Replication of positive-strand RNA viruses occurs in tight association with reorganized host cell membranes. In a concerted fashion, viral and cellular factors generate distinct organelle-like structures, designated viral replication factories. These virus-induced compartments promote highly efficient genome replication, allow spatiotemporal coordination of the different steps of the viral replication cycle, and protect viral RNA from the hostile cytoplasmic environment. The combined use of ultrastructural and functional studies has greatly increased our understanding of the architecture and biogenesis of viral replication factories. Here, we review common concepts and distinct differences in replication organelle morphology and biogenesis within the Flaviviridae family, exemplified by dengue virus and hepatitis C virus. We discuss recent progress made in our understanding of the complex interplay between viral determinants and subverted cellular membrane homeostasis in biogenesis and maintenance of replication factories of this virus family.

Associated Article

There are media items related to this article:
Flaviviridae Replication Organelles: Oh, What a Tangled Web We Weave: Video 1

Associated Article

There are media items related to this article:
Flaviviridae Replication Organelles: Oh, What a Tangled Web We Weave: Video 2

Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. Simmonds P. 1.  2013. The origin of hepatitis C virus. Curr. Top. Microbiol. Immunol. 369:1–15 [Google Scholar]
  2. Bhatt S, Gething PW, Brady OJ, Messina JP, Farlow AW. 2.  et al. 2013. The global distribution and burden of dengue. Nature 496:504–7 [Google Scholar]
  3. Sarrazin C, Hezode C, Zeuzem S, Pawlotsky JM. 3.  2012. Antiviral strategies in hepatitis C virus infection. J. Hepatol. 56:Suppl. 1S88–100 [Google Scholar]
  4. Lavanchy D. 4.  2009. The global burden of hepatitis C. Liver Int. 29:Suppl. 174–81 [Google Scholar]
  5. Fernandez de Castro I, Volonte L, Risco C. 5.  2013. Virus factories: biogenesis and structural design. Cell Microbiol. 15:24–34 [Google Scholar]
  6. Laliberte JF, Zheng H. 6.  2014. Viral manipulation of plant host membranes. Annu. Rev. Virol. 1:237–59 [Google Scholar]
  7. Schmid M, Speiseder T, Dobner T, Gonzalez RA. 7.  2014. DNA virus replication compartments. J. Virol. 88:1404–20 [Google Scholar]
  8. Lucic V, Rigort A, Baumeister W. 8.  2013. Cryo-electron tomography: the challenge of doing structural biology in situ. J. Cell Biol. 202:407–19 [Google Scholar]
  9. Risco C, Fernandez de Castro I, Sanz-Sanchez L, Narayan K, Grandinetti G, Subramaniam S. 9.  2014. Three-dimensional imaging of viral infections. Annu. Rev. Virol. 1:453–73 [Google Scholar]
  10. Welsch S, Miller S, Romero-Brey I, Merz A, Bleck CK. 10.  et al. 2009. Composition and three-dimensional architecture of the dengue virus replication and assembly sites. Cell Host Microbe 5:365–75A study that uses electron tomography to reveal the spatial organization of DV replication and assembly sites. [Google Scholar]
  11. Junjhon J, Pennington JG, Edwards TJ, Perera R, Lanman J, Kuhn RJ. 11.  2014. Ultrastructural characterization and three-dimensional architecture of replication sites in dengue virus-infected mosquito cells. J. Virol. 88:4687–97 [Google Scholar]
  12. Ferraris P, Beaumont E, Uzbekov R, Brand D, Gaillard J. 12.  et al. 2013. Sequential biogenesis of host cell membrane rearrangements induced by hepatitis C virus infection. Cell. Mol. Life Sci. 70:1297–306 [Google Scholar]
  13. Romero-Brey I, Merz A, Chiramel A, Lee JY, Chlanda P. 13.  et al. 2012. Three-dimensional architecture and biogenesis of membrane structures associated with hepatitis C virus replication. PLOS Pathog. 8:e1003056An electron microscopy–based study describing intracellular membrane-remodeling events induced upon HCV infection. [Google Scholar]
  14. Paul D, Bartenschlager R. 14.  2013. Architecture and biogenesis of plus-strand RNA virus replication factories. World J. Virol. 2:32–48 [Google Scholar]
  15. Gillespie LK, Hoenen A, Morgan G, Mackenzie JM. 15.  2010. The endoplasmic reticulum provides the membrane platform for biogenesis of the flavivirus replication complex. J. Virol. 84:10438–47 [Google Scholar]
  16. Offerdahl DK, Dorward DW, Hansen BT, Bloom ME. 16.  2012. A three-dimensional comparison of tick-borne flavivirus infection in mammalian and tick cell lines. PLOS ONE 7:e47912 [Google Scholar]
  17. Miorin L, Romero-Brey I, Maiuri P, Hoppe S, Krijnse-Locker J. 17.  et al. 2013. Three-dimensional architecture of tick-borne encephalitis virus replication sites and trafficking of the replicated RNA. J. Virol. 87:6469–81 [Google Scholar]
  18. Egger D, Wolk B, Gosert R, Bianchi L, Blum HE. 18.  et al. 2002. Expression of hepatitis C virus proteins induces distinct membrane alterations including a candidate viral replication complex. J. Virol. 76:5974–84 [Google Scholar]
  19. Gosert R, Egger D, Lohmann V, Bartenschlager R, Blum HE. 19.  et al. 2003. Identification of the hepatitis C virus RNA replication complex in Huh-7 cells harboring subgenomic replicons. J. Virol. 77:5487–92 [Google Scholar]
  20. Miyanari Y, Hijikata M, Yamaji M, Hosaka M, Takahashi H, Shimotohno K. 20.  2003. Hepatitis C virus non-structural proteins in the probable membranous compartment function in viral genome replication. J. Biol. Chem. 278:50301–8 [Google Scholar]
  21. Quinkert D, Bartenschlager R, Lohmann V. 21.  2005. Quantitative analysis of the hepatitis C virus replication complex. J. Virol. 79:13594–605 [Google Scholar]
  22. Paul D, Hoppe S, Saher G, Krijnse-Locker J, Bartenschlager R. 22.  2013. Morphological and biochemical characterization of the membranous hepatitis C virus replication compartment. J. Virol. 87:10612–27 [Google Scholar]
  23. Limpens RW, van der Schaar HM, Kumar D, Koster AJ, Snijder EJ. 23.  et al. 2011. The transformation of enterovirus replication structures: a three-dimensional study of single- and double-membrane compartments. mBio 2:e00166–11 [Google Scholar]
  24. Belov GA, Nair V, Hansen BT, Hoyt FH, Fischer ER, Ehrenfeld E. 24.  2012. Complex dynamic development of poliovirus membranous replication complexes. J. Virol. 86:302–12 [Google Scholar]
  25. Knoops K, Kikkert M, van den Worm SHE, Zevenhoven-Dobbe JC, van der Meer Y. 25.  et al. 2008. SARS-coronavirus replication is supported by a reticulovesicular network of modified endoplasmic reticulum. PLOS Biol. 6:e226First study to use electron tomography to unravel intracellular membrane rearrangements upon coronavirus infection. [Google Scholar]
  26. Knoops K, Barcena M, Limpens RW, Koster AJ, Mommaas AM, Snijder EJ. 26.  2012. Ultrastructural characterization of arterivirus replication structures: reshaping the endoplasmic reticulum to accommodate viral RNA synthesis. J. Virol. 86:2474–87 [Google Scholar]
  27. Pierson TC, Kielian M. 27.  2013. Flaviviruses: braking the entering. Curr. Opin. Virol. 3:3–12 [Google Scholar]
  28. Ding Q, von Schaewen M, Ploss A. 28.  2014. The impact of hepatitis C virus entry on viral tropism. Cell Host Microbe 16:562–68 [Google Scholar]
  29. Paranjape SM, Harris E. 29.  2010. Control of dengue virus translation and replication. Curr. Top. Microbiol. Immunol. 338:15–34 [Google Scholar]
  30. Niepmann M. 30.  2013. Hepatitis C virus RNA translation. Curr. Top. Microbiol. Immunol. 369:143–66 [Google Scholar]
  31. Romero-López C, Barroso-delJesus A, García-Sacristán A, Briones C, Berzal-Herranz A. 31.  2014. End-to-end crosstalk within the hepatitis C virus genome mediates the conformational switch of the 3′X-tail region. Nucleic Acids Res. 42:567–82 [Google Scholar]
  32. de Borba L, Villordo SM, Iglesias NG, Filomatori CV, Gebhard LG, Gamarnik AV. 32.  2015. Overlapping local and long range RNA-RNA interactions modulate dengue virus genome cyclization and replication. J. Virol. In press. doi: 10.1128/JVI.02677-14
  33. Friedrich S, Schmidt T, Geissler R, Lilie H, Chabierski S. 33.  et al. 2014. AUF1 p45 promotes West Nile virus replication by an RNA chaperone activity that supports cyclization of the viral genome. J. Virol. 88:11586–99 [Google Scholar]
  34. Khromykh AA, Westaway EG. 34.  1997. Subgenomic replicons of the flavivirus Kunjin: construction and applications. J. Virol. 71:1497–505 [Google Scholar]
  35. Lohmann V, Korner F, Koch J, Herian U, Theilmann L, Bartenschlager R. 35.  1999. Replication of subgenomic hepatitis C virus RNAs in a hepatoma cell line. Science 285:110–13 [Google Scholar]
  36. Selisko B, Wang C, Harris E, Canard B. 36.  2014. Regulation of flavivirus RNA synthesis and replication. Curr. Opin. Virol. 9:74–83 [Google Scholar]
  37. Lohmann V. 37.  2013. Hepatitis C virus RNA replication. Curr. Top. Microbiol. Immunol. 369:167–98 [Google Scholar]
  38. Westaway EG, Mackenzie JM, Kenney MT, Jones MK, Khromykh AA. 38.  1997. Ultrastructure of Kunjin virus-infected cells: colocalization of NS1 and NS3 with double-stranded RNA, and of NS2B with NS3, in virus-induced membrane structures. J. Virol. 71:6650–61 [Google Scholar]
  39. Overby AK, Popov VL, Niedrig M, Weber F. 39.  2010. Tick-borne encephalitis virus delays interferon induction and hides its double-stranded RNA in intracellular membrane vesicles. J. Virol. 84:8470–83 [Google Scholar]
  40. Uchida L, Espada-Murao LA, Takamatsu Y, Okamoto K, Hayasaka D. 40.  et al. 2014. The dengue virus conceals double-stranded RNA in the intracellular membrane to escape from an interferon response. Sci. Rep. 4:7395 [Google Scholar]
  41. Ferraris P, Blanchard E, Roingeard P. 41.  2010. Ultrastructural and biochemical analyses of hepatitis C virus-associated host cell membranes. J. Gen. Virol. 91:2230–37 [Google Scholar]
  42. Neufeldt CJ, Joyce MA, Levin A, Steenbergen RH, Pang D. 42.  et al. 2013. Hepatitis C virus-induced cytoplasmic organelles use the nuclear transport machinery to establish an environment conducive to virus replication. PLOS Pathog. 9:e1003744 [Google Scholar]
  43. Levin A, Neufeldt CJ, Pang D, Wilson K, Loewen-Dobler D. 43.  et al. 2014. Functional characterization of nuclear localization and export signals in hepatitis C virus proteins and their role in the membranous web. PLOS ONE 9:e114629 [Google Scholar]
  44. Ando T, Imamura H, Suzuki R, Aizaki H, Watanabe T. 44.  et al. 2012. Visualization and measurement of ATP levels in living cells replicating hepatitis C virus genome RNA. PLOS Pathog. 8:e1002561 [Google Scholar]
  45. Tadano M, Makino Y, Fukunaga T, Okuno Y, Fukai K. 45.  1989. Detection of dengue 4 virus core protein in the nucleus. I. A monoclonal antibody to dengue 4 virus reacts with the antigen in the nucleus and cytoplasm. J. Gen. Virol. 70:1409–15 [Google Scholar]
  46. Barba G, Harper F, Harada T, Kohara M, Goulinet S. 46.  et al. 1997. Hepatitis C virus core protein shows a cytoplasmic localization and associates to cellular lipid storage droplets. PNAS 94:1200–5 [Google Scholar]
  47. Mori Y, Okabayashi T, Yamashita T, Zhao Z, Wakita T. 47.  et al. 2005. Nuclear localization of Japanese encephalitis virus core protein enhances viral replication. J. Virol. 79:3448–58 [Google Scholar]
  48. Oh W, Yang MR, Lee EW, Park KM, Pyo S. 48.  et al. 2006. Jab1 mediates cytoplasmic localization and degradation of West Nile virus capsid protein. J. Biol. Chem. 281:30166–74 [Google Scholar]
  49. Miyanari Y, Atsuzawa K, Usuda N, Watashi K, Hishiki T. 49.  et al. 2007. The lipid droplet is an important organelle for hepatitis C virus production. Nat. Cell Biol. 9:1089–97 [Google Scholar]
  50. Samsa MM, Mondotte JA, Iglesias NG, Assuncao-Miranda I, Barbosa-Lima G. 50.  et al. 2009. Dengue virus capsid protein usurps lipid droplets for viral particle formation. PLOS Pathog. 5:e1000632 [Google Scholar]
  51. Tanaka T, Kuroda K, Ikeda M, Wakita T, Kato N, Makishima M. 51.  2013. Hepatitis C virus NS4B targets lipid droplets through hydrophobic residues in the amphipathic helices. J. Lipid Res. 54:881–92 [Google Scholar]
  52. Appel N, Zayas M, Miller S, Krijnse-Locker J, Schaller T. 52.  et al. 2008. Essential role of domain III of nonstructural protein 5A for hepatitis C virus infectious particle assembly. PLOS Pathog. 4:e1000035 [Google Scholar]
  53. Masaki T, Suzuki R, Murakami K, Aizaki H, Ishii K. 53.  et al. 2008. Interaction of hepatitis C virus nonstructural protein 5A with core protein is critical for the production of infectious virus particles. J. Virol. 82:7964–76 [Google Scholar]
  54. Tellinghuisen TL, Foss KL, Treadaway J. 54.  2008. Regulation of hepatitis C virion production via phosphorylation of the NS5A protein. PLOS Pathog. 4:e1000032 [Google Scholar]
  55. Lindenbach BD, Rice CM. 55.  2013. The ins and outs of hepatitis C virus entry and assembly. Nat. Rev. Microbiol. 11:688–700 [Google Scholar]
  56. Paul D, Madan V, Bartenschlager R. 56.  2014. Hepatitis C virus RNA replication and assembly: living on the fat of the land. Cell Host Microbe 16:569–79 [Google Scholar]
  57. Khromykh AA, Varnavski AN, Sedlak PL, Westaway EG. 57.  2001. Coupling between replication and packaging of flavivirus RNA: evidence derived from the use of DNA-based full-length cDNA clones of Kunjin virus. J. Virol. 75:4633–40 [Google Scholar]
  58. Apte-Sengupta S, Sirohi D, Kuhn RJ. 58.  2014. Coupling of replication and assembly in flaviviruses. Curr. Opin. Virol. 9:134–42 [Google Scholar]
  59. McMahon HT, Gallop JL. 59.  2005. Membrane curvature and mechanisms of dynamic cell membrane remodelling. Nature 438:590–96 [Google Scholar]
  60. Kozlov MM, Campelo F, Liska N, Chernomordik LV, Marrink SJ, McMahon HT. 60.  2014. Mechanisms shaping cell membranes. Curr. Opin. Cell Biol. 29:53–60 [Google Scholar]
  61. Roosendaal J, Westaway EG, Khromykh A, Mackenzie JM. 61.  2006. Regulated cleavages at the West Nile virus NS4A-2K-NS4B junctions play a major role in rearranging cytoplasmic membranes and Golgi trafficking of the NS4A protein. J. Virol. 80:4623–32 [Google Scholar]
  62. Miller S, Kastner S, Krijnse-Locker J, Buhler S, Bartenschlager R. 62.  2007. The non-structural protein 4A of dengue virus is an integral membrane protein inducing membrane alterations in a 2K-regulated manner. J. Biol. Chem. 282:8873–82 [Google Scholar]
  63. Kaufusi PH, Kelley JF, Yanagihara R, Nerurkar VR. 63.  2014. Induction of endoplasmic reticulum-derived replication-competent membrane structures by West Nile virus non-structural protein 4B. PLOS ONE 9:e84040 [Google Scholar]
  64. Miller S, Sparacio S, Bartenschlager R. 64.  2006. Subcellular localization and membrane topology of the dengue virus type 2 non-structural protein 4B. J. Biol. Chem. 281:8854–63 [Google Scholar]
  65. Stern O, Hung YF, Valdau O, Yaffe Y, Harris E. 65.  et al. 2013. An N-terminal amphipathic helix in dengue virus nonstructural protein 4A mediates oligomerization and is essential for replication. J. Virol. 87:4080–85 [Google Scholar]
  66. Zou J, Xie X, Wang QY, Dong H, Lee MY. 66.  et al. 2015. Characterization of dengue virus NS4A and NS4B protein interaction. J. Virol. 89:3455–70 [Google Scholar]
  67. Akey DL, Brown WC, Dutta S, Konwerski J, Jose J. 67.  et al. 2014. Flavivirus NS1 structures reveal surfaces for associations with membranes and the immune system. Science 343:881–85Description of the X-ray crystal structure of NS1 and its interaction with model membranes. [Google Scholar]
  68. Lindenbach BD, Rice CM. 68.  1999. Genetic interaction of flavivirus nonstructural proteins NS1 and NS4A as a determinant of replicase function. J. Virol. 73:4611–21 [Google Scholar]
  69. Youn S, Li T, McCune BT, Edeling MA, Fremont DH. 69.  et al. 2012. Evidence for a genetic and physical interaction between nonstructural proteins NS1 and NS4B that modulates replication of West Nile virus. J. Virol. 86:7360–71 [Google Scholar]
  70. Xie X, Gayen S, Kang C, Yuan Z, Shi PY. 70.  2013. Membrane topology and function of dengue virus NS2A protein. J. Virol. 87:4609–22 [Google Scholar]
  71. Chang YS, Liao CL, Tsao CH, Chen MC, Liu CI. 71.  et al. 1999. Membrane permeabilization by small hydrophobic nonstructural proteins of Japanese encephalitis virus. J. Virol. 73:6257–64 [Google Scholar]
  72. Gouttenoire J, Penin F, Moradpour D. 72.  2010. Hepatitis C virus nonstructural protein 4B: a journey into unexplored territory. Rev. Med. Virol. 20:117–29 [Google Scholar]
  73. Bartenschlager R, Lohmann V, Penin F. 73.  2013. The molecular and structural basis of advanced antiviral therapy for hepatitis C virus infection. Nat. Rev. Microbiol. 11:482–96 [Google Scholar]
  74. Palomares-Jerez MF, Nemesio H, Villalain J. 74.  2012. Interaction with membranes of the full C-terminal domain of protein NS4B from hepatitis C virus. Biochim. Biophys. Acta 1818:2536–49 [Google Scholar]
  75. Palomares-Jerez MF, Nemesio H, Franquelim HG, Castanho MA, Villalain J. 75.  2013. N-terminal AH2 segment of protein NS4B from hepatitis C virus. Binding to and interaction with model biomembranes. Biochim. Biophys. Acta 1828:1938–52 [Google Scholar]
  76. Lundin M, Lindstrom H, Gronwall C, Persson MA. 76.  2006. Dual topology of the processed hepatitis C virus protein NS4B is influenced by the NS5A protein. J. Gen. Virol. 87:3263–72 [Google Scholar]
  77. Gouttenoire J, Montserret R, Paul D, Castillo R, Meister S. 77.  et al. 2014. Aminoterminal amphipathic α-helix AH1 of hepatitis C virus nonstructural protein 4B possesses a dual role in RNA replication and virus production. PLOS Pathog. 10:e1004501 [Google Scholar]
  78. Gouttenoire J, Roingeard P, Penin F, Moradpour D. 78.  2010. Amphipathic α-helix AH2 is a major determinant for the oligomerization of hepatitis C virus nonstructural protein 4B. J. Virol. 84:12529–37 [Google Scholar]
  79. Paul D, Romero-Brey I, Gouttenoire J, Stoitsova S, Krijnse-Locker J. 79.  et al. 2011. NS4B self-interaction through conserved C-terminal elements is required for the establishment of functional hepatitis C virus replication complexes. J. Virol. 85:6963–76 [Google Scholar]
  80. Tellinghuisen TL, Marcotrigiano J, Rice CM. 80.  2005. Structure of the zinc-binding domain of an essential component of the hepatitis C virus replicase. Nature 435:374–79 [Google Scholar]
  81. Love RA, Brodsky O, Hickey MJ, Wells PA, Cronin CN. 81.  2009. Crystal structure of a novel dimeric form of NS5A domain I protein from hepatitis C virus. J. Virol. 83:4395–403 [Google Scholar]
  82. Penin F, Brass V, Appel N, Ramboarina S, Montserret R. 82.  et al. 2004. Structure and function of the membrane anchor domain of hepatitis C virus nonstructural protein 5A. J. Biol. Chem. 279:40835–43 [Google Scholar]
  83. Palomares-Jerez MF, Guillen J, Villalain J. 83.  2010. Interaction of the N-terminal segment of HCV protein NS5A with model membranes. Biochim. Biophys. Acta 1798:1212–24 [Google Scholar]
  84. David N, Yaffe Y, Hagoel L, Elazar M, Glenn JS. 84.  et al. 2015. The interaction between the hepatitis C proteins NS4B and NS5A is involved in viral replication. Virology 475:139–49 [Google Scholar]
  85. Madan V, Paul D, Lohmann V, Bartenschlager R. 85.  2014. Inhibition of HCV replication by cyclophilin antagonists is linked to replication fitness and occurs by inhibition of membranous web formation. Gastroenterology 146:1361–72 [Google Scholar]
  86. Berger C, Romero-Brey I, Radujkovic D, Terreux R, Zayas M. 86.  et al. 2014. Daclatasvir-like inhibitors of NS5A block early biogenesis of hepatitis C virus-induced membranous replication factories, independent of RNA replication. Gastroenterology 147:1094–105 [Google Scholar]
  87. Teo CS, Chu JJ. 87.  2014. Cellular vimentin regulates construction of dengue virus replication complexes through interaction with NS4A protein. J. Virol. 88:1897–913 [Google Scholar]
  88. Mooren OL, Galletta BJ, Cooper JA. 88.  2012. Roles for actin assembly in endocytosis. Annu. Rev. Biochem. 81:661–86 [Google Scholar]
  89. Schwartz M, Chen J, Janda M, Sullivan M, den Boon J, Ahlquist P. 89.  2002. A positive-strand RNA virus replication complex parallels form and function of retrovirus capsids. Mol. Cell 9:505–14 [Google Scholar]
  90. Diaz A, Wang X, Ahlquist P. 90.  2010. Membrane-shaping host reticulon proteins play crucial roles in viral RNA replication compartment formation and function. PNAS 107:16291–96An elegant study describing the subversion of cellular membrane-shaping proteins for viral replication. [Google Scholar]
  91. Hu J, Prinz WA, Rapoport TA. 91.  2011. Weaving the web of ER tubules. Cell 147:1226–31 [Google Scholar]
  92. Wu MJ, Ke PY, Hsu JT, Yeh CT, Horng JT. 92.  2014. Reticulon 3 interacts with NS4B of the hepatitis C virus and negatively regulates viral replication by disrupting NS4B self-interaction. Cell Microbiol. 16:1603–18 [Google Scholar]
  93. Chao TC, Su WC, Huang JY, Chen YC, Jeng KS. 93.  et al. 2012. Proline-serine-threonine phosphatase-interacting protein 2 (PSTPIP2), a host membrane-deforming protein, is critical for membranous web formation in hepatitis C virus replication. J. Virol. 86:1739–49 [Google Scholar]
  94. Qualmann B, Koch D, Kessels MM. 94.  2011. Let's go bananas: revisiting the endocytic BAR code. EMBO J. 30:3501–15 [Google Scholar]
  95. Rao Y, Haucke V. 95.  2011. Membrane shaping by the Bin/amphiphysin/Rvs (BAR) domain protein superfamily. Cell. Mol. Life Sci. 68:3983–93 [Google Scholar]
  96. Sir D, Kuo CF, Tian Y, Liu HM, Huang EJ. 96.  et al. 2012. Replication of hepatitis C virus RNA on autophagosomal membranes. J. Biol. Chem. 287:18036–43 [Google Scholar]
  97. Dreux M, Gastaminza P, Wieland SF, Chisari FV. 97.  2009. The autophagy machinery is required to initiate hepatitis C virus replication. PNAS 106:14046–51 [Google Scholar]
  98. Perera R, Riley C, Isaac G, Hopf-Jannasch AS, Moore RJ. 98.  et al. 2012. Dengue virus infection perturbs lipid homeostasis in infected mosquito cells. PLOS Pathog. 8:e1002584 [Google Scholar]
  99. Diamond DL, Syder AJ, Jacobs JM, Sorensen CM, Walters KA. 99.  et al. 2010. Temporal proteome and lipidome profiles reveal hepatitis C virus-associated reprogramming of hepatocellular metabolism and bioenergetics. PLOS Pathog. 6:e1000719 [Google Scholar]
  100. Brown MS, Goldstein JL. 100.  1997. The SREBP pathway: regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor. Cell 89:331–40 [Google Scholar]
  101. Waris G, Felmlee DJ, Negro F, Siddiqui A. 101.  2007. Hepatitis C virus induces proteolytic cleavage of sterol regulatory element binding proteins and stimulates their phosphorylation via oxidative stress. J. Virol. 81:8122–30 [Google Scholar]
  102. Park CY, Jun HJ, Wakita T, Cheong JH, Hwang SB. 102.  2009. Hepatitis C virus nonstructural 4B protein modulates sterol regulatory element-binding protein signaling via the AKT pathway. J. Biol. Chem. 284:9237–46 [Google Scholar]
  103. Ye J, Wang C, Sumpter R Jr, Brown MS, Goldstein JL, Gale M Jr. 103.  2003. Disruption of hepatitis C virus RNA replication through inhibition of host protein geranylgeranylation. PNAS 100:15865–70 [Google Scholar]
  104. Kapadia SB, Chisari FV. 104.  2005. Hepatitis C virus RNA replication is regulated by host geranylgeranylation and fatty acids. PNAS 102:2561–66 [Google Scholar]
  105. Li Q, Pene V, Krishnamurthy S, Cha H, Liang TJ. 105.  2013. Hepatitis C virus infection activates an innate pathway involving IKK-α in lipogenesis and viral assembly. Nat. Med. 19:722–29A report describing how HCV subverts an RNA-triggered innate immunity pathway to stimulate lipid biosynthesis. [Google Scholar]
  106. Olmstead AD, Knecht W, Lazarov I, Dixit SB, Jean F. 106.  2012. Human subtilase SKI-1/S1P is a master regulator of the HCV lifecycle and a potential host cell target for developing indirect-acting antiviral agents. PLOS Pathog. 8:e1002468 [Google Scholar]
  107. Pena J, Harris E. 107.  2012. Early dengue virus protein synthesis induces extensive rearrangement of the endoplasmic reticulum independent of the UPR and SREBP-2 pathway. PLOS ONE 7:e38202 [Google Scholar]
  108. Heaton NS, Randall G. 108.  2010. Dengue virus-induced autophagy regulates lipid metabolism. Cell Host Microbe 8:422–32 [Google Scholar]
  109. Heaton NS, Perera R, Berger KL, Khadka S, Lacount DJ. 109.  et al. 2010. Dengue virus nonstructural protein 3 redistributes fatty acid synthase to sites of viral replication and increases cellular fatty acid synthesis. PNAS 107:17345–50A study demonstrating how DV uses a cellular enzyme to synthesize lipids at viral replication sites. [Google Scholar]
  110. Smith S, Witkowski A, Joshi AK. 110.  2003. Structural and functional organization of the animal fatty acid synthase. Prog. Lipid Res. 42:289–317 [Google Scholar]
  111. Tang WC, Lin RJ, Liao CL, Lin YL. 111.  2014. Rab18 facilitates dengue virus infection by targeting fatty acid synthase to sites of viral replication. J. Virol. 88:6793–804 [Google Scholar]
  112. Elias M, Brighouse A, Gabernet-Castello C, Field MC, Dacks JB. 112.  2012. Sculpting the endomembrane system in deep time: high resolution phylogenetics of Rab GTPases. J. Cell Sci. 125:2500–8 [Google Scholar]
  113. Salloum S, Wang H, Ferguson C, Parton RG, Tai AW. 113.  2013. Rab18 binds to hepatitis C virus NS5A and promotes interaction between sites of viral replication and lipid droplets. PLOS Pathog. 9:e1003513 [Google Scholar]
  114. Martín-Acebes MA, Blázquez AB, Jiménez de Oya N, Escribano-Romero E, Saiz JC. 114.  2011. West Nile virus replication requires fatty acid synthesis but is independent on phosphatidylinositol-4-phosphate lipids. PLOS ONE 6:e24970 [Google Scholar]
  115. Huang JT, Tseng CP, Liao MH, Lu SC, Yeh WZ. 115.  et al. 2013. Hepatitis C virus replication is modulated by the interaction of nonstructural protein NS5B and fatty acid synthase. J. Virol. 87:4994–5004 [Google Scholar]
  116. van Meer G, Voelker DR, Feigenson GW. 116.  2008. Membrane lipids: where they are and how they behave. Nat. Rev. Mol. Cell Biol. 9:112–24 [Google Scholar]
  117. Balla T. 117.  2013. Phosphoinositides: tiny lipids with giant impact on cell regulation. Physiol. Rev. 93:1019–137 [Google Scholar]
  118. Berger KL, Cooper JD, Heaton NS, Yoon R, Oakland TE. 118.  et al. 2009. Roles for endocytic trafficking and phosphatidylinositol 4-kinase III alpha in hepatitis C virus replication. PNAS 106:7577–82 [Google Scholar]
  119. Li Q, Brass AL, Ng A, Hu Z, Xavier RJ. 119.  et al. 2009. A genome-wide genetic screen for host factors required for hepatitis C virus propagation. PNAS 106:16410–15 [Google Scholar]
  120. Tai AW, Benita Y, Peng LF, Kim SS, Sakamoto N. 120.  et al. 2009. A functional genomic screen identifies cellular cofactors of hepatitis C virus replication. Cell Host Microbe 5:298–307 [Google Scholar]
  121. Trotard M, Lepère-Douard C, Régeard M, Piquet-Pellorce C, Lavillette D. 121.  et al. 2009. Kinases required in hepatitis C virus entry and replication highlighted by small interference RNA screening. FASEB J. 23:3780–89 [Google Scholar]
  122. Reiss S, Rebhan I, Backes P, Romero-Brey I, Erfle H. 122.  et al. 2011. Recruitment and activation of a lipid kinase by hepatitis C virus NS5A is essential for integrity of the membranous replication compartment. Cell Host Microbe 9:32–45Identification of the mechanism by which PI4KIIIα contributes to the induction of HCV replication factories. [Google Scholar]
  123. Borawski J, Troke P, Puyang X, Gibaja V, Zhao S. 123.  et al. 2009. Class III phosphatidylinositol 4-kinase alpha and beta are novel host factor regulators of hepatitis C virus replication. J. Virol. 83:10058–74 [Google Scholar]
  124. Altan-Bonnet N, Balla T. 124.  2012. Phosphatidylinositol 4-kinases: hostages harnessed to build panviral replication platforms. Trends Biochem. Sci. 37:293–302 [Google Scholar]
  125. Bianco A, Reghellin V, Donnici L, Fenu S, Alvarez R. 125.  et al. 2012. Metabolism of phosphatidylinositol 4-kinase IIIα-dependent PI4P is subverted by HCV and is targeted by a 4-anilino quinazoline with antiviral activity. PLOS Pathog. 8:e1002576 [Google Scholar]
  126. Keaney EP, Connolly M, Dobler M, Karki R, Honda A. 126.  et al. 2014. 2-Alkyloxazoles as potent and selective PI4KIIIβ inhibitors demonstrating inhibition of HCV replication. Bioorg. Med. Chem. Lett. 24:3714–18 [Google Scholar]
  127. Vaillancourt FH, Brault M, Pilote L, Uyttersprot N, Gaillard ET. 127.  et al. 2012. Evaluation of phosphatidylinositol-4-kinase IIIα as a hepatitis C virus drug target. J. Virol. 86:11595–607 [Google Scholar]
  128. Berger KL, Kelly SM, Jordan TX, Tartell MA, Randall G. 128.  2011. Hepatitis C virus stimulates the phosphatidylinositol 4-kinase III alpha-dependent phosphatidylinositol 4-phosphate production that is essential for its replication. J. Virol. 85:8870–83 [Google Scholar]
  129. Wang H, Perry JW, Lauring AS, Neddermann P, De Francesco R, Tai AW. 129.  2014. Oxysterol-binding protein is a phosphatidylinositol 4-kinase effector required for HCV replication membrane integrity and cholesterol trafficking. Gastroenterology 146:1373–85A report describing the functional involvement of a lipid transfer protein in HCV RNA replication. [Google Scholar]
  130. Holthuis JC, Menon AK. 130.  2014. Lipid landscapes and pipelines in membrane homeostasis. Nature 510:48–57 [Google Scholar]
  131. Evans MJ, Rice CM, Goff SP. 131.  2004. Phosphorylation of hepatitis C virus nonstructural protein 5A modulates its protein interactions and viral RNA replication. PNAS 101:13038–43 [Google Scholar]
  132. Gao L, Aizaki H, He JW, Lai MM. 132.  2004. Interactions between viral nonstructural proteins and host protein hVAP-33 mediate the formation of hepatitis C virus RNA replication complex on lipid raft. J. Virol. 78:3480–88 [Google Scholar]
  133. Mesmin B, Bigay J, Moser von Filseck J, Lacas-Gervais S, Drin G, Antonny B. 133.  2013. A four-step cycle driven by PI(4)P hydrolysis directs sterol/PI(4)P exchange by the ER-Golgi tether OSBP. Cell 155:830–43 [Google Scholar]
  134. Chen Y, Wang S, Yi Z, Tian H, Aliyari R. 134.  et al. 2014. Interferon-inducible cholesterol-25-hydroxylase inhibits hepatitis C virus replication via distinct mechanisms. Sci. Rep. 4:7242 [Google Scholar]
  135. Khan I, Katikaneni DS, Han Q, Sanchez-Felipe L, Hanada K. 135.  et al. 2014. Modulation of hepatitis C virus genome replication by glycosphingolipids and four-phosphate adaptor protein 2. J. Virol. 88:12276–95 [Google Scholar]
  136. Weng L, Hirata Y, Arai M, Kohara M, Wakita T. 136.  et al. 2010. Sphingomyelin activates hepatitis C virus RNA polymerase in a genotype-specific manner. J. Virol. 84:11761–70 [Google Scholar]
  137. Hirata Y, Ikeda K, Sudoh M, Tokunaga Y, Suzuki A. 137.  et al. 2012. Self-enhancement of hepatitis C virus replication by promotion of specific sphingolipid biosynthesis. PLOS Pathog. 8:e1002860 [Google Scholar]
  138. Shi ST, Lee KJ, Aizaki H, Hwang SB, Lai MM. 138.  2003. Hepatitis C virus RNA replication occurs on a detergent-resistant membrane that cofractionates with caveolin-2. J. Virol. 77:4160–68 [Google Scholar]
  139. Mackenzie JM, Khromykh AA, Parton RG. 139.  2007. Cholesterol manipulation by West Nile virus perturbs the cellular immune response. Cell Host Microbe 2:229–39A study showing how perturbation of cholesterol homeostasis by a flavivirus affects the interferon response. [Google Scholar]
  140. Rothwell C, Lebreton A, Young NC, Lim JY, Liu W. 140.  et al. 2009. Cholesterol biosynthesis modulation regulates dengue viral replication. Virology 389:8–19 [Google Scholar]
  141. Barajas D, Xu K, de Castro Martin IF, Sasvari Z, Brandizzi F. 141.  et al. 2014. Co-opted oxysterol-binding ORP and VAP proteins channel sterols to RNA virus replication sites via membrane contact sites. PLOS Pathog. 10:e1004388 [Google Scholar]
  142. Kooijman EE, Chupin V, Fuller NL, Kozlov MM, de Kruijff B. 142.  et al. 2005. Spontaneous curvature of phosphatidic acid and lysophosphatidic acid. Biochemistry 44:2097–102 [Google Scholar]
  143. Yang JS, Gad H, Lee SY, Mironov A, Zhang L. 143.  et al. 2008. A role for phosphatidic acid in COPI vesicle fission yields insights into Golgi maintenance. Nat. Cell Biol. 10:1146–53 [Google Scholar]
  144. Kukulski W, Schorb M, Kaksonen M, Briggs JA. 144.  2012. Plasma membrane reshaping during endocytosis is revealed by time-resolved electron tomography. Cell 150:508–20 [Google Scholar]
  145. Hong M, Zhang Y, Hu F. 145.  2012. Membrane protein structure and dynamics from NMR spectroscopy. Annu. Rev. Phys. Chem. 63:1–24 [Google Scholar]
  146. Brügger B, Sandhoff R, Wegehingel S, Gorgas K, Malsam J. 146.  et al. 2000. Evidence for segregation of sphingomyelin and cholesterol during formation of COPI-coated vesicles. J. Cell Biol. 151:507–18 [Google Scholar]
  147. Takamori S, Holt M, Stenius K, Lemke EA, Gronborg M. 147.  et al. 2006. Molecular anatomy of a trafficking organelle. Cell 127:831–46 [Google Scholar]
  148. Lundin A, Dijkman R, Bergstrom T, Kann N, Adamiak B. 148.  et al. 2014. Targeting membrane-bound viral RNA synthesis reveals potent inhibition of diverse coronaviruses including the Middle East respiratory syndrome virus. PLOS Pathog. 10:e1004166 [Google Scholar]

Data & Media loading...

    Morphology of dengue virus (DV) replication organelles. Electron tomography with 3D reconstruction reveals the continuity of endoplasmic reticulum membranes () and DV-induced vesicular invaginations. Budding of DV progeny virions () juxtaposed to vesicle openings is frequently observed. Golgi membranes are depicted in green. Adapted with permission from Welsch et al., 5:365–75 (2009).

    Morphology of hepatitis C virus (HCV) replication organelles consisting primarily of double-membrane vesicles (DMVs). Color-coded 3D surface model shows outer membranes of DMVs in light brown and inner membranes in orange. DMVs emerge as protrusions from the endoplasmic reticulum () and are thus commonly found to be connected to this compartment. Small single-membrane vesicles are depicted in pink, intermediate filaments in dark blue, and Golgi membranes in green. Reproduced with permission from Romero-Brey et al., . 8:e1003056 (2012).

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error