had MCPyV exposure (
      • Martel-Jantin C.
      • Pedergnana V.
      • Nicol J.T.
      • Leblond V.
      • Tregouet D.A.
      • Tortevoye P.
      • et al.
      Merkel cell polyomavirus infection occurs during early childhood and is transmitted between siblings.
      ,
      • Nicol J.T.
      • Robinot R.
      • Carpentier A.
      • Carandina G.
      • Mazzoni E.
      • Tognon M.
      • et al.
      Age-specific seroprevalences of merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus.
      ) (Table 3). MCPyV appears to be the cutaneous PyV most frequently shed from the skin, with studies suggesting shedding from up to 61.5% of healthy individuals (
      • Hampras S.S.
      • Giuliano A.R.
      • Lin H.Y.
      • Fisher K.J.
      • Abrahamsen M.E.
      • McKay-Chopin S.
      • et al.
      Natural history of polyomaviruses in men: the HPV infection in men (HIM) study.
      ,
      • Schowalter R.M.
      • Pastrana D.V.
      • Pumphrey K.A.
      • Moyer A.L.
      • Buck C.B.
      Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin.
      ) (Table 3). An increasing body of research has strongly implicated MCPyV as a cause of its associated carcinoma (
      • DeCaprio J.A.
      Merkel cell polyomavirus and Merkel cell carcinoma.
      ,
      • Feng H.
      • Shuda M.
      • Chang Y.
      • Moore P.S.
      Clonal integration of a polyomavirus in human Merkel cell carcinoma.
      ). Links between MCPyV and other inflammatory or malignant skin conditions remain unconfirmed.
      Table 3Seroprevalence, skin prevalence, and disease associations of cutaneous polyomaviruses
      PolyomavirusSeroprevalence in AdultsDNA Prevalence on Adult SkinDisease Associations
      MCPyV60–96% (
      • Gossai A.
      • Waterboer T.
      • Hoen A.G.
      • Farzan S.F.
      • Nelson H.H.
      • Michel A.
      • et al.
      Human polyomaviruses and incidence of cutaneous squamous cell carcinoma in the New Hampshire skin cancer study.
      ,
      • Martel-Jantin C.
      • Pedergnana V.
      • Nicol J.T.
      • Leblond V.
      • Tregouet D.A.
      • Tortevoye P.
      • et al.
      Merkel cell polyomavirus infection occurs during early childhood and is transmitted between siblings.
      ,
      • Nicol J.T.
      • Robinot R.
      • Carpentier A.
      • Carandina G.
      • Mazzoni E.
      • Tognon M.
      • et al.
      Age-specific seroprevalences of merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus.
      )
      40–61.5% (
      • Hampras S.S.
      • Giuliano A.R.
      • Lin H.Y.
      • Fisher K.J.
      • Abrahamsen M.E.
      • McKay-Chopin S.
      • et al.
      Natural history of polyomaviruses in men: the HPV infection in men (HIM) study.
      ,
      • Schowalter R.M.
      • Pastrana D.V.
      • Pumphrey K.A.
      • Moyer A.L.
      • Buck C.B.
      Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin.
      )
      Merkel cell carcinoma (
      • Feng H.
      • Shuda M.
      • Chang Y.
      • Moore P.S.
      Clonal integration of a polyomavirus in human Merkel cell carcinoma.
      ,
      • Kassem A.
      • Schopflin A.
      • Diaz C.
      • Weyers W.
      • Stickeler E.
      • Werner M.
      • et al.
      Frequent detection of Merkel cell polyomavirus in human Merkel cell carcinomas and identification of a unique deletion in the VP1 gene.
      ,
      • Moshiri A.S.
      • Doumani R.
      • Yelistratova L.
      • Blom A.
      • Lachance K.
      • Shinohara M.M.
      • et al.
      Polyomavirus-negative merkel cell carcinoma: a more aggressive subtype based on analysis of 282 cases using multimodal tumor virus detection.
      )

      Chronic lymphocytic leukemia (
      • Pantulu N.D.
      • Pallasch C.P.
      • Kurz A.K.
      • Kassem A.
      • Frenzel L.
      • Sodenkamp S.
      • et al.
      Detection of a novel truncating Merkel cell polyomavirus large T antigen deletion in chronic lymphocytic leukemia cells.
      )
      TSPyV63–81% (
      • Chen T.
      • Mattila P.S.
      • Jartti T.
      • Ruuskanen O.
      • Soderlund-Venermo M.
      • Hedman K.
      Seroepidemiology of the newly found trichodysplasia spinulosa-associated polyomavirus.
      ,
      • Nicol J.T.
      • Robinot R.
      • Carpentier A.
      • Carandina G.
      • Mazzoni E.
      • Tognon M.
      • et al.
      Age-specific seroprevalences of merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus.
      ,
      • Sroller V.
      • Hamsikova E.
      • Ludvikova V.
      • Musil J.
      • Nemeckova S.
      • Salakova M.
      Seroprevalence rates of HPyV6, HPyV7, TSPyV, HPyV9, MWPyV and KIPyV polyomaviruses among the healthy blood donors.
      ,
      • van der Meijden E.
      • Kazem S.
      • Burgers M.M.
      • Janssens R.
      • Bouwes Bavinck J.N.
      • de Melker H.
      • et al.
      Seroprevalence of trichodysplasia spinulosa-associated polyomavirus.
      )
      0–3.8% (
      • Hampras S.S.
      • Giuliano A.R.
      • Lin H.Y.
      • Fisher K.J.
      • Abrahamsen M.E.
      • McKay-Chopin S.
      • et al.
      Natural history of polyomaviruses in men: the HPV infection in men (HIM) study.
      ,
      • Schowalter R.M.
      • Pastrana D.V.
      • Pumphrey K.A.
      • Moyer A.L.
      • Buck C.B.
      Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin.
      ,
      • Wieland U.
      • Silling S.
      • Hellmich M.
      • Potthoff A.
      • Pfister H.
      • Kreuter A.
      Human polyomaviruses 6, 7, 9, 10 and Trichodysplasia spinulosa-associated polyomavirus in HIV-infected men.
      )
      Trichodysplasia spinulosa (
      • Kazem S.
      • van der Meijden E.
      • Kooijman S.
      • Rosenberg A.S.
      • Hughey L.C.
      • Browning J.C.
      • et al.
      Trichodysplasia spinulosa is characterized by active polyomavirus infection.
      ,
      • Kazem S.
      • van der Meijden E.
      • Wang R.C.
      • Rosenberg A.S.
      • Pope E.
      • Benoit T.
      • et al.
      Polyomavirus-associated trichodysplasia spinulosa involves hyperproliferation, pRB phosphorylation and upregulation of p16 and p21.
      ,
      • Matthews M.R.
      • Wang R.C.
      • Reddick R.L.
      • Saldivar V.A.
      • Browning J.C.
      Viral-associated trichodysplasia spinulosa: a case with electron microscopic and molecular detection of the trichodysplasia spinulosa-associated human polyomavirus.
      ,
      • van der Meijden E.
      • Janssens R.W.
      • Lauber C.
      • Bouwes Bavinck J.N.
      • Gorbalenya A.E.
      • Feltkamp M.C.
      Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient.
      )
      HPyV669–88% (
      • Sroller V.
      • Hamsikova E.
      • Ludvikova V.
      • Musil J.
      • Nemeckova S.
      • Salakova M.
      Seroprevalence rates of HPyV6, HPyV7, TSPyV, HPyV9, MWPyV and KIPyV polyomaviruses among the healthy blood donors.
      )
      12–27.6% (
      • Hampras S.S.
      • Giuliano A.R.
      • Lin H.Y.
      • Fisher K.J.
      • Abrahamsen M.E.
      • McKay-Chopin S.
      • et al.
      Natural history of polyomaviruses in men: the HPV infection in men (HIM) study.
      ,
      • Schowalter R.M.
      • Pastrana D.V.
      • Pumphrey K.A.
      • Moyer A.L.
      • Buck C.B.
      Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin.
      ,
      • Wieland U.
      • Silling S.
      • Hellmich M.
      • Potthoff A.
      • Pfister H.
      • Kreuter A.
      Human polyomaviruses 6, 7, 9, 10 and Trichodysplasia spinulosa-associated polyomavirus in HIV-infected men.
      )
      Human polyomavirus 6 associated pruritic and dyskeratotic dermatitis (H6PD) (
      • Nguyen K.D.
      • Lee E.E.
      • Yue Y.
      • Štork J.
      • Pock L.
      • North J.P.
      • et al.
      Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses.
      )

      BRAF inhibitor-associated epithelial neoplasm (
      • Schrama D.
      • Groesser L.
      • Ugurel S.
      • Hafner C.
      • Pastrana D.V.
      • Buck C.B.
      • et al.
      Presence of human polyomavirus 6 in mutation-specific BRAF inhibitor-induced epithelial proliferations.
      )

      Keratoacanthomas (
      • Beckervordersandforth J.
      • Pujari S.
      • Rennspiess D.
      • Speel E.J.
      • Winnepenninckx V.
      • Diaz C.
      • et al.
      Frequent detection of human polyomavirus 6 in keratoacanthomas.
      )

      Angiolymphoid hyperplasia with eosinophilia (
      • Rascovan N.
      • Bouchard S.M.
      • Grob J.J.
      • Collet-Villette A.M.
      • Gaudy-Marqueste C.
      • Penicaud M.
      • et al.
      Human polyomavirus-6 infecting lymph nodes of a patient with an angiolymphoid hyperplasia with eosinophilia or Kimura disease.
      )
      HPyV735–66% (
      • Sroller V.
      • Hamsikova E.
      • Ludvikova V.
      • Musil J.
      • Nemeckova S.
      • Salakova M.
      Seroprevalence rates of HPyV6, HPyV7, TSPyV, HPyV9, MWPyV and KIPyV polyomaviruses among the healthy blood donors.
      )
      2.1–13.4% (
      • Schowalter R.M.
      • Pastrana D.V.
      • Pumphrey K.A.
      • Moyer A.L.
      • Buck C.B.
      Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin.
      ,
      • Wieland U.
      • Silling S.
      • Hellmich M.
      • Potthoff A.
      • Pfister H.
      • Kreuter A.
      Human polyomaviruses 6, 7, 9, 10 and Trichodysplasia spinulosa-associated polyomavirus in HIV-infected men.
      )
      Human polyomavirus 7 associated pruritic and dyskeratotic dermatitis (H7PD) (
      • Canavan T.N.
      • Baddley J.W.
      • Pavlidakey P.
      • Tallaj J.A.
      • Elewski B.E.
      Human polyomavirus-7-associated eruption successfully treated with acitretin.
      ;
      • Ho J.
      • Jedrych J.J.
      • Feng H.
      • Natalie A.A.
      • Grandinetti L.
      • Mirvish E.
      • et al.
      Human polyomavirus 7-associated pruritic rash and viremia in transplant recipients.
      ;
      • Nguyen K.D.
      • Lee E.E.
      • Yue Y.
      • Štork J.
      • Pock L.
      • North J.P.
      • et al.
      Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses.
      ,
      • Smith S.D.B.
      • Erdag G.
      • Cuda J.D.
      • Rangwala S.
      • Girardi N.
      • Bibee K.
      • et al.
      Treatment of human polyomavirus-7-associated rash and pruritus with topical cidofovir in a lung transplant patient: Case report and literature review.
      )

      Human thymic epithelial tumors (
      • Rennspiess D.
      • Pujari S.
      • Keijzers M.
      • Abdul-Hamid M.A.
      • Hochstenbag M.
      • Dingemans A.-M.
      • et al.
      Detection of human polyomavirus 7 in human thymic epithelial tumors.
      )
      MWPyV (HPyV10)42–99% (
      • Gossai A.
      • Waterboer T.
      • Hoen A.G.
      • Farzan S.F.
      • Nelson H.H.
      • Michel A.
      • et al.
      Human polyomaviruses and incidence of cutaneous squamous cell carcinoma in the New Hampshire skin cancer study.
      ,
      • Nicol J.T.
      • Leblond V.
      • Arnold F.
      • Guerra G.
      • Mazzoni E.
      • Tognon M.
      • et al.
      Seroprevalence of human Malawi polyomavirus.
      )
      3.4–9.3% (
      • Wieland U.
      • Silling S.
      • Hellmich M.
      • Potthoff A.
      • Pfister H.
      • Kreuter A.
      Human polyomaviruses 6, 7, 9, 10 and Trichodysplasia spinulosa-associated polyomavirus in HIV-infected men.
      )
      None
      Abbreviations: HPyV, human polyomavirus; MCPyV, Merkel cell polyomavirus; MWPyV, Malawi polyomavirus; TSPyV, trichodysplasia spinulosa polyomavirus.

      Trichodysplasia Spinulosa Polyomavirus

      Case reports in the early 2000s identified a facial, folliculocentric eruption and alopecia in immunosuppressed patients first described as “pilomatrix dysplasia” and later “cyclosporine-induced folliculodystrophy” (
      • Chastain M.A.
      • Millikan L.E.
      Pilomatrix dysplasia in an immunosuppressed patient.
      ,
      • Haycox C.L.
      • Kim S.
      • Fleckman P.
      • Smith L.T.
      • Piepkorn M.
      • Sundberg J.P.
      • et al.
      Trichodysplasia spinulosa—a newly described folliculocentric viral infection in an immunocompromised host.
      ,
      • Heaphy Jr., M.R.
      • Shamma H.N.
      • Hickmann M.
      • White M.J.
      Cyclosporine-induced folliculodystrophy.
      ,
      • Sperling L.C.
      • Tomaszewski M.-M.
      • Thomas D.A.
      Viral-associated trichodysplasia in patients who are immunocompromised.
      ). While some reports implicated cyclosporine, electron microscopy suggested a viral etiology (
      • Haycox C.L.
      • Kim S.
      • Fleckman P.
      • Smith L.T.
      • Piepkorn M.
      • Sundberg J.P.
      • et al.
      Trichodysplasia spinulosa—a newly described folliculocentric viral infection in an immunocompromised host.
      ,
      • Sperling L.C.
      • Tomaszewski M.-M.
      • Thomas D.A.
      Viral-associated trichodysplasia in patients who are immunocompromised.
      ). In 2010, van der Meijden and colleagues identified the causative virus, TSPyV in the disease (
      • van der Meijden E.
      • Janssens R.W.
      • Lauber C.
      • Bouwes Bavinck J.N.
      • Gorbalenya A.E.
      • Feltkamp M.C.
      Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient.
      ). TSPyV viral loads average ∼106 copies per cell in lesional skin samples compared to <102 copies per cell in non-lesional and healthy control skin samples (
      • Kazem S.
      • van der Meijden E.
      • Kooijman S.
      • Rosenberg A.S.
      • Hughey L.C.
      • Browning J.C.
      • et al.
      Trichodysplasia spinulosa is characterized by active polyomavirus infection.
      ).
      Children are often born with maternal antibodies to TSPyV, but begin producing their own antibodies in the first year after primary exposure (
      • Chen T.
      • Mattila P.S.
      • Jartti T.
      • Ruuskanen O.
      • Soderlund-Venermo M.
      • Hedman K.
      Seroepidemiology of the newly found trichodysplasia spinulosa-associated polyomavirus.
      ,
      • Fukumoto H.
      • Li T.-C.
      • Kataoka M.
      • Hasegawa H.
      • Wakita T.
      • Saeki H.
      • et al.
      Seroprevalence of trichodysplasia spinulosa-associated polyomavirus in Japan.
      ,
      • van der Meijden E.
      • Bialasiewicz S.
      • Rockett R.J.
      • Tozer S.J.
      • Sloots T.P.
      • Feltkamp M.C.W.
      Different serologic behavior of MCPyV, TSPyV, HPyV6, HPyV7 and HPyV9 polyomaviruses found on the skin.
      ). Transmission may occur through family members, possibly through respiratory secretions (
      • Bialasiewicz S.
      • Byrom L.
      • Fraser C.
      • Clark J.
      Potential route of transmission for trichodysplasia spinulosa polyomavirus.
      ,
      • Pedergnana V.
      • Martel-Jantin C.
      • Nicol J.T.J.
      • Leblond V.
      • Tortevoye P.
      • Coursaget P.
      • et al.
      Trichodysplasia spinulosa polyomavirus infection occurs during early childhood with intrafamilial transmission, especially from mother to child.
      ). Adult seroprevalence ranges from 63.2% to 81% (
      • Chen T.
      • Mattila P.S.
      • Jartti T.
      • Ruuskanen O.
      • Soderlund-Venermo M.
      • Hedman K.
      Seroepidemiology of the newly found trichodysplasia spinulosa-associated polyomavirus.
      ,
      • Nicol J.T.
      • Robinot R.
      • Carpentier A.
      • Carandina G.
      • Mazzoni E.
      • Tognon M.
      • et al.
      Age-specific seroprevalences of merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus.
      ,
      • Sroller V.
      • Hamsikova E.
      • Ludvikova V.
      • Musil J.
      • Nemeckova S.
      • Salakova M.
      Seroprevalence rates of HPyV6, HPyV7, TSPyV, HPyV9, MWPyV and KIPyV polyomaviruses among the healthy blood donors.
      ,
      • van der Meijden E.
      • Kazem S.
      • Burgers M.M.
      • Janssens R.
      • Bouwes Bavinck J.N.
      • de Melker H.
      • et al.
      Seroprevalence of trichodysplasia spinulosa-associated polyomavirus.
      ,
      • van der Meijden E.
      • Bialasiewicz S.
      • Rockett R.J.
      • Tozer S.J.
      • Sloots T.P.
      • Feltkamp M.C.W.
      Different serologic behavior of MCPyV, TSPyV, HPyV6, HPyV7 and HPyV9 polyomaviruses found on the skin.
      ). Skin infection appears to be transient, as skin swabs show low prevalence of viral DNA (0–3.8% in adults) (
      • Hampras S.S.
      • Giuliano A.R.
      • Lin H.Y.
      • Fisher K.J.
      • Abrahamsen M.E.
      • McKay-Chopin S.
      • et al.
      Natural history of polyomaviruses in men: the HPV infection in men (HIM) study.
      ,
      • Schowalter R.M.
      • Pastrana D.V.
      • Pumphrey K.A.
      • Moyer A.L.
      • Buck C.B.
      Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin.
      ,
      • Wieland U.
      • Silling S.
      • Hellmich M.
      • Potthoff A.
      • Pfister H.
      • Kreuter A.
      Human polyomaviruses 6, 7, 9, 10 and Trichodysplasia spinulosa-associated polyomavirus in HIV-infected men.
      ).
      TS patients have numerous, mildly pruritic, folliculocentric, flesh-colored to pink papules with central keratinaceous spines (Figure 1a) (
      • Haycox C.L.
      • Kim S.
      • Fleckman P.
      • Smith L.T.
      • Piepkorn M.
      • Sundberg J.P.
      • et al.
      Trichodysplasia spinulosa—a newly described folliculocentric viral infection in an immunocompromised host.
      ,
      • Matthews M.R.
      • Wang R.C.
      • Reddick R.L.
      • Saldivar V.A.
      • Browning J.C.
      Viral-associated trichodysplasia spinulosa: a case with electron microscopic and molecular detection of the trichodysplasia spinulosa-associated human polyomavirus.
      ,
      • Sperling L.C.
      • Tomaszewski M.-M.
      • Thomas D.A.
      Viral-associated trichodysplasia in patients who are immunocompromised.
      ,
      • van der Meijden E.
      • Janssens R.W.
      • Lauber C.
      • Bouwes Bavinck J.N.
      • Gorbalenya A.E.
      • Feltkamp M.C.
      Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient.
      ). Alopecia favoring the eyebrows and sometimes skin thickening creating a leonine facies, may occur concomitantly (
      • van der Meijden E.
      • Janssens R.W.
      • Lauber C.
      • Bouwes Bavinck J.N.
      • Gorbalenya A.E.
      • Feltkamp M.C.
      Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient.
      ). All cases have been associated with iatrogenic immunosuppressive medications, including cyclosporine, prednisone, mycophenolate, azathioprine, methotrexate, tacrolimus, and numerous chemotherapies (
      • Aleissa M.
      • Konstantinou M.P.
      • Samimi M.
      • Lamant L.
      • Gaboriaud P.
      • Touzé A.
      • et al.
      Trichodysplasia spinulosa associated with HIV infection: clinical response to acitretin and valganciclovir.
      ,
      • Matthews M.R.
      • Wang R.C.
      • Reddick R.L.
      • Saldivar V.A.
      • Browning J.C.
      Viral-associated trichodysplasia spinulosa: a case with electron microscopic and molecular detection of the trichodysplasia spinulosa-associated human polyomavirus.
      ). There is recent evidence that TS may result from a primary infection rather than viral reactivation (
      • Bialasiewicz S.
      • Byrom L.
      • Fraser C.
      • Clark J.
      Potential route of transmission for trichodysplasia spinulosa polyomavirus.
      ,
      • van der Meijden E.
      • Horváth B.
      • Nijland M.
      • de Vries K.
      • Rácz E.K.
      • Diercks G.F.
      • et al.
      Primary polyomavirus infection, not reactivation, as the cause of trichodysplasia spinulosa in immunocompromised patients.
      ).
      Figure thumbnail gr1
      Figure 1Clinical and histologic features of human polyomavirus infections. (a) In trichodysplasia spinulosa, patients present with folliculocentric, flesh-colored and pink papules with complete eyebrow alopecia. Though not seen here, keratinaceous spines may protrude from the center of the papules. (b) These hair follicles are dilated and filled with dystrophic material. The hair shaft is malformed. Enlarged cells with increased trichohyaline granules are present in the inner root sheath epithelium (left, scale bar = 500 μm). Expansion of the inner root sheath epithelium is frequently noted (right, scale = 200 μm). (c) HPyV6/7 associated pruritic and dyskeratotic dermatitis (H6PD/H7PD) presents as gray-brown, lichenified plaques on the trunk and extremities. These changes were visible on the trunk and upper extremities in this patient’s posterior deltoid (left) and back (right). Clinical images reproduced with permission from (
      • Smith S.D.B.
      • Erdag G.
      • Cuda J.D.
      • Rangwala S.
      • Girardi N.
      • Bibee K.
      • et al.
      Treatment of human polyomavirus-7-associated rash and pruritus with topical cidofovir in a lung transplant patient: Case report and literature review.
      ). (d) Histology shows epidermal papillomatosis and irregular columns of parakeratosis (left, scale bar = 100 μm). Dyskeratotic keratinocytes and irregular columns of parakeratosis are visible at higher magnification (right, scale bar = 50 μm). Histologic images courtesy of Peter Pavlidakey.
      Histology reveals distended anagen hair follicles with dilated infundibula that are plugged with refractile, dystrophic material (Figure 1b) (
      • Haycox C.L.
      • Kim S.
      • Fleckman P.
      • Smith L.T.
      • Piepkorn M.
      • Sundberg J.P.
      • et al.
      Trichodysplasia spinulosa—a newly described folliculocentric viral infection in an immunocompromised host.
      ,
      • Matthews M.R.
      • Wang R.C.
      • Reddick R.L.
      • Saldivar V.A.
      • Browning J.C.
      Viral-associated trichodysplasia spinulosa: a case with electron microscopic and molecular detection of the trichodysplasia spinulosa-associated human polyomavirus.
      ,
      • Sperling L.C.
      • Tomaszewski M.-M.
      • Thomas D.A.
      Viral-associated trichodysplasia in patients who are immunocompromised.
      ,
      • van der Meijden E.
      • Janssens R.W.
      • Lauber C.
      • Bouwes Bavinck J.N.
      • Gorbalenya A.E.
      • Feltkamp M.C.
      Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient.
      ). Hair shafts are poorly formed or absent (
      • Haycox C.L.
      • Kim S.
      • Fleckman P.
      • Smith L.T.
      • Piepkorn M.
      • Sundberg J.P.
      • et al.
      Trichodysplasia spinulosa—a newly described folliculocentric viral infection in an immunocompromised host.
      ,
      • van der Meijden E.
      • Janssens R.W.
      • Lauber C.
      • Bouwes Bavinck J.N.
      • Gorbalenya A.E.
      • Feltkamp M.C.
      Discovery of a new human polyomavirus associated with trichodysplasia spinulosa in an immunocompromized patient.
      ). An expanded inner root sheath epithelium contains enlarged cells with increased trichohyaline granules and increased apoptotic cells (Figure 1c) (
      • Haycox C.L.
      • Kim S.
      • Fleckman P.
      • Smith L.T.
      • Piepkorn M.
      • Sundberg J.P.
      • et al.
      Trichodysplasia spinulosa—a newly described folliculocentric viral infection in an immunocompromised host.
      ,
      • Leitenberger J.J.
      • Abdelmalek M.
      • Wang R.C.
      • Strasfeld L.
      • Hopkins R.S.
      Two cases of trichodysplasia spinulosa responsive to compounded topical cidofovir 3% cream.
      ,
      • Sperling L.C.
      • Tomaszewski M.-M.
      • Thomas D.A.
      Viral-associated trichodysplasia in patients who are immunocompromised.
      ).
      In the skin, TSPyV infects the inner root sheath keratinocytes (
      • Fischer M.K.
      • Kao G.F.
      • Nguyen H.P.
      • Drachenberg C.B.
      • Rady P.L.
      • Tyring S.K.
      • et al.
      Specific detection of trichodysplasia spinulosa–associated polyomavirus DNA in skin and renal allograft tissues in a patient with trichodysplasia spinulosa.
      ,
      • Rouanet J.
      • Aubin F.
      • Gaboriaud P.
      • Berthon P.
      • Feltkamp M.C.
      • Bessenay L.
      • et al.
      Trichodysplasia spinulosa: a polyomavirus infection specifically targeting follicular keratinocytes in immunocompromised patients.
      ,
      • Wanat K.A.
      • Holler P.D.
      • Dentchev T.
      • Simbiri K.
      • Robertson E.
      • Seykora J.T.
      • et al.
      Viral-associated trichodysplasia: characterization of a novel polyomavirus infection with therapeutic insights.
      ). The virus has also been identified in the blood, cerebrospinal fluid, respiratory tract, urinary tract, feces, cardiac tissue, and renal allografts, suggesting it may be a systemic infection (
      • Fischer M.K.
      • Kao G.F.
      • Nguyen H.P.
      • Drachenberg C.B.
      • Rady P.L.
      • Tyring S.K.
      • et al.
      Specific detection of trichodysplasia spinulosa–associated polyomavirus DNA in skin and renal allograft tissues in a patient with trichodysplasia spinulosa.
      ,
      • Rockett R.J.
      • Sloots T.P.
      • Bowes S.
      • O'Neill N.
      • Ye S.
      • Robson J.
      • et al.
      Detection of novel polyomaviruses, TSPyV, HPyV6, HPyV7, HPyV9 and MWPyV in feces, urine, blood, respiratory swabs and cerebrospinal fluid.
      ,
      • Tsuzuki S.
      • Fukumoto H.
      • Mine S.
      • Sato N.
      • Mochizuki M.
      • Hasegawa H.
      • et al.
      Detection of trichodysplasia spinulosa-associated polyomavirus in a fatal case of myocarditis in a seven-month-old girl.
      ,
      • Urbano P.R.
      • Nali L.H.
      • Bicalho C.S.
      • Pierrotti L.C.
      • David-Neto E.
      • Pannuti C.S.
      • et al.
      New findings about trichodysplasia spinulosa-associated polyomavirus (TSPyV)—novel qPCR detects TSPyV-DNA in blood samples.
      ,
      • van der Meijden E.
      • Horváth B.
      • Nijland M.
      • de Vries K.
      • Rácz E.K.
      • Diercks G.F.
      • et al.
      Primary polyomavirus infection, not reactivation, as the cause of trichodysplasia spinulosa in immunocompromised patients.
      ). Despite its broad tissue distribution, TSPyV has not been linked to other diseases (
      • Fava P.
      • Merlino C.
      • Novelli M.
      • Ponti R.
      • Galliano I.
      • Montanari P.
      • et al.
      HPyV6, HPyV7 and TSPyV DNA sequences detection in skin disease patients and healthy subjects.
      ,
      • Toptan T.
      • Yousem S.A.
      • Ho J.
      • Matsushima Y.
      • Stabile L.P.
      • Fernández-Figueras M.-T.
      • et al.
      Survey for human polyomaviruses in cancer.
      ).
      Successful treatments for TS have only been reported for a handful of patients. Clearance with cautious reduction in immunosuppressive therapies has been reported (
      • Coogle L.P.
      • Holland K.E.
      • Pan C.
      • Van Why S.K.
      Complete resolution of trichodysplasia spinulosa in a pediatric renal transplant patient: Case report and literature review.
      ,
      • van der Meijden E.
      • Horváth B.
      • Nijland M.
      • de Vries K.
      • Rácz E.K.
      • Diercks G.F.
      • et al.
      Primary polyomavirus infection, not reactivation, as the cause of trichodysplasia spinulosa in immunocompromised patients.
      ). Topical antiviral medicines (e.g., cidofovir 1% or 3%) and physical measures (e.g., plucking and shaving) have been successful (
      • Aleissa M.
      • Konstantinou M.P.
      • Samimi M.
      • Lamant L.
      • Gaboriaud P.
      • Touzé A.
      • et al.
      Trichodysplasia spinulosa associated with HIV infection: clinical response to acitretin and valganciclovir.
      ,
      • Barton M.
      • Lockhart S.
      • Sidbury R.
      • Wang R.
      • Brandling-Bennett H.
      Trichodysplasia spinulosa in a 7-year-old boy managed using physical extraction of keratin spicules.
      ,
      • Benoit T.
      • Bacelieri R.
      • Morrell D.S.
      • Metcalf J.
      Viral-associated trichodysplasia of immunosuppression: report of a pediatric patient with response to oral valganciclovir.
      ,
      • Campbell R.M.
      • Ney A.
      • Gohh R.
      • Robinson-Bostom L.
      Spiny hyperkeratotic projections on the face and extremities of a kidney transplant recipient.
      ,
      • Coogle L.P.
      • Holland K.E.
      • Pan C.
      • Van Why S.K.
      Complete resolution of trichodysplasia spinulosa in a pediatric renal transplant patient: Case report and literature review.
      ,
      • Leitenberger J.J.
      • Abdelmalek M.
      • Wang R.C.
      • Strasfeld L.
      • Hopkins R.S.
      Two cases of trichodysplasia spinulosa responsive to compounded topical cidofovir 3% cream.
      ,
      • Santesteban R.
      • Feito M.
      • Mayor A.
      • Beato M.
      • Ramos E.
      • de Lucas R.
      Trichodysplasia spinulosa in a 20-month-old girl with a good response to topical cidofovir 1%.
      ,
      • van der Meijden E.
      • Horváth B.
      • Nijland M.
      • de Vries K.
      • Rácz E.K.
      • Diercks G.F.
      • et al.
      Primary polyomavirus infection, not reactivation, as the cause of trichodysplasia spinulosa in immunocompromised patients.
      ,
      • Wanat K.A.
      • Holler P.D.
      • Dentchev T.
      • Simbiri K.
      • Robertson E.
      • Seykora J.T.
      • et al.
      Viral-associated trichodysplasia: characterization of a novel polyomavirus infection with therapeutic insights.
      ). Treatment with oral valgancyclovir, acitretin, and leflunomide has also been reported (
      • Aleissa M.
      • Konstantinou M.P.
      • Samimi M.
      • Lamant L.
      • Gaboriaud P.
      • Touzé A.
      • et al.
      Trichodysplasia spinulosa associated with HIV infection: clinical response to acitretin and valganciclovir.
      ,
      • Kassar R.
      • Chang J.
      • Chan A.-W.
      • Lilly L.B.
      • Al Habeeb A.
      • Rotstein C.
      Leflunomide for the treatment of trichodysplasia spinulosa in a liver transplant recipient.
      ). There have been some reports of success using combinations of the aforementioned therapies, such as the reduction of immunosuppression combined with topical or oral therapies (
      • Coogle L.P.
      • Holland K.E.
      • Pan C.
      • Van Why S.K.
      Complete resolution of trichodysplasia spinulosa in a pediatric renal transplant patient: Case report and literature review.
      ,
      • van der Meijden E.
      • Horváth B.
      • Nijland M.
      • de Vries K.
      • Rácz E.K.
      • Diercks G.F.
      • et al.
      Primary polyomavirus infection, not reactivation, as the cause of trichodysplasia spinulosa in immunocompromised patients.
      ) and the combination oral acitretin and oral valganciclovir (
      • Aleissa M.
      • Konstantinou M.P.
      • Samimi M.
      • Lamant L.
      • Gaboriaud P.
      • Touzé A.
      • et al.
      Trichodysplasia spinulosa associated with HIV infection: clinical response to acitretin and valganciclovir.
      ).

      Human Polyomaviruses 6 and 7

      Rolling-circle amplification of human skin swabs identified the closely related HPyV6 and HPyV7 from the skin of healthy volunteers (
      • Schowalter R.M.
      • Pastrana D.V.
      • Pumphrey K.A.
      • Moyer A.L.
      • Buck C.B.
      Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin.
      ). Like MCPyV, their detection in healthy volunteers suggested the ability of these viruses to be shed through latent or subclinical infections. While most newborns are seropositive (∼80% for HPyV6, ∼60% for HPyV7), seropositivity fell after the first 6 months of life, then rose with older cohorts, consistent with HPyV6/7 infection early in life for most individuals (
      • Nicol J.T.
      • Robinot R.
      • Carpentier A.
      • Carandina G.
      • Mazzoni E.
      • Tognon M.
      • et al.
      Age-specific seroprevalences of merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus.
      ,
      • van der Meijden E.
      • Bialasiewicz S.
      • Rockett R.J.
      • Tozer S.J.
      • Sloots T.P.
      • Feltkamp M.C.W.
      Different serologic behavior of MCPyV, TSPyV, HPyV6, HPyV7 and HPyV9 polyomaviruses found on the skin.
      ). Adult seroprevalences are 69–83% for HPyV6 and 35–66% for HPyV7 in populations throughout the world (
      • Gossai A.
      • Waterboer T.
      • Nelson H.H.
      • Michel A.
      • Willhauck-Fleckenstein M.
      • Farzan S.F.
      • et al.
      Seroepidemiology of human polyomaviruses in a US population.
      ,
      • Nicol J.T.
      • Robinot R.
      • Carpentier A.
      • Carandina G.
      • Mazzoni E.
      • Tognon M.
      • et al.
      Age-specific seroprevalences of merkel cell polyomavirus, human polyomaviruses 6, 7, and 9, and trichodysplasia spinulosa-associated polyomavirus.
      ,
      • Schowalter R.M.
      • Pastrana D.V.
      • Pumphrey K.A.
      • Moyer A.L.
      • Buck C.B.
      Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin.
      ,
      • Sroller V.
      • Hamsikova E.
      • Ludvikova V.
      • Musil J.
      • Nemeckova S.
      • Salakova M.
      Seroprevalence rates of HPyV6, HPyV7, TSPyV, HPyV9, MWPyV and KIPyV polyomaviruses among the healthy blood donors.
      ,
      • van der Meijden E.
      • Bialasiewicz S.
      • Rockett R.J.
      • Tozer S.J.
      • Sloots T.P.
      • Feltkamp M.C.W.
      Different serologic behavior of MCPyV, TSPyV, HPyV6, HPyV7 and HPyV9 polyomaviruses found on the skin.
      ). Examination of skin swabs revealed the presence of HPyV6 in 12–27.6% samples and HPyV7 2.1–13.4% (
      • Hampras S.S.
      • Giuliano A.R.
      • Lin H.Y.
      • Fisher K.J.
      • Abrahamsen M.E.
      • McKay-Chopin S.
      • et al.
      Natural history of polyomaviruses in men: the HPV infection in men (HIM) study.
      ,
      • Hashida Y.
      • Higuchi T.
      • Matsuzaki S.
      • Nakajima K.
      • Sano S.
      • Daibata M.
      Prevalence and genetic variability of human polyomaviruses 6 and 7 in healthy skin among asymptomatic individuals.
      ,
      • Schowalter R.M.
      • Pastrana D.V.
      • Pumphrey K.A.
      • Moyer A.L.
      • Buck C.B.
      Merkel cell polyomavirus and two previously unknown polyomaviruses are chronically shed from human skin.
      ,
      • Wieland U.
      • Silling S.
      • Hellmich M.
      • Potthoff A.
      • Pfister H.
      • Kreuter A.
      Human polyomaviruses 6, 7, 9, 10 and Trichodysplasia spinulosa-associated polyomavirus in HIV-infected men.
      ). Higher levels were detected in an HIV-positive population (39% for HPyV6 and 21% for HPyV7) (
      • Wieland U.
      • Silling S.
      • Hellmich M.
      • Potthoff A.
      • Pfister H.
      • Kreuter A.
      Human polyomaviruses 6, 7, 9, 10 and Trichodysplasia spinulosa-associated polyomavirus in HIV-infected men.
      ). Persistence of viral DNA shedding over 6 months in the majority of individuals further support chronic skin infection and asymptomatic shedding in a portion of individuals infected with HPyV6 and HPyV7 (
      • Hashida Y.
      • Higuchi T.
      • Matsuzaki S.
      • Nakajima K.
      • Sano S.
      • Daibata M.
      Prevalence and genetic variability of human polyomaviruses 6 and 7 in healthy skin among asymptomatic individuals.
      ).
      The constellation of clinical findings of HPyV6/7 infection have been referred to as “HPyV6- and HPyV7-associated pruritic and dyskeratotic dermatoses,” “human polyomavirus-7-associated rash and pruritus,” and “HPyV-associated hyperproliferative keratinopathy plus/minus pruritus” (
      • Canavan T.N.
      • Baddley J.W.
      • Pavlidakey P.
      • Tallaj J.A.
      • Elewski B.E.
      Human polyomavirus-7-associated eruption successfully treated with acitretin.
      ;
      • Ho J.
      • Jedrych J.J.
      • Feng H.
      • Natalie A.A.
      • Grandinetti L.
      • Mirvish E.
      • et al.
      Human polyomavirus 7-associated pruritic rash and viremia in transplant recipients.
      ;
      • Nguyen K.D.
      • Lee E.E.
      • Yue Y.
      • Štork J.
      • Pock L.
      • North J.P.
      • et al.
      Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses.
      ,
      • Smith S.D.B.
      • Erdag G.
      • Cuda J.D.
      • Rangwala S.
      • Girardi N.
      • Bibee K.
      • et al.
      Treatment of human polyomavirus-7-associated rash and pruritus with topical cidofovir in a lung transplant patient: Case report and literature review.
      ). Cutaneous HPyV6 and HPyV7 infection manifests with pruritic, brown to gray, lichenified plaques involving the trunk and extremities (Figure 1c) (
      • Canavan T.N.
      • Baddley J.W.
      • Pavlidakey P.
      • Tallaj J.A.
      • Elewski B.E.
      Human polyomavirus-7-associated eruption successfully treated with acitretin.
      ;
      • Ho J.
      • Jedrych J.J.
      • Feng H.
      • Natalie A.A.
      • Grandinetti L.
      • Mirvish E.
      • et al.
      Human polyomavirus 7-associated pruritic rash and viremia in transplant recipients.
      ;
      • Nguyen K.D.
      • Lee E.E.
      • Yue Y.
      • Štork J.
      • Pock L.
      • North J.P.
      • et al.
      Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses.
      ,
      • Smith S.D.B.
      • Erdag G.
      • Cuda J.D.
      • Rangwala S.
      • Girardi N.
      • Bibee K.
      • et al.
      Treatment of human polyomavirus-7-associated rash and pruritus with topical cidofovir in a lung transplant patient: Case report and literature review.
      ). With the exception of one case occurring in a patient immunosuppressed from HIV infection (
      • Nguyen K.D.
      • Lee E.E.
      • Yue Y.
      • Štork J.
      • Pock L.
      • North J.P.
      • et al.
      Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses.
      ), published cases have been associated with cardiac and lung transplants (
      • Canavan T.N.
      • Baddley J.W.
      • Pavlidakey P.
      • Tallaj J.A.
      • Elewski B.E.
      Human polyomavirus-7-associated eruption successfully treated with acitretin.
      ;
      • Ho J.
      • Jedrych J.J.
      • Feng H.
      • Natalie A.A.
      • Grandinetti L.
      • Mirvish E.
      • et al.
      Human polyomavirus 7-associated pruritic rash and viremia in transplant recipients.
      ;
      • Smith S.D.B.
      • Erdag G.
      • Cuda J.D.
      • Rangwala S.
      • Girardi N.
      • Bibee K.
      • et al.
      Treatment of human polyomavirus-7-associated rash and pruritus with topical cidofovir in a lung transplant patient: Case report and literature review.
      ). Immunosuppressive medicines in these organ transplant recipients included prednisone, azathioprine, sirolimus, tacrolimus, everolimus, and mycophenolate (
      • Canavan T.N.
      • Baddley J.W.
      • Pavlidakey P.
      • Tallaj J.A.
      • Elewski B.E.
      Human polyomavirus-7-associated eruption successfully treated with acitretin.
      ;
      • Ho J.
      • Jedrych J.J.
      • Feng H.
      • Natalie A.A.
      • Grandinetti L.
      • Mirvish E.
      • et al.
      Human polyomavirus 7-associated pruritic rash and viremia in transplant recipients.
      ;
      • Smith S.D.B.
      • Erdag G.
      • Cuda J.D.
      • Rangwala S.
      • Girardi N.
      • Bibee K.
      • et al.
      Treatment of human polyomavirus-7-associated rash and pruritus with topical cidofovir in a lung transplant patient: Case report and literature review.
      ). Histopathology reveals epidermal papillomatosis, dyskeratotic keratinocytes in the epidermis, and irregular columns of parakeratosis, the latter referred to as “peacock plumage,” “columnar dyskeratosis,” or “tiered parakeratosis with dyskeratosis” (Figure 1d) (
      • Canavan T.N.
      • Baddley J.W.
      • Pavlidakey P.
      • Tallaj J.A.
      • Elewski B.E.
      Human polyomavirus-7-associated eruption successfully treated with acitretin.
      ,
      • Champagne C.
      • Moore L.
      • Reule R.
      • Dyer J.A.
      • Rady P.
      • Tyring S.K.
      • et al.
      Cornoid Lamella-like structures in HIV-associated epidermodysplasia verruciformis: a unique histopathologic finding.
      ;
      • Ho J.
      • Jedrych J.J.
      • Feng H.
      • Natalie A.A.
      • Grandinetti L.
      • Mirvish E.
      • et al.
      Human polyomavirus 7-associated pruritic rash and viremia in transplant recipients.
      ;
      • Nguyen K.D.
      • Lee E.E.
      • Yue Y.
      • Štork J.
      • Pock L.
      • North J.P.
      • et al.
      Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses.
      ,
      • Pock L.
      • Stork J.
      Two case reports of columnar dyskeratosis, an unusual keratinisation disorder.
      ). In the upper dermis, there may be sparse, perivascular, lymphocytic infiltrates (
      • Ho J.
      • Jedrych J.J.
      • Feng H.
      • Natalie A.A.
      • Grandinetti L.
      • Mirvish E.
      • et al.
      Human polyomavirus 7-associated pruritic rash and viremia in transplant recipients.
      ;
      • Pock L.
      • Stork J.
      Two case reports of columnar dyskeratosis, an unusual keratinisation disorder.
      ). Viral T antigen and capsid proteins have been identified within keratinocytes, strongly suggesting that keratinocytes are the principal cell infected by HPyV7 in these dermatoses (
      • Ho J.
      • Jedrych J.J.
      • Feng H.
      • Natalie A.A.
      • Grandinetti L.
      • Mirvish E.
      • et al.
      Human polyomavirus 7-associated pruritic rash and viremia in transplant recipients.
      ;
      • Nguyen K.D.
      • Lee E.E.
      • Yue Y.
      • Štork J.
      • Pock L.
      • North J.P.
      • et al.
      Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses.
      ). Compared to healthy, control, skin samples, viral loads in lesional skin samples are several orders of magnitude higher (∼1.44–2.37 × 106 copies/LINE repeat vs. ∼3.11 × 101 copies/LINE repeat for HPyV6, ∼2.90 × 103 copies/LINE repeat vs. ∼1.43 × 101 copies/LINE repeat for HPyV7; 7.28–32.27 × 102 copies/cell vs. 0–0.4 copies/cell for HPyV7) (
      • Nguyen K.D.
      • Lee E.E.
      • Yue Y.
      • Štork J.
      • Pock L.
      • North J.P.
      • et al.
      Human polyomavirus 6 and 7 are associated with pruritic and dyskeratotic dermatoses.
      ,
      • Ho J.
      • Jedrych J.J.
      • Feng H.
      • Natalie A.A.
      • Grandinetti L.
      • Mirvish E.
      • et al.
      Human polyomavirus 7-associated pruritic rash and viremia in transplant recipients.
      ). HPyV6 has been linked to keratoacanthomas, BRAF inhibitor–associated epithelial neoplasms, and Kimura disease (
      • Beckervordersandforth J.
      • Pujari S.
      • Rennspiess D.
      • Speel E.J.
      • Winnepenninckx V.
      • Diaz C.
      • et al.
      Frequent detection of human polyomavirus 6 in keratoacanthomas.
      ,
      • Rascovan N.
      • Bouchard S.M.
      • Grob J.J.
      • Collet-Villette A.M.
      • Gaudy-Marqueste C.
      • Penicaud M.
      • et al.
      Human polyomavirus-6 infecting lymph nodes of a patient with an angiolymphoid hyperplasia with eosinophilia or Kimura disease.
      ,
      • Schrama D.
      • Groesser L.
      • Ugurel S.
      • Hafner C.
      • Pastrana D.V.
      • Buck C.B.
      • et al.
      Presence of human polyomavirus 6 in mutation-specific BRAF inhibitor-induced epithelial proliferations.
      ). However, other research has refuted the link between HPyV6/HPyV7 and other skin diseases, including both neoplastic and inflammatory skin diseases (
      • Bergallo M.
      • Dapra V.
      • Fava P.
      • Ponti R.
      • Calvi C.
      • Montanari P.
      • et al.
      DNA from human polyomaviruses, MWPyV, HPyV6, HPyV7, HPyV9 and HPyV12 in cutaneous T-cell lymphomas.
      ,
      • Fava P.
      • Merlino C.
      • Novelli M.
      • Ponti R.
      • Galliano I.
      • Montanari P.
      • et al.
      HPyV6, HPyV7 and TSPyV DNA sequences detection in skin disease patients and healthy subjects.
      ,
      • Frouin E.
      • Guillot B.
      • Larrieux M.
      • Tempier A.
      • Boulle N.
      • Foulongne V.
      • et al.
      Cutaneous epithelial tumors induced by vemurafenib involve the MAPK and Pi3KCA pathways but not HPV nor HPyV viral infection.
      ,
      • Haeggblom L.
      • Franzén J.
      • Näsman A.
      Human polyomavirus DNA detection in keratoacanthoma and Spitz naevus: no evidence for a causal role.
      ,
      • Schrama D.
      • Buck C.B.
      • Houben R.
      • Becker J.C.
      No evidence for association of HPyV6 or HPyV7 with different skin cancers.
      ,
      • Scola N.
      • Wieland U.
      • Silling S.
      • Altmeyer P.
      • Stucker M.
      • Kreuter A.
      Prevalence of human polyomaviruses in common and rare types of non-Merkel cell carcinoma skin cancer.
      ).
      Like MCPyV and TSPyV, HPyV6 and HPyV7 have also been identified in other tissues. HPyV6 has been detected in tonsillar tissue, cerebrospinal fluid, human bile, the respiratory tract, and feces, while HPyV7 has been noted in tonsillar tissue, human thymic epithelial tumors, urine, the respiratory tract, and feces (
      • Chan J.F.W.
      • Tee K.-M.
      • Choi G.K.Y.
      • Zhu Z.
      • Poon R.W.S.
      • Ng K.T.P.
      • et al.
      First detection and complete genome sequence of a phylogenetically distinct human polyomavirus 6 highly prevalent in human bile samples.
      ,
      • Delbue S.
      • Elia F.
      • Signorini L.
      • Bella R.
      • Villani S.
      • Marchioni E.
      • et al.
      Human polyomavirus 6 DNA in the cerebrospinal fluid of an HIV-positive patient with leukoencephalopathy.
      ,
      • Franzen J.
      • Ramqvist T.
      • Bogdanovic G.
      • Grun N.
      • Mattson J.
      • Dalianis T.
      Studies of human polyomaviruses, with HPyV7, BKPyV, and JCPyV present in urine of allogeneic hematopoietic stem cell transplanted patients with or without hemorrhagic cystitis.
      ,
      • Rennspiess D.
      • Pujari S.
      • Keijzers M.
      • Abdul-Hamid M.A.
      • Hochstenbag M.
      • Dingemans A.-M.
      • et al.
      Detection of human polyomavirus 7 in human thymic epithelial tumors.
      ,
      • Rockett R.J.
      • Sloots T.P.
      • Bowes S.
      • O'Neill N.
      • Ye S.
      • Robson J.
      • et al.
      Detection of novel polyomaviruses, TSPyV, HPyV6, HPyV7, HPyV9 and MWPyV in feces, urine, blood, respiratory swabs and cerebrospinal fluid.
      ,
      • Salakova M.
      • Koslabova E.
      • Vojtechova Z.
      • Tachezy R.
      • Sroller V.
      Detection of human polyomaviruses MCPyV, HPyV6, and HPyV7 in malignant and non-malignant tonsillar tissues.
      ,
      • Zheng W-z
      • Wei T-l
      • Ma F-l
      • Yuan W-m
      • Zhang Q.
      • Zhang Y.-X.
      • et al.
      Human polyomavirus type six in respiratory samples from hospitalized children with respiratory tract infections in Beijing, China.
      ). No link has been found between HPyV6/7 and internal malignancy (
      • Toptan T.
      • Yousem S.A.
      • Ho J.
      • Matsushima Y.
      • Stabile L.P.
      • Fernández-Figueras M.-T.
      • et al.
      Survey for human polyomaviruses in cancer.
      ).
      Treatments for infections linked to HPyV6 and HPyV7 remain anecdotal. Specifically, topical and intravenous cidofovir have been successful in isolated cases of HPyV7 infection, likely through its inhibition of viral replication (
      • Canavan T.N.
      • Baddley J.W.
      • Pavlidakey P.
      • Tallaj J.A.
      • Elewski B.E.
      Human polyomavirus-7-associated eruption successfully treated with acitretin.
      ,
      • Smith S.D.B.
      • Erdag G.
      • Cuda J.D.
      • Rangwala S.
      • Girardi N.
      • Bibee K.
      • et al.
      Treatment of human polyomavirus-7-associated rash and pruritus with topical cidofovir in a lung transplant patient: Case report and literature review.
      ). There are contradictory reports on the benefit of acitretin: one patient had complete resolution of his eruption with acitretin and another patient had no response (
      • Canavan T.N.
      • Baddley J.W.
      • Pavlidakey P.
      • Tallaj J.A.
      • Elewski B.E.
      Human polyomavirus-7-associated eruption successfully treated with acitretin.
      ,
      • Smith S.D.B.
      • Erdag G.
      • Cuda J.D.
      • Rangwala S.
      • Girardi N.
      • Bibee K.
      • et al.
      Treatment of human polyomavirus-7-associated rash and pruritus with topical cidofovir in a lung transplant patient: Case report and literature review.
      ). Of note, the patient with complete resolution received acitretin 25 mg twice daily, while the nonresponder patient received 25 mg once daily, leaving open the possibility that the dose and frequency of treatment may impact the efficacy. No reports have investigated the use of cidofovir or acitretin for HPyV6 infection.

      Malawi Polyomvirus (Human Polyomavirus 10)

      MWPyV was discovered in the stool from a healthy child in Malawi after pyrosequencing of purified virus-like particles (
      • Siebrasse E.A.
      • Reyes A.
      • Lim E.S.
      • Zhao G.
      • Mkakosya R.S.
      • Manary M.J.
      • et al.
      Identification of MW polyomavirus, a novel polyomavirus in human stool.
      ). A nearly identical species, HPyV10, was independently identified through rolling-circle amplification of virions prepared from condyloma on the buttock of a patient with warts, hypogammglobulinemia, infections, and myelokathexis syndrome (
      • Buck C.B.
      • Phan G.Q.
      • Raiji M.T.
      • Murphy P.M.
      • McDermott D.H.
      • McBride A.A.
      Complete genome sequence of a tenth human polyomavirus.
      ). Follow-up studies have confirmed the presence of MWPyV/HPyV10 in the stool of both healthy individuals and those with acute diarrheal illness (
      • Yu G.
      • Greninger A.L.
      • Isa P.
      • Phan T.G.
      • Martinez M.A.
      • de la Luz Sanchez M.
      • et al.
      Discovery of a novel polyomavirus in acute diarrheal samples from children.
      ). The seroprevalence of MWPyV/HPyV10 is very high with estimates of 42–99% in adults (
      • Gossai A.
      • Waterboer T.
      • Hoen A.G.
      • Farzan S.F.
      • Nelson H.H.
      • Michel A.
      • et al.
      Human polyomaviruses and incidence of cutaneous squamous cell carcinoma in the New Hampshire skin cancer study.
      ,
      • Nicol J.T.
      • Leblond V.
      • Arnold F.
      • Guerra G.
      • Mazzoni E.
      • Tognon M.
      • et al.
      Seroprevalence of human Malawi polyomavirus.
      ). Skin swabs detected the virus in 3.4% of healthy individuals and 9.3% of HIV-infected men (
      • Wieland U.
      • Silling S.
      • Hellmich M.
      • Potthoff A.
      • Pfister H.
      • Kreuter A.
      Human polyomaviruses 6, 7, 9, 10 and Trichodysplasia spinulosa-associated polyomavirus in HIV-infected men.
      ) (Table 3). Although MWPyV/HPyV10 DNA is most frequently detected in stool, it is also present in the skin and respiratory samples from symptomatic children (
      • Rockett R.J.
      • Sloots T.P.
      • Bowes S.
      • O'Neill N.
      • Ye S.
      • Robson J.
      • et al.
      Detection of novel polyomaviruses, TSPyV, HPyV6, HPyV7, HPyV9 and MWPyV in feces, urine, blood, respiratory swabs and cerebrospinal fluid.
      ). Given these findings, it remains unclear whether the bona fide tissue tropism of this virus is the skin or whether it represents a superficial contamination of the epidermis from another tissue source, like the gastrointestinal or respiratory tracts.

      Conclusions

      In contrast to the hundreds of species of papillomaviruses, there appears to be a smaller cohort of PyVs (n = 10–15) that infects humans. Seroprevalence studies have revealed that many of the more recently discovered PyVs appear to be zoonotic (
      • Kamminga S.
      • van der Meijden E.
      • Wunderink H.F.
      • Touze A.
      • Zaaijer H.L.
      • Feltkamp M.C.W.
      Development and evaluation of a broad bead-based multiplex immunoassay to measure IgG seroreactivity against human polyomaviruses.
      ), perhaps suggesting that the discovery of HPyVs is nearing saturation. Five HPyVs are shed chronically from human skin at varying levels. Recent work has linked TSPyV to a folliculocentric eruption; HPyV6 and HPyV7 to diffuse, hyperproliferative, pruritic eruptions; and MCPyV to a deadly skin cancer. MWPyV has not yet been linked to any diseases. Despite similarities in their overall genomic structures, subtle differences in both the early and late regions of these cutaneous PyVs in concert with interactions with the host tissues allow the viruses to have distinct tissue tropism and clinical manifestations.
      Serologic studies have revealed that cutaneous PyV infections occur in most individuals, yet even among immunosuppressed patients, PyV-mediated diseases are exceedingly rare. Additional studies are necessary to identify the PyV- and host-specific factors that drive the development of clinically relevant infections in rare individuals. Hopefully, these studies will also yield better treatments for the patients who develop these rare, but serious infections. Additional studies may reveal whether cutaneous PyVs contribute to currently idiopathic inflammatory skin conditions or exacerbate common skin diseases. These studies may also reveal whether cutaneous PyVs play commensal or even beneficial roles as members of the skin microbiome. Finally, consistent with the groundbreaking studies of SV40, the continued study of cutaneous PyVs will likely continue to contribute to our understanding of human tumorigenesis.

      Conflicts of Interest

      The authors state no conflict of interest.

      Acknowledgments

      We thank the Wang laboratory for helpful discussions and Peter Pavlidakey for the histologic images of HPyV7 infection. RW is supported by a National Institute of Arthritis and Musculoskeletal and Skin Diseases 1R01AR072655 , a Burroughs Wellcome Fund Career Award for Medical Scientists (1010978), and American Cancer Society Research Scholar Award (RSG-18-058-01).

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