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Abstract

Molluscum contagiosum virus (MCV) is a common cause of benign skin lesions in young children and currently the only endemic human poxvirus. Following the infection of primary keratinocytes in the epidermis, MCV induces the proliferation of infected cells and this results in the production of wart-like growths. Full productive infection is observed only after the infected cells differentiate. During this prolonged replication cycle the virus must avoid elimination by the host immune system. We therefore sought to investigate the function of the two major histocompatibility complex class-I-related genes encoded by the MCV genes mc033 and mc080. Following insertion into a replication-deficient adenovirus vector, codon-optimized versions of mc033 and mc080 were expressed as endoglycosidase-sensitive glycoproteins that localized primarily in the endoplasmic reticulum. MC080, but not MC033, downregulated cell-surface expression of endogenous classical human leucocyte antigen (HLA) class I and non-classical HLA-E by a transporter associated with antigen processing (TAP)-independent mechanism. MC080 exhibited a capacity to inhibit or activate NK cells in autologous assays in a donor-specific manner. MC080 consistently inhibited antigen-specific T cells being activated by peptide-pulsed targets. We therefore propose that MC080 acts to promote evasion of HLA-I-restricted cytotoxic T cells.

Funding
This study was supported by the:
  • Wellcome Trust (Award 204870/Z/16/Z)
    • Principle Award Recipient: Richard J. Stanton
  • H2020 European Research Council (Award 695551)
    • Principle Award Recipient: James Traherne
  • This is an open-access article distributed under the terms of the Creative Commons Attribution License. This article was made open access via a Publish and Read agreement between the Microbiology Society and the corresponding author’s institution.
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2020-06-08
2024-03-29
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References

  1. López-Bueno A, Parras-Moltó M, López-Barrantes O, Belda S, Alejo A. Recombination events and variability among full-length genomes of co-circulating molluscum contagiosum virus subtypes 1 and 2. J Gen Virol 2017; 98:1073–1079 [View Article]
    [Google Scholar]
  2. Mohr S, Grandemange Stéphanie, Massimi P, Darai G, Banks L et al. Targeting the retinoblastoma protein by MC007L, gene product of the molluscum contagiosum virus: detection of a novel virus-cell interaction by a member of the poxviruses. J Virol 2008; 82:10625–10633 [View Article]
    [Google Scholar]
  3. Reed RJ, Parkinson RP. The histogenesis of molluscum contagiosum. Am J Surg Pathol 1977; 1:161–166 [View Article]
    [Google Scholar]
  4. Vermi W, Fisogni S, Salogni L, Schärer L, Kutzner H et al. Spontaneous regression of highly immunogenic Molluscum contagiosum virus (MCV)-induced skin lesions is associated with plasmacytoid dendritic cells and IFN-DC infiltration. J Invest Dermatol 2011; 131:426–434 [View Article]
    [Google Scholar]
  5. Chen X, Anstey AV, Bugert JJ. Molluscum contagiosum virus infection. Lancet Infect Dis 2013; 13:877–888 [View Article]
    [Google Scholar]
  6. Senkevich TG, Bugert JJ, Sisler JR, Koonin EV, Darai G et al. Genome sequence of a human tumorigenic poxvirus: prediction of specific host response-evasion genes. Science 1996; 273:813–816 [View Article]
    [Google Scholar]
  7. Senkevich TG, Koonin EV, Bugert JJ, Darai G, Moss B. The genome of molluscum contagiosum virus: analysis and comparison with other poxviruses. Virology 1997; 233:19–42 [View Article]
    [Google Scholar]
  8. Smith GL, Benfield CTO, Maluquer de Motes C, Mazzon M, Ember SWJ et al. Vaccinia virus immune evasion: mechanisms, virulence and immunogenicity. Journal of General Virology 2013; 94:2367–2392 [View Article]
    [Google Scholar]
  9. Bugert JJ, Lohmüller C, Damon I, Moss B, Darai G. Chemokine homolog of molluscum contagiosum virus: sequence conservation and expression. Virology 1998; 242:51–59 [View Article]
    [Google Scholar]
  10. Hüttmann J, Krause E, Schommartz T, Brune W. Functional comparison of molluscum contagiosum virus vFLIP MC159 with murine cytomegalovirus M36/vICA and M45/vIRA proteins. J Virol 2016; 90:2895–2905 [View Article]
    [Google Scholar]
  11. Burshtyn DN. Nk cells and poxvirus infection. Front Immunol 2013; 4: [View Article]
    [Google Scholar]
  12. Alzhanova D, Edwards DM, Hammarlund E, Scholz IG, Horst D et al. Cowpox virus inhibits the transporter associated with antigen processing to evade T cell recognition. Cell Host Microbe 2009; 6:433–445 [View Article]
    [Google Scholar]
  13. Byun M, Verweij MC, Pickup DJ, Wiertz EJHJ, Hansen TH et al. Two mechanistically distinct immune evasion proteins of cowpox virus combine to avoid antiviral CD8 T cells. Cell Host Microbe 2009; 6:422–432 [View Article]
    [Google Scholar]
  14. Byun M, Wang X, Pak M, Hansen TH, Yokoyama WM. Cowpox virus exploits the endoplasmic reticulum retention pathway to inhibit MHC class I transport to the cell surface. Cell Host Microbe 2007; 2:306–315 [View Article]
    [Google Scholar]
  15. Dasgupta A, Hammarlund E, Slifka MK, Früh K. Cowpox virus evades CTL recognition and inhibits the intracellular transport of MHC class I molecules. J Immunol 2007; 178:1654–1661 [View Article]
    [Google Scholar]
  16. Brooks CR, Elliott T, Parham P, Khakoo SI. The inhibitory receptor NKG2A determines lysis of vaccinia virus-infected autologous targets by NK cells. J Immunol 2006; 176:1141–1147 [View Article][PubMed]
    [Google Scholar]
  17. Jarahian M, Fiedler M, Cohnen A, Djandji D, Hämmerling GJ et al. Modulation of NKp30- and NKp46-mediated natural killer cell responses by poxviral hemagglutinin. PLoS Pathog 2011; 7:e1002195 [View Article]
    [Google Scholar]
  18. Prod’homme V, Griffin C, Aicheler RJ, Wang ECY, McSharry BP et al. The Human Cytomegalovirus MHC Class I Homolog UL18 Inhibits LIR-1+ but Activates LIR-1- NK Cells. J Immunol 2007; 178:4473–4481 [View Article]
    [Google Scholar]
  19. Wills MR, Ashiru O, Reeves MB, Okecha G, Trowsdale J et al. Human cytomegalovirus encodes an MHC class I-like molecule (UL142) that functions to inhibit NK cell lysis. J Immunol 2005; 175:7457–7465 [View Article]
    [Google Scholar]
  20. Campbell JA, Trossman DS, Yokoyama WM, Carayannopoulos LN. Zoonotic orthopoxviruses encode a high-affinity antagonist of NKG2D. J Exp Med 2007; 204:1311–1317 [View Article]
    [Google Scholar]
  21. Lazear E, Peterson LW, Nelson CA, Fremont DH. Crystal structure of the cowpox virus-encoded NKG2D ligand OMCP. J Virol 2013; 87:840–850 [View Article]
    [Google Scholar]
  22. Sanchez LM, Chirimo AJ, Bjorkman PJ. Crystal structure of human ZAG, a fat-depleting factor related to MHC molecules. Science 1999; 283:1914–1919
    [Google Scholar]
  23. Senkevich TG, Moss B. Domain structure, intracellular trafficking, and β2-microglobulin binding of a major histocompatibility complex class I homolog encoded by molluscum contagiosum virus. Virology 1998; 250:397–407 [View Article]
    [Google Scholar]
  24. Harvey IB, Wang X, Fremont DH. Molluscum contagiosum virus MC80 sabotages MHC-I antigen presentation by targeting tapasin for ER-associated degradation. PLoS Pathog 2019; 15:e1007711 [View Article]
    [Google Scholar]
  25. Elasifer H. Analysis of MHC-I Homologues in Molluscum Contagiosum and Cytomegalovirus In Medical Microbiology: Cardiff University; 2018
    [Google Scholar]
  26. Lehner PJ, Karttunen JT, Wilkinson GWG, Cresswell P. The human cytomegalovirus US6 glycoprotein inhibits transporter associated with antigen processing-dependent peptide translocation. Proc Natl Acad Sci U S A 1997; 94:6904–6909 [View Article]
    [Google Scholar]
  27. Tomasec P, Wang ECY, Davison AJ, Vojtesek B, Armstrong M et al. Downregulation of natural killer cell–activating ligand CD155 by human cytomegalovirus UL141. Nat Immunol 2005; 6:181–188 [View Article]
    [Google Scholar]
  28. Ashiru O, Bennett NJ, Boyle LH, Thomas M, Trowsdale J et al. NKG2D ligand MICA is retained in the cis-Golgi apparatus by human cytomegalovirus protein UL142. J Virol 2009; 83:12345–12354 [View Article]
    [Google Scholar]
  29. Chalupny NJ, Rein-Weston A, Dosch S, Cosman D. Down-Regulation of the NKG2D ligand MICA by the human cytomegalovirus glycoprotein UL142. Biochem Biophys Res Commun 2006; 346:175–181 [View Article]
    [Google Scholar]
  30. Braud VM, Allan DSJ, Wilson D, McMichael AJ. TAP- and tapasin-dependent HLA-E surface expression correlates with the binding of an MHC class I leader peptide. Curr Biol 1998; 8:1–10 [View Article]
    [Google Scholar]
  31. Tomasec P, Braud VM, Rickards C, Powell MB, McSharry BP et al. Surface expression of HLA-E, an inhibitor of natural killer cells, enhanced by human cytomegalovirus gpUL40. Science 2000; 287:1031–1033 [View Article][PubMed]
    [Google Scholar]
  32. Guéguen M, Biddison WE, Long EO. T cell recognition of an HLA-A2-restricted epitope derived from a cleaved signal sequence. J Exp Med 1994; 180:1989–1994 [View Article]
    [Google Scholar]
  33. Wang ECY, McSharry B, Retiere C, Tomasec P, Williams S et al. UL40-mediated NK evasion during productive infection with human cytomegalovirus. Proc Natl Acad Sci U S A 2002; 99:7570–7575 [View Article]
    [Google Scholar]
  34. Hammer Q, Rückert T, Borst EM, Dunst J, Haubner A et al. Peptide-Specific recognition of human cytomegalovirus strains controls adaptive natural killer cells. Nat Immunol 2018; 19:453–463 [View Article]
    [Google Scholar]
  35. Pietra G, Romagnani C, Mazzarino P, Falco M, Millo E et al. HLA-E-restricted recognition of cytomegalovirus-derived peptides by human CD8+ cytolytic T lymphocytes. Proc Natl Acad Sci U S A 2003; 100:10896–10901 [View Article]
    [Google Scholar]
  36. Wang ECY, Pjechova M, Nightingale K, Vlahava V-M, Patel M et al. Suppression of costimulation by human cytomegalovirus promotes evasion of cellular immune defenses. Proc Natl Acad Sci U S A 2018; 115:4998–5003 [View Article]
    [Google Scholar]
  37. Wilkinson GW, Aicheler RJ. Natural killer cells and human cytomegalovirus. In Reddehase MJ. editor Cytomegaloviruses: From Molecular Biology to Intervention, p. Caister Academic Press Caister Academic Press; 2013
    [Google Scholar]
  38. Ehmann R, Brandes K, Antwerpen M, Walter M, von Schlippenbach K et al. Molecular and genomic characterization of a novel equine molluscum contagiosum-like virus. J Gen Virol 2020; 112: [View Article]
    [Google Scholar]
  39. McSharry BP, Jones CJ, Skinner JW, Kipling D, Wilkinson GWG. Human telomerase reverse transcriptase-immortalized MRC-5 and HCA2 human fibroblasts are fully permissive for human cytomegalovirus. J Gen Virol 2001; 82:855–863 [View Article]
    [Google Scholar]
  40. Stanton RJ, McSharry BP, Armstrong M, Tomasec P, Wilkinson GWG. Re-Engineering adenovirus vector systems to enable high-throughput analyses of gene function. Biotechniques 2008; 45:659–668 [View Article]
    [Google Scholar]
  41. Prod'homme V, Sugrue DM, Stanton RJ, Nomoto A, Davies J et al. Human cytomegalovirus UL141 promotes efficient downregulation of the natural killer cell activating ligand CD112. J Gen Virol 2010; 91:2034–2039 [View Article]
    [Google Scholar]
  42. Prod’homme V, Tomasec P, Cunningham C, Lemberg MK, Stanton RJ et al. Human cytomegalovirus UL40 signal peptide regulates cell surface expression of the NK cell ligands HLA-E and gpUL18. J.i. 2012; 188:2794–2804 [View Article]
    [Google Scholar]
  43. Fielding CA, Aicheler R, Stanton RJ, Wang ECY, Han S et al. Two novel human cytomegalovirus NK cell evasion functions target MICA for lysosomal degradation. PLoS Pathog 2014; 10:e1004058 [View Article]
    [Google Scholar]
  44. Jayaraman J, Kirgizova V, Di D, Johnson C, Jiang W et al. qKAT: quantitative semi-automated typing of killer-cell immunoglobulin-like receptor genes. JoVE 2019e58646 [View Article]
    [Google Scholar]
  45. Wagner I, Schefzyk D, Pruschke J, Schöfl G, Schöne B, Gruber B et al. Allele-Level Kir genotyping of more than a million samples: workflow, algorithm, and observations. Front Immunol 2018; 9: [View Article]
    [Google Scholar]
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