Virologica Sinica

, Volume 31, Issue 5, pp 363–379 | Cite as

Three-dimensional cell culture models for investigating human viruses



Three-dimensional (3D) culture models are physiologically relevant, as they provide reproducible results, experimental flexibility and can be adapted for high-throughput experiments. Moreover, these models bridge the gap between traditional two-dimensional (2D) monolayer cultures and animal models. 3D culture systems have significantly advanced basic cell science and tissue engineering, especially in the fields of cell biology and physiology, stem cell research, regenerative medicine, cancer research, drug discovery, and gene and protein expression studies. In addition, 3D models can provide unique insight into bacteriology, virology, parasitology and host-pathogen interactions. This review summarizes and analyzes recent progress in human virological research with 3D cell culture models. We discuss viral growth, replication, proliferation, infection, virus-host interactions and antiviral drugs in 3D culture models.


three-dimensional (3D) cell culture models scaffolds human viruses 


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  1. Achilli TM, Meyer J, Morgan JR. 2012. Advances in the formation, use and understanding of multi-cellular spheroids. Expert Opin Biol Ther, 12: 1347–1360.PubMedPubMedCentralCrossRefGoogle Scholar
  2. Aizaki H, Nagamori S, Matsuda M, Kawakami H, Hashimoto O, Ishiko H, Kawada M, Matsuura T, Hasumura S, Matsuura Y, Suzuki T, Miyamura T. 2003. Production and release of infectious hepatitis C virus from human liver cell cultures in the three-dimensional radial-flow bioreactor. Virology, 314: 16–25.PubMedCrossRefGoogle Scholar
  3. Alemany R, Balague C, Curiel DT. 2000. Replicative adenoviruses for cancer therapy. Nat Biotechnol, 18: 723–727.PubMedCrossRefGoogle Scholar
  4. Aly HH, Shimotohno K, Hijikata M. 2009. 3D cultured immortalized human hepatocytes useful to develop drugs for blood-borne HCV. Biochem Biophys Res Commun, 379: 330–334.PubMedCrossRefGoogle Scholar
  5. Anacker D, Moody C. 2012. Generation of organotypic raft cultures from primary human keratinocytes. J Vis Exp, 60:1–4Google Scholar
  6. Andrei G. 2006. Three-dimensional culture models for human viral diseases and antiviral drug development. Antiviral Res, 71: 96–107.PubMedCrossRefGoogle Scholar
  7. Andrei G, Duraffour S, Van den Oord J, Snoeck R. 2010. Epithelial raft cultures for investigations of virus growth, pathogenesis and efficacy of antiviral agents. Antiviral Res, 85: 431–449.PubMedCrossRefGoogle Scholar
  8. Andrei G, van den Oord J, Fiten P, Opdenakker G, De Wolf-Peeters C, De Clercq E, Snoeck R. 2005. Organotypic epithelial raft cultures as a model for evaluating compounds against alphaherpesviruses. Antimicrob Agents Chemother, 49: 4671–4680.PubMedPubMedCentralCrossRefGoogle Scholar
  9. Antoni D, Burckel H, Josset E, Noel G. 2015. Three-dimensional cell culture: a breakthrough in vivo. Int J Mol Sci, 16: 5517–5527.PubMedPubMedCentralCrossRefGoogle Scholar
  10. Arvin AM. 1996. Varicella-zoster virus. Clin Microbiol Rev, 9: 361–381.PubMedPubMedCentralGoogle Scholar
  11. Asselineau D, Prunieras M. 1984. Reconstruction of 'simplified' skin: control of fabrication. Br J Dermatol, 111 Suppl 27: 219–222.PubMedCrossRefGoogle Scholar
  12. Asthana A, Kisaalita WS. 2012. Microtissue size and hypoxia in HTS with 3D cultures. Drug Discov Today, 17: 810–817.PubMedCrossRefGoogle Scholar
  13. Atac B, Wagner I, Horland R, Lauster R, Marx U, Tonevitsky AG, Azar RP, Lindner G. 2013. Skin and hair on-a-chip: in vitro skin models versus ex vivo tissue maintenance with dynamic perfusion. Lab Chip, 13: 3555–3561.PubMedCrossRefGoogle Scholar
  14. Baker BM, Chen CS. 2012. Deconstructing the third dimension: how 3D culture microenvironments alter cellular cues. J Cell Sci, 125: 3015–3024.PubMedPubMedCentralCrossRefGoogle Scholar
  15. Balague C, Noya F, Alemany R, Chow LT, Curiel DT. 2001. Human papillomavirus E6E7-mediated adenovirus cell killing: selectivity of mutant adenovirus replication in organotypic cultures of human keratinocytes. J Virol, 75: 7602–7611.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Balzarini J, Andrei G, Balestra E, Huskens D, Vanpouille C, Introini A, Zicari S, Liekens S, Snoeck R, Holy A, Perno CF, Margolis L, Schols D. 2013. A multi-targeted drug candidate with dual anti-HIV and anti-HSV activity. PLoS Pathog, 9: e1003456.PubMedPubMedCentralCrossRefGoogle Scholar
  17. Barbaresi S, Cortese MS, Quinn J, Ashrafi GH, Graham SV, Campo MS. 2010. Effects of human papillomavirus type 16 E5 deletion mutants on epithelial morphology: functional characterization of each transmembrane domain. J Gen Virol, 91: 521–530.PubMedCrossRefGoogle Scholar
  18. Barre-Sinoussi F, Chermann JC, Rey F, Nugeyre MT, Chamaret S, Gruest J, Dauguet C, Axler-Blin C, Vezinet-Brun F, Rouzioux C, Rozenbaum W, Montagnier L. 1983. Isolation of a T-lymphotropic retrovirus from a patient at risk for acquired immune deficiency syndrome (AIDS). Science, 220: 868–871.PubMedCrossRefGoogle Scholar
  19. Barrila J, Radtke AL, Crabbe A, Sarker SF, Herbst-Kralovetz MM, Ott CM, Nickerson CA. 2010. Organotypic 3D cell culture models: using the rotating wall vessel to study host-pathogen interactions. Nat Rev Microbiol, 8: 791–801.PubMedCrossRefGoogle Scholar
  20. Bernard HU, Burk RD, Chen Z, van Doorslaer K, zur Hausen H, de Villiers EM. 2010. Classification of papillomaviruses (PVs) based on 189 PV types and proposal of taxonomic amendments. Virology, 401: 70–79.PubMedPubMedCentralCrossRefGoogle Scholar
  21. Berto A, Van der Poel WH, Hakze-van der Honing R, Martelli F, La Ragione RM, Inglese N, Collins J, Grierson S, Johne R, Reetz J, Dastjerdi A, Banks M. 2013. Replication of hepatitis E virus in three-dimensional cell culture. J Virol Methods, 187: 327–332.PubMedCrossRefGoogle Scholar
  22. Borgogna C, Zavattaro E, De Andrea M, Griffin HM, Dell' Oste V, Azzimonti B, Landini MM, Peh WL, Pfister H, Doorbar J, Landolfo S, Gariglio M. 2012. Characterization of beta papillomavirus E4 expression in tumours from Epidermodysplasia Verruciformis patients and in experimental models. Virology, 423: 195–204.PubMedCrossRefGoogle Scholar
  23. Bowser BS, Chen HS, Conway MJ, Christensen ND, Meyers C. 2011. Human papillomavirus type 18 chimeras containing the L2/L1 capsid genes from evolutionarily diverse papillomavirus types generate infectious virus. Virus Res, 160: 246–255.PubMedPubMedCentralCrossRefGoogle Scholar
  24. Breslin S, O' Driscoll L. 2013. Three-dimensional cell culture: the missing link in drug discovery. Drug Discov Today, 18: 240–249.PubMedCrossRefGoogle Scholar
  25. Cerwinka WH, Sharp SM, Boyan BD, Zhau HE, Chung LW, Yates C. 2012. Differentiation of human mesenchymal stem cell spheroids under microgravity conditions. Cell Regen (Lond), 1: 2.CrossRefGoogle Scholar
  26. Cho NJ, Elazar M, Xiong A, Lee W, Chiao E, Baker J, Frank CW, Glenn JS. 2009. Viral infection of human progenitor and liverderived cells encapsulated in three-dimensional PEG-based hydrogel. Biomed Mater, 4: 011001.PubMedCrossRefGoogle Scholar
  27. Choi DJ, Choi SM, Kang HY, Min HJ, Lee R, Ikram M, Subhan F, Jin SW, Jeong YH, Kwak JY, Yoon S. 2015. Bioactive fish collagen/polycaprolactone composite nanofibrous scaffolds fabricated by electrospinning for 3D cell culture. J Biotechnol, 205: 47–58.PubMedCrossRefGoogle Scholar
  28. Choo QL, Kuo G, Weiner AJ, Overby LR, Bradley DW, Houghton M. 1989. Isolation of a cDNA clone derived from a blood-borne non-A, non-B viral hepatitis genome. Science, 244: 359–362.PubMedCrossRefGoogle Scholar
  29. Chow LT. 2015. Model systems to study the life cycle of human papillomaviruses and HPV-associated cancers. Virol Sin, 30: 92–100.PubMedCrossRefGoogle Scholar
  30. Chow LT, Duffy AA, Wang HK, Broker TR. 2009. A highly efficient system to produce infectious human papillomavirus: Elucidation of natural virus-host interactions. Cell Cycle, 8: 1319–1323.PubMedCrossRefGoogle Scholar
  31. Chung BG, Lee KH, Khademhosseini A, Lee SH. 2012. Microfluidic fabrication of microengineered hydrogels and their application in tissue engineering. Lab Chip, 12: 45–59.PubMedCrossRefGoogle Scholar
  32. Cox AL. 2015. MEDICINE. Global control of hepatitis C virus. Science, 349: 790–791.PubMedGoogle Scholar
  33. Cukierman E, Pankov R, Yamada KM. 2002. Cell interactions with three-dimensional matrices. Curr Opin Cell Biol, 14: 633–639.PubMedCrossRefGoogle Scholar
  34. Dash P, Barnett PV, Denyer MS, Jackson T, Stirling CM, Hawes PC, Simpson JL, Monaghan P, Takamatsu HH. 2010. Foot-andmouth disease virus replicates only transiently in well-differentiated porcine nasal epithelial cells. J Virol, 84: 9149–9160.PubMedPubMedCentralCrossRefGoogle Scholar
  35. De Clercq E. 2007. The design of drugs for HIV and HCV. Nat Rev Drug Discov, 6: 1001–1018.PubMedCrossRefGoogle Scholar
  36. Doorbar J. 2016. Model systems of human papillomavirus-associated disease. J Pathol, 238: 166–179.PubMedCrossRefGoogle Scholar
  37. Doorbar J, Quint W, Banks L, Bravo IG, Stoler M, Broker TR, Stanley MA. 2012. The biology and life-cycle of human papillomaviruses. Vaccine, 30 Suppl 5: F55–F70.PubMedCrossRefGoogle Scholar
  38. Edmondson R, Broglie JJ, Adcock AF, Yang L. 2014. Three-dimensional cell culture systems and their applications in drug discovery and cell-based biosensors. Assay Drug Dev Technol, 12: 207–218.PubMedPubMedCentralCrossRefGoogle Scholar
  39. Ettayebi K, Crawford SE, Murakami K, Broughman JR, Karandikar U, Tenge VR, Neill FH, Blutt SE, Zeng XL, Qu L, Kou B, Opekun AR, Burrin D, Graham DY, Ramani S, Atmar RL, Estes MK. 2016. Replication of human noroviruses in stem cell-derived human enteroids. Science, 353: 1387–1393.PubMedCrossRefGoogle Scholar
  40. Fang L, Meyers C, Budgeon LR, Howett MK. 2006. Induction of productive human papillomavirus type 11 life cycle in epithelial cells grown in organotypic raft cultures. Virology, 347: 28–35.PubMedCrossRefGoogle Scholar
  41. Fotheringham JA, Raab-Traub N. 2013. Epstein-Barr virus latent membrane protein 2 effects on epithelial acinus development reveal distinct requirements for the PY and YEEA motifs. J Virol, 87: 13803–13815.PubMedPubMedCentralCrossRefGoogle Scholar
  42. Frey O, Misun PM, Fluri DA, Hengstler JG, Hierlemann A. 2014. Reconfigurable microfluidic hanging drop network for multitissue interaction and analysis. Nat Commun, 5: 4250.PubMedCrossRefGoogle Scholar
  43. Friedl P, Alexander S. 2011. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell, 147: 992–1009.PubMedCrossRefGoogle Scholar
  44. Friedl P, Sahai E, Weiss S, Yamada KM. 2012. New dimensions in cell migration. Nat Rev Mol Cell Biol, 13: 743–747.PubMedCrossRefGoogle Scholar
  45. Ghosh S, Spagnoli GC, Martin I, Ploegert S, Demougin P, Heberer M, Reschner A. 2005. Three-dimensional culture of melanoma cells profoundly affects gene expression profile: a high density oligonucleotide array study. J Cell Physiol, 204: 522–531.PubMedCrossRefGoogle Scholar
  46. Goodwin TJ, Jessup JM, Wolf DA. 1992. Morphologic differentiation of colon carcinoma cell lines HT-29 and HT-29KM in rotating-wall vessels. In Vitro Cell Dev Biol, 28A: 47–60.PubMedCrossRefGoogle Scholar
  47. Goodwin TJ, McCarthy M, Cohrs RJ, Kaufer BB. 2015. 3D tissuelike assemblies: A novel approach to investigate virus-cell interactions. Methods, 90: 76–84.PubMedCrossRefGoogle Scholar
  48. Goodwin TJ, McCarthy M, Osterrieder N, Cohrs RJ, Kaufer BB. 2013. Three-dimensional normal human neural progenitor tissue-like assemblies: a model of persistent varicella-zoster virus infection. PLoS Pathog, 9: e1003512.PubMedPubMedCentralCrossRefGoogle Scholar
  49. Goodwin TJ, Prewett TL, Wolf DA, Spaulding GF. 1993. Reduced shear stress: a major component in the ability of mammalian tissues to form three-dimensional assemblies in simulated microgravity. J Cell Biochem, 51: 301–311.PubMedCrossRefGoogle Scholar
  50. Griffith LG, Swartz MA. 2006. Capturing complex 3D tissue physiology in vitro. Nat Rev Mol Cell Biol, 7: 211–224.PubMedCrossRefGoogle Scholar
  51. Grill J, Lamfers ML, van Beusechem VW, Dirven CM, Pherai DS, Kater M, Van der Valk P, Vogels R, Vandertop WP, Pinedo HM, Curiel DT, Gerritsen WR. 2002. The organotypic multicellular spheroid is a relevant three-dimensional model to study adenovirus replication and penetration in human tumors in vitro. Mol Ther, 6: 609–614.PubMedCrossRefGoogle Scholar
  52. Grinnell F, Petroll WM. 2010. Cell motility and mechanics in three-dimensional collagen matrices. Annu Rev Cell Dev Biol, 26: 335–361.PubMedCrossRefGoogle Scholar
  53. Guilak F, Cohen DM, Estes BT, Gimble JM, Liedtke W, Chen CS. 2009. Control of stem cell fate by physical interactions with the extracellular matrix. Cell Stem Cell, 5: 17–26.PubMedPubMedCentralCrossRefGoogle Scholar
  54. Gunatillake PA, Adhikari R. 2003. Biodegradable synthetic polymers for tissue engineering. Eur Cell Mater, 5: 1–16PubMedGoogle Scholar
  55. Haisler WL, Timm DM, Gage JA, Tseng H, Killian TC, Souza GR. 2013. Three-dimensional cell culturing by magnetic levitation. Nat Protoc, 8: 1940–1949.PubMedCrossRefGoogle Scholar
  56. Hamilton G. 1998. Multicellular spheroids as an in vitro tumor model. Cancer Lett, 131: 29–34.PubMedCrossRefGoogle Scholar
  57. Hammond TG, Hammond JM. 2001. Optimized suspension culture: the rotating-wall vessel. Am J Physiol Renal Physiol, 281: F12–F25.PubMedGoogle Scholar
  58. Haycock JW. 2010. In: 3D Cell Culture Methods and Protocols. New York: Humana Press.Google Scholar
  59. Heesterbeek H, Anderson RM, Andreasen V, Bansal S, De Angelis D, Dye C, Eames KT, Edmunds WJ, Frost SD, Funk S, Hollingsworth TD, House T, Isham V, Klepac P, Lessler J, Lloyd-Smith JO, Metcalf CJ, Mollison D, Pellis L, Pulliam JR, Roberts MG, Viboud C, Isaac Newton Institute IDDC. 2015. Modeling infectious disease dynamics in the complex landscape of global health. Science, 347: aaa4339.PubMedPubMedCentralCrossRefGoogle Scholar
  60. Heininger U, Seward JF. 2006. Varicella. Lancet, 368: 1365–1376.PubMedCrossRefGoogle Scholar
  61. Hermonat PL, You H, Chiriva-Internati CM, Liu Y. 2005. Analysis of adeno-associated virus and HPV interaction. Methods Mol Med, 119: 397–409.PubMedGoogle Scholar
  62. Heymann DL, Chen L, Takemi K, Fidler DP, Tappero JW, Thomas MJ, Kenyon TA, Frieden TR, Yach D, Nishtar S, Kalache A, Olliaro PL, Horby P, Torreele E, Gostin LO, Ndomondo-Sigonda M, Carpenter D, Rushton S, Lillywhite L, Devkota B, Koser K, Yates R, Dhillon RS, Rannan-Eliya RP. 2015. Global health security: the wider lessons from the west African Ebola virus disease epidemic. Lancet, 385: 1884–1901.PubMedCrossRefGoogle Scholar
  63. Hjelm BE, Berta AN, Nickerson CA, Arntzen CJ, Herbst-Kralovetz MM. 2010. Development and characterization of a three-dimensional organotypic human vaginal epithelial cell model. Biol Reprod, 82: 617–627.PubMedCrossRefGoogle Scholar
  64. Huang GY, Zhou LH, Zhang QC, Chen YM, Sun W, Xu F, Lu TJ. 2011. Microfluidic hydrogels for tissue engineering. Biofabrication, 3: 012001.PubMedCrossRefGoogle Scholar
  65. Hukkanen V, Mikola H, Nykanen M, Syrjanen S. 1999. Herpes simplex virus type 1 infection has two separate modes of spread in three-dimensional keratinocyte culture. J Gen Virol, 80: 2149–2155.PubMedCrossRefGoogle Scholar
  66. Hutmacher DW. 2010. Biomaterials offer cancer research the third dimension. Nat Mater, 9: 90–93.PubMedCrossRefGoogle Scholar
  67. Israr M, Mitchell D, Alam S, Dinello D, Kishel JJ, Meyers C. 2010. Effect of the HIV protease inhibitor amprenavir on the growth and differentiation of primary gingival epithelium. Antivir Ther, 15: 253–265.PubMedPubMedCentralCrossRefGoogle Scholar
  68. Israr M, Mitchell D, Alam S, Dinello D, Kishel JJ, Meyers C. 2011. The HIV protease inhibitor lopinavir/ritonavir (Kaletra) alters the growth, differentiation and proliferation of primary gingival epithelium. HIV Med, 12: 145–156.PubMedCrossRefGoogle Scholar
  69. Kapikian AZ, Wyatt RG, Dolin R, Thornhill TS, Kalica AR, Chanock RM. 1972. Visualization by immune electron microscopy of a 27-nm particle associated with acute infectious nonbacterial gastroenteritis. J Virol, 10: 1075–1081.PubMedPubMedCentralGoogle Scholar
  70. Karlsson H, Fryknas M, Larsson R, Nygren P. 2012. Loss of cancer drug activity in colon cancer HCT-116 cells during spheroid formation in a new 3-D spheroid cell culture system. Exp Cell Res, 318: 1577–1585.PubMedCrossRefGoogle Scholar
  71. Kawada M, Nagamori S, Aizaki H, Fukaya K, Niiya M, Matsuura T, Sujino H, Hasumura S, Yashida H, Mizutani S, Ikenaga H. 1998. Massive culture of human liver cancer cells in a newly developed radial flow bioreactor system: ultrafine structure of functionally enhanced hepatocarcinoma cell lines. In Vitro Cell Dev Biol Anim, 34: 109–115.PubMedCrossRefGoogle Scholar
  72. Keane TJ, Badylak SF. 2014. Biomaterials for tissue engineering applications. Semin Pediatr Surg, 23: 112–118.PubMedCrossRefGoogle Scholar
  73. Kelm JM, Timmins NE, Brown CJ, Fussenegger M, Nielsen LK. 2003. Method for generation of homogeneous multicellular tumor spheroids applicable to a wide variety of cell types. Biotechnol Bioeng, 83: 173–180.PubMedCrossRefGoogle Scholar
  74. Kim JA, Choi JH, Kim M, Rhee WJ, Son B, Jung HK, Park TH. 2013. High-throughput generation of spheroids using magnetic nanoparticles for three-dimensional cell culture. Biomaterials, 34: 8555–8563.PubMedCrossRefGoogle Scholar
  75. Kim JB. 2005. Three-dimensional tissue culture models in cancer biology. Semin Cancer Biol, 15: 365–377.PubMedCrossRefGoogle Scholar
  76. Kleinman HK, Martin GR. 2005. Matrigel: basement membrane matrix with biological activity. Semin Cancer Biol, 15: 378–386.PubMedCrossRefGoogle Scholar
  77. Lam TT, Wang J, Shen Y, Zhou B, Duan L, Cheung CL, Ma C, Lycett SJ, Leung CY, Chen X, Li L, Hong W, Chai Y, Zhou L, Liang H, Ou Z, Liu Y, Farooqui A, Kelvin DJ, Poon LL, Smith DK, Pybus OG, Leung GM, Shu Y, Webster RG, Webby RJ, Peiris JS, Rambaut A, Zhu H, Guan Y. 2013. The genesis and source of the H7N9 influenza viruses causing human infections in China. Nature, 502: 241–244.PubMedPubMedCentralCrossRefGoogle Scholar
  78. Lam V, Bigley T, Terhune SS, Wakatsuki T. 2012. A method for quantifying mechanical properties of tissue following viral infection. PLoS One, 7: e42197.PubMedPubMedCentralCrossRefGoogle Scholar
  79. Lee J, Cuddihy MJ, Kotov NA. 2008. Three-dimensional cell culture matrices: state of the art. Tissue Eng Part B Rev, 14: 61–86.PubMedCrossRefGoogle Scholar
  80. Lee J, Lee S, Roh K, Jung E, Park D. 2015. A novel culture system to induce melanin synthesis by three-dimensional spheroid culture. Biotechnology and Bioprocess Engineering, 20: 194–200.CrossRefGoogle Scholar
  81. Lessler J, Chaisson LH, Kucirka LM, Bi Q, Grantz K, Salje H, Carcelen AC, Ott CT, Sheffield JS, Ferguson NM, Cummings DA, Metcalf CJ, Rodriguez-Barraquer I. 2016. Assessing the global threat from Zika virus. Science, 353: aaf8160.PubMedCrossRefGoogle Scholar
  82. Li Z, Cui Z. 2014. Three-dimensional perfused cell culture. Biotechnol Adv, 32: 243–254.PubMedCrossRefGoogle Scholar
  83. Lin RZ, Chang HY. 2008. Recent advances in three-dimensional multicellular spheroid culture for biomedical research. Biotechnol J, 3: 1172–1184.PubMedCrossRefGoogle Scholar
  84. Lindenbach BD, Evans MJ, Syder AJ, Wolk B, Tellinghuisen TL, Liu CC, Maruyama T, Hynes RO, Burton DR, McKeating JA, Rice CM. 2005. Complete replication of hepatitis C virus in cell culture. Science, 309: 623–626.PubMedCrossRefGoogle Scholar
  85. Liu S, Chen R, Hagedorn CH. 2014. Direct visualization of hepatitis C virus-infected Huh7.5 cells with a high titre of infectious chimeric JFH1-EGFP reporter virus in three-dimensional Matrigel cell cultures. J Gen Virol, 95: 423–433.PubMedPubMedCentralCrossRefGoogle Scholar
  86. Loessner D, Stok KS, Lutolf MP, Hutmacher DW, Clements JA, Rizzi SC. 2010. Bioengineered 3D platform to explore cell-ECM interactions and drug resistance of epithelial ovarian cancer cells. Biomaterials, 31: 8494–8506.PubMedCrossRefGoogle Scholar
  87. Long JP, Pierson S, Hughes JH. 1998. Rhinovirus replication in HeLa cells cultured under conditions of simulated microgravity. Aviat Space Environ Med, 69: 851–856.PubMedGoogle Scholar
  88. Louz D, Bergmans HE, Loos BP, Hoeben RC. 2013. Animal models in virus research: their utility and limitations. Crit Rev Microbiol, 39: 325–361.PubMedCrossRefGoogle Scholar
  89. Lutolf MP, Hubbell JA. 2005. Synthetic biomaterials as instructive extracellular microenvironments for morphogenesis in tissue engineering. Nat Biotechnol, 23: 47–55.PubMedCrossRefGoogle Scholar
  90. Maartens G, Celum C, Lewin SR. 2014. HIV infection: epidemiology, pathogenesis, treatment, and prevention. Lancet, 384: 258–271.PubMedCrossRefGoogle Scholar
  91. Madsen CD, Sahai E. 2010. Cancer dissemination—lessons from leukocytes. Dev Cell, 19: 13–26.PubMedCrossRefGoogle Scholar
  92. Malik H, Khan FH, Ahsan H. 2014. Human papillomavirus: current status and issues of vaccination. Arch Virol, 159: 199–205.PubMedCrossRefGoogle Scholar
  93. Margolis LB, Fitzgerald W, Glushakova S, Hatfill S, Amichay N, Baibakov B, Zimmerberg J. 1997. Lymphocyte trafficking and HIV infection of human lymphoid tissue in a rotating wall vessel bioreactor. AIDS Res Hum Retroviruses, 13: 1411–1420.PubMedCrossRefGoogle Scholar
  94. Mazzoleni G, Di Lorenzo D, Steimberg N. 2009. Modelling tissues in 3D: the next future of pharmaco-toxicology and food research? Genes Nutr, 4: 13–22.PubMedCrossRefGoogle Scholar
  95. McGuigan C, Pathirana RN, Migliore M, Adak R, Luoni G, Jones AT, Diez-Torrubia A, Camarasa MJ, Velazquez S, Henson G, Verbeken E, Sienaert R, Naesens L, Snoeck R, Andrei G, Balzarini J. 2007. Preclinical development of bicyclic nucleoside analogues as potent and selective inhibitors of varicella zoster virus. J Antimicrob Chemother, 60: 1316–1330.PubMedCrossRefGoogle Scholar
  96. McLaughlin-Drubin ME, Christensen ND, Meyers C. 2004. Propagation, infection, and neutralization of authentic HPV16 virus. Virology, 322: 213–219.PubMedCrossRefGoogle Scholar
  97. McLaughlin-Drubin ME, Meyers C. 2005. Propagation of infectious, high-risk HPV in organotypic "raft" culture. Methods Mol Med, 119: 171–186.PubMedGoogle Scholar
  98. McLaughlin-Drubin ME, Wilson S, Mullikin B, Suzich J, Meyers C. 2003. Human papillomavirus type 45 propagation, infection, and neutralization. Virology, 312: 1–7.PubMedCrossRefGoogle Scholar
  99. Meyers C, Andreansky SS, Courtney RJ. 2003. Replication and interaction of herpes simplex virus and human papillomavirus in differentiating host epithelial tissue. Virology, 315: 43–55.PubMedCrossRefGoogle Scholar
  100. Meyers C, Bromberg-White JL, Zhang J, Kaupas ME, Bryan JT, Lowe RS, Jansen KU. 2002. Infectious virions produced from a human papillomavirus type 18/16 genomic DNA chimera. J Virol, 76: 4723–4733.PubMedPubMedCentralCrossRefGoogle Scholar
  101. Meyers C, Frattini MG, Hudson JB, Laimins LA. 1992. Biosynthesis of human papillomavirus from a continuous cell line upon epithelial differentiation. Science, 257: 971–973.PubMedCrossRefGoogle Scholar
  102. Mihalcin M, Polak P, Husa P. 2015. Hepatitis E—overview of the latest knowledge. Epidemiol Mikrobiol Imunol, 64: 72–78. (In Czech)PubMedGoogle Scholar
  103. Mitchell D, Israr M, Alam S, Dinello D, Kishel J, Jia R, Meyers C. 2014. HIV nucleoside reverse transcriptase inhibitors efavirenz and tenofovir change the growth and differentiation of primary gingival epithelium. HIV Med, 15: 196–202.PubMedCrossRefGoogle Scholar
  104. Mitchell D, Israr M, Alam S, Kishel J, Dinello D, Meyers C. 2012. Effect of the HIV nucleoside reverse transcriptase inhibitor zidovudine on the growth and differentiation of primary gingival epithelium. HIV Med, 13: 276–290.PubMedPubMedCentralCrossRefGoogle Scholar
  105. Mole S, McFarlane M, Chuen-Im T, Milligan SG, Millan D, Graham SV. 2009. RNA splicing factors regulated by HPV16 during cervical tumour progression. J Pathol, 219: 383–391.PubMedPubMedCentralCrossRefGoogle Scholar
  106. Molina-Jimenez F, Benedicto I, Dao Thi VL, Gondar V, Lavillette D, Marin JJ, Briz O, Moreno-Otero R, Aldabe R, Baumert TF, Cosset FL, Lopez-Cabrera M, Majano PL. 2012. Matrigelembedded 3D culture of Huh-7 cells as a hepatocyte-like polarized system to study hepatitis C virus cycle. Virology, 425: 31–39.PubMedCrossRefGoogle Scholar
  107. Moore PS, Chang Y. 2010. Why do viruses cause cancer? Highlights of the first century of human tumour virology. Nat Rev Cancer, 10: 878–889.PubMedPubMedCentralCrossRefGoogle Scholar
  108. Morens DM, Folkers GK, Fauci AS. 2004. The challenge of emerging and re-emerging infectious diseases. Nature, 430: 242–249.PubMedCrossRefGoogle Scholar
  109. Murakami K, Inoue Y, Hmwe SS, Omata K, Hongo T, Ishii K, Yoshizaki S, Aizaki H, Matsuura T, Shoji I, Miyamura T, Suzuki T. 2008. Dynamic behavior of hepatitis C virus quasispecies in a long-term culture of the three-dimensional radial-flow bioreactor system. J Virol Methods, 148: 174–181.PubMedCrossRefGoogle Scholar
  110. Murakami K, Ishii K, Ishihara Y, Yoshizaki S, Tanaka K, Gotoh Y, Aizaki H, Kohara M, Yoshioka H, Mori Y, Manabe N, Shoji I, Sata T, Bartenschlager R, Matsuura Y, Miyamura T, Suzuki T. 2006. Production of infectious hepatitis C virus particles in three-dimensional cultures of the cell line carrying the genomelength dicistronic viral RNA of genotype 1b. Virology, 351: 381–392.PubMedCrossRefGoogle Scholar
  111. Nickerson CA, Ott CM, Wilson JW, Ramamurthy R, Pierson DL. 2004. Microbial responses to microgravity and other low-shear environments. Microbiol Mol Biol Rev, 68: 345–361.PubMedPubMedCentralCrossRefGoogle Scholar
  112. Nickerson CA, Richter EG, Ott CM. 2007. Studying host-pathogen interactions in 3-D: organotypic models for infectious disease and drug development. J Neuroimmune Pharmacol, 2: 26–31.PubMedCrossRefGoogle Scholar
  113. Nicoll MP, Proenca JT, Efstathiou S. 2012. The molecular basis of herpes simplex virus latency. FEMS Microbiol Rev, 36: 684–705.PubMedPubMedCentralCrossRefGoogle Scholar
  114. Noya F, Balague C, Banerjee NS, Curiel DT, Broker TR, Chow LT. 2003. Activation of adenovirus early promoters and lytic phase in differentiated strata of organotypic cultures of human keratinocytes. J Virol, 77: 6533–6540.PubMedPubMedCentralCrossRefGoogle Scholar
  115. Osterman A, Stellberger T, Gebhardt A, Kurz M, Friedel CC, Uetz P, Nitschko H, Baiker A, Vizoso-Pinto MG. 2015. The Hepatitis E virus intraviral interactome. Sci Rep, 5: 13872.PubMedPubMedCentralCrossRefGoogle Scholar
  116. Ozbun MA. 2002. Infectious human papillomavirus type 31b: purification and infection of an immortalized human keratinocyte cell line. J Gen Virol, 83: 2753–2763.PubMedCrossRefGoogle Scholar
  117. Ozbun MA, Patterson NA. 2014. Using organotypic (raft) epithelial tissue cultures for the biosynthesis and isolation of infectious human papillomaviruses. Curr Protoc Microbiol, 34. doi: 10.1002/9780471729259.mc14b03s34.Google Scholar
  118. Page H, Flood P, Reynaud EG. 2013. Three-dimensional tissue cultures: current trends and beyond. Cell Tissue Res, 352: 123–131.PubMedCrossRefGoogle Scholar
  119. Pampaloni F, Reynaud EG, Stelzer EH. 2007. The third dimension bridges the gap between cell culture and live tissue. Nat Rev Mol Cell Biol, 8: 839–845.PubMedCrossRefGoogle Scholar
  120. Papafragkou E, Hewitt J, Park GW, Greening G, Vinje J. 2014. Challenges of culturing human norovirus in three-dimensional organoid intestinal cell culture models. PLoS One, 8: e63485.PubMedCrossRefGoogle Scholar
  121. Petrie RJ, Gavara N, Chadwick RS, Yamada KM. 2012. Nonpolarized signaling reveals two distinct modes of 3D cell migration. J Cell Biol, 197: 439–455.PubMedPubMedCentralCrossRefGoogle Scholar
  122. Petrie RJ, Yamada KM. 2012. At the leading edge of three-dimensional cell migration. J Cell Sci, 125: 5917–5926.PubMedPubMedCentralCrossRefGoogle Scholar
  123. Poynard T, Yuen MF, Ratziu V, Lai CL. 2003. Viral hepatitis C. Lancet, 362: 2095–2100.PubMedCrossRefGoogle Scholar
  124. Rajalakshmy AR, Malathi J, Madhavan HN, Samuel JK. 2015. Mebiolgel, a thermoreversible polymer as a scaffold for three dimensional culture of Huh7 cell line with improved hepatocyte differentiation marker expression and HCV replication. Indian J Med Microbiol, 33: 554–559.PubMedCrossRefGoogle Scholar
  125. Ravi M, Paramesh V, Kaviya SR, Anuradha E, Solomon FD. 2015. 3D cell culture systems: advantages and applications. J Cell Physiol, 230: 16–26.PubMedCrossRefGoogle Scholar
  126. Rhee HW, Zhau HE, Pathak S, Multani AS, Pennanen S, Visakorpi T, Chung LW. 2001. Permanent phenotypic and genotypic changes of prostate cancer cells cultured in a three-dimensional rotating-wall vessel. In Vitro Cell Dev Biol Anim, 37: 127–140.PubMedCrossRefGoogle Scholar
  127. Richard C, Lanner C, Naryzhny SN, Sherman L, Lee H, Lambert PF, Zehbe I. 2010. The immortalizing and transforming ability of two common human papillomavirus 16 E6 variants with different prevalences in cervical cancer. Oncogene, 29: 3435–3445.PubMedCrossRefGoogle Scholar
  128. Robinson CM, Pfeiffer JK. 2014. Virology. Leaping the norovirus hurdle. Science, 346: 700–701.PubMedGoogle Scholar
  129. Ruedinger F, Lavrentieva A, Blume C, Pepelanova I, Scheper T. 2015. Hydrogels for 3D mammalian cell culture: a starting guide for laboratory practice. Appl Microbiol Biotechnol, 99: 623–636.PubMedCrossRefGoogle Scholar
  130. Sainz B, Jr., Barretto N, Uprichard SL. 2009a. Hepatitis C virus infection in phenotypically distinct Huh7 cell lines. PLoS One, 4: e6561.PubMedPubMedCentralCrossRefGoogle Scholar
  131. Sainz B, Jr., TenCate V, Uprichard SL. 2009b. Three-dimensional Huh7 cell culture system for the study of Hepatitis C virus infection. Virol J, 6: 103.PubMedPubMedCentralCrossRefGoogle Scholar
  132. Samuelson L, Gerber DA. 2013. Improved function and growth of pancreatic cells in a three-dimensional bioreactor environment. Tissue Eng Part C Methods, 19: 39–47.PubMedCrossRefGoogle Scholar
  133. Satsuka A, Yoshida S, Kajitani N, Nakamura H, Sakai H. 2010. Novel human papillomavirus type 18 replicon and its application in screening the antiviral effects of cytokines. Cancer Sci, 101: 536–542.PubMedCrossRefGoogle Scholar
  134. Saxena K, Blutt SE, Ettayebi K, Zeng XL, Broughman JR, Crawford SE, Karandikar UC, Sastri NP, Conner ME, Opekun AR, Graham DY, Qureshi W, Sherman V, Foulke-Abel J, In J, Kovbasnjuk O, Zachos NC, Donowitz M, Estes MK. 2015. Human intestinal enteroids: a new model to study human rotavirus infection, host restriction, and pathophysiology. J Virol, 90: 43–56.PubMedPubMedCentralCrossRefGoogle Scholar
  135. Schiffman M, Castle PE, Jeronimo J, Rodriguez AC, Wacholder S. 2007. Human papillomavirus and cervical cancer. Lancet, 370: 890–907.PubMedCrossRefGoogle Scholar
  136. Souza GR, Molina JR, Raphael RM, Ozawa MG, Stark DJ, Levin CS, Bronk LF, Ananta JS, Mandelin J, Georgescu MM, Bankson JA, Gelovani JG, Killian TC, Arap W, Pasqualini R. 2010. Three-dimensional tissue culture based on magnetic cell levitation. Nat Nanotechnol, 5: 291–296.PubMedPubMedCentralCrossRefGoogle Scholar
  137. Straub TM, Bartholomew RA, Valdez CO, Valentine NB, Dohnalkova A, Ozanich RM, Bruckner-Lea CJ, Call DR. 2011. Human norovirus infection of caco-2 cells grown as a three-dimensional tissue structure. J Water Health, 9: 225–240.PubMedPubMedCentralCrossRefGoogle Scholar
  138. Straub TM, Honer zu Bentrup K, Orosz-Coghlan P, Dohnalkova A, Mayer BK, Bartholomew RA, Valdez CO, Bruckner-Lea CJ, Gerba CP, Abbaszadegan M, Nickerson CA. 2007. In vitro cell culture infectivity assay for human noroviruses. Emerg Infect Dis, 13: 396–403.PubMedPubMedCentralCrossRefGoogle Scholar
  139. Syrjanen S, Mikola H, Nykanen M, Hukkanen V. 1996. In vitro establishment of lytic and nonproductive infection by herpes simplex virus type 1 in three-dimensional keratinocyte culture. J Virol, 70: 6524–6528.PubMedPubMedCentralGoogle Scholar
  140. Tan M, Jiang X. 2014. Vaccine against norovirus. Hum Vaccin Immunother, 10: 1449–1456.PubMedCrossRefGoogle Scholar
  141. Tapparel C, Sobo K, Constant S, Huang S, Van Belle S, Kaiser L. 2013. Growth and characterization of different human rhinovirus C types in three-dimensional human airway epithelia reconstituted in vitro. Virology, 446: 1–8.PubMedCrossRefGoogle Scholar
  142. Team WHOER. 2014. Ebola virus disease in West Africa—the first 9 months of the epidemic and forward projections. N Engl J Med, 371: 1481–1495.CrossRefGoogle Scholar
  143. Tran NM, Dufresne M, Duverlie G, Castelain S, Defarge C, Paullier P, Legallais C. 2013. An appropriate selection of a 3D alginate culture model for hepatic Huh-7 cell line encapsulation intended for viral studies. Tissue Eng Part A, 19: 103–113.PubMedCrossRefGoogle Scholar
  144. Trietsch SJ, Israels GD, Joore J, Hankemeier T, Vulto P. 2013. Microfluidic titer plate for stratified 3D cell culture. Lab Chip, 13: 3548–3554.PubMedCrossRefGoogle Scholar
  145. Tseng H, Gage JA, Raphael RM, Moore RH, Killian TC, Grande-Allen KJ, Souza GR. 2013. Assembly of a three-dimensional multitype bronchiole coculture model using magnetic levitation. Tissue Eng Part C Methods, 19: 665–675.PubMedCrossRefGoogle Scholar
  146. Unsworth BR, Lelkes PI. 1998. Growing tissues in microgravity. Nat Med, 4: 901–907.PubMedCrossRefGoogle Scholar
  147. van Duinen V, Trietsch SJ, Joore J, Vulto P, Hankemeier T. 2015. Microfluidic 3D cell culture: from tools to tissue models. Curr Opin Biotechnol, 35: 118–126.PubMedCrossRefGoogle Scholar
  148. Vinci M, Box C, Eccles SA. 2015. Three-dimensional (3D) tumor spheroid invasion assay. J Vis Exp: e52686.Google Scholar
  149. Vinci M, Gowan S, Boxall F, Patterson L, Zimmermann M, Court W, Lomas C, Mendiola M, Hardisson D, Eccles SA. 2012. Advances in establishment and analysis of three-dimensional tumor spheroid-based functional assays for target validation and drug evaluation. BMC Biol, 10: 29.PubMedPubMedCentralCrossRefGoogle Scholar
  150. Visalli RJ, Courtney RJ, Meyers C. 1997. Infection and replication of herpes simplex virus type 1 in an organotypic epithelial culture system. Virology, 230: 236–243.PubMedCrossRefGoogle Scholar
  151. Wang HK, Duffy AA, Broker TR, Chow LT. 2009. Robust production and passaging of infectious HPV in squamous epithelium of primary human keratinocytes. Genes Dev, 23: 181–194.PubMedPubMedCentralCrossRefGoogle Scholar
  152. Wang N, Zhang H, Zhang BQ, Liu W, Zhang Z, Qiao M, Zhang H, Deng F, Wu N, Chen X, Wen S, Zhang J, Liao Z, Zhang Q, Yan Z, Yin L, Ye J, Deng Y, Luu HH, Haydon RC, Liang H, He TC. 2014. Adenovirus-mediated efficient gene transfer into cultured three-dimensional organoids. PLoS One, 9: e93608.PubMedPubMedCentralCrossRefGoogle Scholar
  153. WHO 2013. Mortality and global health estimates 2013. Available: Scholar
  154. Worthington P, Pochan DJ, Langhans SA. 2015. Peptide Hydrogels -Versatile Matrices for 3D Cell Culture in Cancer Medicine. Front Oncol, 5: 92.PubMedPubMedCentralCrossRefGoogle Scholar
  155. Xu X, Farach-Carson MC, Jia X. 2014. Three-dimensional in vitro tumor models for cancer research and drug evaluation. Biotechnol Adv, 32: 1256–1268.PubMedPubMedCentralCrossRefGoogle Scholar
  156. Yamada KM, Cukierman E. 2007. Modeling tissue morphogenesis and cancer in 3D. Cell, 130: 601–610PubMedCrossRefGoogle Scholar
  157. Zerboni L, Sen N, Oliver SL, Arvin AM. 2014. Molecular mechanisms of varicella zoster virus pathogenesis. Nat Rev Microbiol, 12: 197–210.PubMedPubMedCentralCrossRefGoogle Scholar
  158. Zhang W, Zhuang A, Gu P, Zhou H, Fan X. 2016. A review of the three-dimensional cell culture technique: Approaches, advantages and applications. Curr Stem Cell Res Ther, 11: 370–380.PubMedCrossRefGoogle Scholar

Copyright information

© Wuhan Institute of Virology, CAS and Springer Science+Business Media Singapore 2016

Authors and Affiliations

  1. 1.State Key Laboratory of Infection Disease Prevention and Control, National Institute for Viral Disease Control and PreventionChinese Center for Disease Control and PreventionBeijingChina

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