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. 2014 Jun 6;29(3):139–147. doi: 10.1007/s12250-014-3476-0

Viral exploitation of actin: force-generation and scaffolding functions in viral infection

Mark Spear 1, Yuntao Wu 1,✉
PMCID: PMC4373664  NIHMSID: NIHMS672812  PMID: 24938714

Abstract

As a fundamental component of the host cellular cytoskeleton, actin is routinely engaged by infecting viruses. Furthermore, viruses from diverse groups, and infecting diverse hosts, have convergently evolved an array of mechanisms for manipulating the actin cytoskeleton for efficacious infection. An ongoing chorus of research now indicates that the actin cytoskeleton is critical for viral replication at many stages of the viral life cycle, including binding, entry, nuclear localization, genomic transcription and reverse transcription, assembly, and egress/dissemination. Specifically, viruses subvert the force-generating and macromolecular scaffolding properties of the actin cytoskeleton to propel viral surfing, internalization, and migration within the cell. Additionally, viruses utilize the actin cytoskeleton to support and organize assembly sites, and eject budding virions for cell-to-cell transmission. It is the purpose of this review to provide an overview of current research, focusing on the various mechanisms and themes of virus-mediated actin modulation described therein.

Keywords: viral infection, actin, cytoskeleton, cofilin, LIMK, Arp2/3, GTPase

References

  1. Aggarwal A, Iemma T L, Shih I, Newsome T P, McAllery S, Cunningham A L, Turville S G. Mobilization of HIV spread by diaphanous 2 dependent filopodia in infected dendritic cells. PLoS Pathog. 2012;8:e1002762. doi: 10.1371/journal.ppat.1002762. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Agosto L M, Zhong P, Munro J, Mothes W. Highly Active Antiretroviral Therapies Are Effective against HIV-1 Cell-to-Cell Transmission. PLoS Pathog. 2014;10:e1003982. doi: 10.1371/journal.ppat.1003982. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Alvarez D E, Agaisse H. Casein kinase 2 regulates vaccinia virus actin tail formation. Virology. 2012;423:143–151. doi: 10.1016/j.virol.2011.12.003. [DOI] [PubMed] [Google Scholar]
  4. Alvarez D E, Agaisse H. The formin FHOD1 and the small GTPase Rac1 promote vaccinia virus actin-based motility. J Cell Biol. 2013;202:1075–1090. doi: 10.1083/jcb.201303055. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Barrero-Villar M, Cabrero J R, Gordón-Alonso M, Barroso-González J, Alvarez-Losada S, Muñoz-Fernández M A, Sánchez-Madrid F, Valenzuela-Fernández A. Moesin is required for HIV-1-induced CD4-CXCR4 interaction, F-actin redistribution, membrane fusion and viral infection in lymphocytes. J Cell Sci. 2009;122:103–113. doi: 10.1242/jcs.035873. [DOI] [PubMed] [Google Scholar]
  6. Bohn W, Rutter G, Hohenberg H, Mannweiler K, Nobis P. Involvement of actin filaments in budding of measles virus: studies on cytoskeletons of infected cells. Virology. 1986;149:91–106. doi: 10.1016/0042-6822(86)90090-5. [DOI] [PubMed] [Google Scholar]
  7. Brandenburg B, Lee L Y, Lakadamyali M, Rust M J, Zhuang X, Hogle J M. Imaging poliovirus entry in live cells. PLoS Biol. 2007;5:e183. doi: 10.1371/journal.pbio.0050183. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Bukrinskaya A, Brichacek B, Mann A, Stevenson M. Establishment of a functional human immunodeficiency virus type 1 (HIV-1) reverse transcription complex involves the cytoskeleton. J Exp Med. 1998;188:2113–2125. doi: 10.1084/jem.188.11.2113. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Cameron P U, Saleh S, Sallmann G, Solomon A, Wightman F, Evans V A, Boucher G, Haddad E K, Sekaly R-P, Harman A N, Anderson J L, Jones K L, Mak J, Cunningham A L, Jaworowski A, Lewin S R. Establishment of HIV-1 latency in resting CD4+ T cells depends on chemokine-induced changes in the actin cytoskeleton. Proc Natl Acad Sci U S A. 2010;107:16934–16939. doi: 10.1073/pnas.1002894107. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Carter G C, Bernstone L, Baskaran D, James W. HIV-1 infects macrophages by exploiting an endocytic route dependent on dynamin, Rac1 and Pak1. Virology. 2011;409:234–250. doi: 10.1016/j.virol.2010.10.018. [DOI] [PubMed] [Google Scholar]
  11. Chen P, Hübner W, Spinelli M A, Chen B K. Predominant mode of human immunodeficiency virus transfer between T cells is mediated by sustained Env-dependent neutralization-resistant virological synapses. J Virol. 2007;81:12582–12595. doi: 10.1128/JVI.00381-07. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Clement C, Tiwari V, Scanlan P M, Valyi-Nagy T, Yue B Y, Shukla D. A novel role for phagocytosis-like uptake in herpes simplex virus entry. J Cell Biol. 2006;174:1009–1021. doi: 10.1083/jcb.200509155. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. Coller K E, Berger K L, Heaton N S, Cooper J D, Yoon R, Randall G. RNA interference and single particle tracking analysis of hepatitis C virus endocytosis. PLoS Pathog. 2009;5:e1000702. doi: 10.1371/journal.ppat.1000702. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Cudmore S, Cossart P, Griffiths G, Way M. Actin-based motility of vaccinia virus. Nature. 1995;378:636–638. doi: 10.1038/378636a0. [DOI] [PubMed] [Google Scholar]
  15. Dierkes R, Warnking K, Liedmann S, Seyer R, Ludwig S, Ehrhardt C. The Rac1 inhibitor NSC23766 exerts anti-influenza virus properties by affecting the viral polymerase complex activity. PloS One. 2014;9:e88520. doi: 10.1371/journal.pone.0088520. [DOI] [PMC free article] [PubMed] [Google Scholar]
  16. Dietzel E, Kolesnikova L, Maisner A. Actin filaments disruption and stabilization affect measles virus maturation by different mechanisms. Virol J. 2013;10:249. doi: 10.1186/1743-422X-10-249. [DOI] [PMC free article] [PubMed] [Google Scholar]
  17. Dixit R, Tiwari V, Shukla D. Herpes simplex virus type 1 induces filopodia in differentiated P19 neural cells to facilitate viral spread. Neurosci Lett. 2008;440:113–118. doi: 10.1016/j.neulet.2008.05.031. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Frischknecht F, Cudmore S, Moreau V, Reckmann I, Röttger S, Way M. Tyrosine phosphorylation is required for ac tin-based motility of vaccinia but not Listeria or Shigella. Curr Biol. 1999;9:89–92. doi: 10.1016/S0960-9822(99)80020-7. [DOI] [PubMed] [Google Scholar]
  19. Frischknecht F, Moreau V, Röttger S, Gonfloni S, Reckmann I, Superti-Furga G, Way M. Actin-based motility of vaccinia virus mimics receptor tyrosine kinase signaling. Nature. 1999;401:926–929. doi: 10.1038/44860. [DOI] [PubMed] [Google Scholar]
  20. Gao Y, Dickerson J B, Guo F, Zheng J, Zheng Y. Rational design and characterization of a Rac GTPase-specific small molecule inhibitor. Proc Natl Acad Sci U S A. 2004;101:7618–7623. doi: 10.1073/pnas.0307512101. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Goley E D, Ohkawa T, Mancuso J, Woodruff J B, D’Alessio J A, Cande W Z, Volkman L E, Welch M D. Dynamic Nuclear Actin Assembly by Arp2/3 Complex and a Baculovirus WASPLike Protein. Science. 2006;314:464–467. doi: 10.1126/science.1133348. [DOI] [PubMed] [Google Scholar]
  22. Harmon B, Campbell N, Ratner L. Role of Abl kinase and the Wave2 signaling complex in HIV-1 entry at a post-hemifusion step. PLoS Pathog. 2010;6:e1000956. doi: 10.1371/journal.ppat.1000956. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Harmon B, Ratner L. Induction of the Galpha(q) signaling cascade by the human immunodeficiency virus envelope is required for virus entry. J Virol. 2008;82:9191–9205. doi: 10.1128/JVI.00424-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Harries P A, Park J-W, Sasaki N, Ballard K D, Maule A J, Nelson R S. Differing requirements for actin and myosin by plant viruses for sustained intercellular movement. Proc Natl Acad Sci U S A. 2009;106:17594–17599. doi: 10.1073/pnas.0909239106. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Higgs H N, Pollard T D. Regulation of actin polymerization by Arp2/3 complex and WASp/Scar proteins. J Biol Chem. 1999;274:32531–32534. doi: 10.1074/jbc.274.46.32531. [DOI] [PubMed] [Google Scholar]
  26. Higgs H N, Pollard T D. Regulation of actin filament network formation through ARP2/3 complex: activation by a diverse array of proteins. Annu Rev Biochem. 2001;70:649–676. doi: 10.1146/annurev.biochem.70.1.649. [DOI] [PubMed] [Google Scholar]
  27. Hiller G, Jungwirth C, Weber K. Fluorescence microscopical analysis of the life cycle of vaccinia virus in chick embryo fibroblasts. Virus-cytoskeleton interactions. Exp Cell Res. 1981;132:81–87. doi: 10.1016/0014-4827(81)90085-9. [DOI] [PubMed] [Google Scholar]
  28. Hiller G, Weber K, Schneider L, Parajsz C, Jungwirth C. Interaction of assembled progeny pox viruses with the cellular cytoskeleton. Virology. 1979;98:142–153. doi: 10.1016/0042-6822(79)90533-6. [DOI] [PubMed] [Google Scholar]
  29. Hottiger M, Gramatikoff K, Georgiev O, Chaponnier C, Schaffner W, Hübscher U. The large subunit of HIV-1 reverse transcriptase interacts with beta-actin. Nucleic Acids Res. 1995;23:736–741. doi: 10.1093/nar/23.5.736. [DOI] [PMC free article] [PubMed] [Google Scholar]
  30. Huttunen M, Waris M, Kajander R, Hyypiä T, Marjomäki V. Coxsackievirus A9 infects cells via nonacidic multivesicular bodies. J Virol. 2014;88:5138–5151. doi: 10.1128/JVI.03275-13. [DOI] [PMC free article] [PubMed] [Google Scholar]
  31. Jiménez-Baranda S, Gómez-Moutón C, Rojas A, Martínez-Prats L, Mira E, Ana Lacalle R, Valencia A, Dimitrov DS, Viola A, Delgado R, Martínez-A C, Mañes S. Filamin-A regulates actin-dependent clustering of HIV receptors. Nat Cell Biol. 2007;9:838–846. doi: 10.1038/ncb1610. [DOI] [PubMed] [Google Scholar]
  32. Jolly C, Kashefi K, Hollinshead M, Sattentau Q J. HIV-1 cell to cell transfer across an Env-induced, actin-dependent synapse. J Exp Med. 2004;199:283–293. doi: 10.1084/jem.20030648. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Jolly C, Mitar I, Sattentau Q J. Requirement for an intact T-cell actin and tubulin cytoskeleton for efficient assembly and spread of human immunodeficiency virus type 1. J Virol. 2007;81:5547–5560. doi: 10.1128/JVI.01469-06. [DOI] [PMC free article] [PubMed] [Google Scholar]
  34. Kimura T, Hashimoto I, Yamamoto A, Nishikawa M, Fujisawa J I. Rev-dependent association of the intron-containing HIV-1 gag mRNA with the nuclear actin bundles and the inhibition of its nucleocytoplasmic transport by latrunculin-B. Genes Cells Devoted Mol Cell Mech. 2000;5:289–307. doi: 10.1046/j.1365-2443.2000.00326.x. [DOI] [PubMed] [Google Scholar]
  35. Krempien U, Schneider L, Hiller G, Weber K, Katz E, Jungwirth C. Conditions for pox virus-specific microvilli formation studied during synchronized virus assembly. Virology. 1981;113:556–564. doi: 10.1016/0042-6822(81)90183-5. [DOI] [PubMed] [Google Scholar]
  36. Lehmann M J, Sherer N M, Marks C B, Pypaert M, Mothes W. Actin-and myosin-driven movement of viruses along filopodia precedes their entry into cells. J Cell Biol. 2005;170:317–325. doi: 10.1083/jcb.200503059. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. Machesky L M, Insall R H. WASP homology sequences in baculoviruses. Trends Cell Biol. 2001;11:286–287. doi: 10.1016/S0962-8924(01)02009-8. [DOI] [PubMed] [Google Scholar]
  38. Mercer J, Helenius A. Vaccinia virus uses macropinocytosis and apoptotic mimicry to enter host cells. Science. 2008;320:531–535. doi: 10.1126/science.1155164. [DOI] [PubMed] [Google Scholar]
  39. Moss B. Poxvirus cell entry: how many proteins does it take? Viruses. 2012;4:688–707. doi: 10.3390/v4050688. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Moreau V, Frischknecht F, Reckmann I, Vincentelli R, Rabut G, Stewart D, Way M. A complex of N-WASP and WIP integrates signalling cascades that lead to actin polymerization. Nat Cell Biol. 2000;2:441–448. doi: 10.1038/35017080. [DOI] [PubMed] [Google Scholar]
  41. Nolen B J, Tomasevic N, Russell A, Pierce D W, Jia Z, McCormick C D, Hartman J, Sakowicz R, Pollard T D. Characterization of two classes of small molecule inhibitors of Arp2/3 complex. Nature. 2009;460:1031–1034. doi: 10.1038/nature08231. [DOI] [PMC free article] [PubMed] [Google Scholar]
  42. Ohkawa T, Volkman L E, Welch M D. Actin-based motility drives baculovirus transit to the nucleus and cell surface. J Cell Biol. 2010;190:187–195. doi: 10.1083/jcb.201001162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Ohkawa T, Volkman L E. Nuclear F-Actin Is Required for AcMNPV Nucleocapsid Morphogenesis. Virology. 1999;264:1–4. doi: 10.1006/viro.1999.0008. [DOI] [PubMed] [Google Scholar]
  44. Pollard T D, Borisy G G. Cellular motility driven by assembly and disassembly of actin filaments. Cell. 2003;112:453–465. doi: 10.1016/S0092-8674(03)00120-X. [DOI] [PubMed] [Google Scholar]
  45. Roberts P C, Compans R W. Host cell dependence of viral morphology. Proc Natl Acad Sci U S A. 1998;95:5746–5751. doi: 10.1073/pnas.95.10.5746. [DOI] [PMC free article] [PubMed] [Google Scholar]
  46. Röttger S, Frischknecht F, Reckmann I, Smith G L, Way M. Interactions between vaccinia virus IEV membrane proteins and their roles in IEV assembly and actin tail formation. J Virol. 1999;73:2863–2875. doi: 10.1128/jvi.73.4.2863-2875.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  47. Sánchez E G, Quintas A, Pérez-Núñez D, Nogal M, Barroso S, Carrascosa L, Revilla Y. African swine fever virus uses macropinocytosis to enter host cells. PLoS Pathog. 2012;8:e1002754. doi: 10.1371/journal.ppat.1002754. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Scaplehorn N, Holmström A, Moreau V, Frischknecht F, Reckmann I, Way M. Grb2 and Nck act cooperatively to promote actin-based motility of vaccinia virus. Curr Biol CB. 2002;12:740–745. doi: 10.1016/S0960-9822(02)00812-6. [DOI] [PubMed] [Google Scholar]
  49. Schelhaas M, Ewers H, Rajamäki M-L, Day P M, Schiller J T, Helenius A. Human papillomavirus type 16 entry: retrograde cell surface transport along actin-rich protrusions. PLoS Pathog. 2008;4:e1000148. doi: 10.1371/journal.ppat.1000148. [DOI] [PMC free article] [PubMed] [Google Scholar]
  50. Schelhaas M, Shah B, Holzer M, Blattmann P, Kühling L, Day P M, Schiller J T, Helenius A. Entry of Human Papillomavirus Type 16 by Actin-Dependent, Clathrin- and Lipid Raft-Independent Endocytosis. PLoS Pathog. 2012;8:e1002657. doi: 10.1371/journal.ppat.1002657. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Simpson-Holley M, Ellis D, Fisher D, Elton D, McCauley J, Digard P. A functional link between the actin cytoskeleton and lipid rafts during budding of filamentous influenza virions. Virology. 2002;301:212–225. doi: 10.1006/viro.2002.1595. [DOI] [PubMed] [Google Scholar]
  52. Simpson-Holley M, Ellis D, Fisher D, Elton D, McCauley J, Digard P. A Functional Link between the Actin Cytoskeleton and Lipid Rafts during Budding of Filamentous Influenza Virions. Virology. 2002;301:212–225. doi: 10.1006/viro.2002.1595. [DOI] [PubMed] [Google Scholar]
  53. Sowinski S, Jolly C, Berninghausen O, Purbhoo M A, Chauveau A, Köhler K, Oddos S, Eissmann P, Brodsky F M, Hopkins C, Onfelt B, Sattentau Q, Davis D M. Membrane nanotubes physically connect T cells over long distances presenting a novel route for HIV-1 transmission. Nat Cell Biol. 2008;10:211–219. doi: 10.1038/ncb1682. [DOI] [PubMed] [Google Scholar]
  54. Spear M, Guo J, Turner A, Yu D, Wang W, Meltzer B, He S, Hu X, Shang H, Kuhn J, Wu Y. HIV-1 Triggers WAVE2 Phosphorylation in Primary CD4 T Cells and Macrophages, Mediating Arp2/3-dependent Nuclear Migration. J Biol Chem. 2014;289:6949–6959. doi: 10.1074/jbc.M113.492132. [DOI] [PMC free article] [PubMed] [Google Scholar]
  55. Stallcup K C, Raine C S, Fields B N. Cytochalasin B inhibits the maturation of measles virus. Virology. 1983;124:59–74. doi: 10.1016/0042-6822(83)90290-8. [DOI] [PubMed] [Google Scholar]
  56. Stokes G V. High-voltage electron microscope study of the release of vaccinia virus from whole cells. J Virol. 1976;18:636–643. doi: 10.1128/jvi.18.2.636-643.1976. [DOI] [PMC free article] [PubMed] [Google Scholar]
  57. Tilsner J, Linnik O, Wright K M, Bell K, Roberts A G, Lacomme C, Santa Cruz S, Oparka K J. The TGB1 movement protein of Potato virus X reorganizes actin and endomembranes into the X-body, a viral replication factory. Plant Physiol. 2012;158:1359–1370. doi: 10.1104/pp.111.189605. [DOI] [PMC free article] [PubMed] [Google Scholar]
  58. Vasiliver-Shamis G, Cho M W, Hioe C E, Dustin M L. Human Immunodeficiency Virus Type 1 Envelope gp120-Induced Partial T-Cell Receptor Signaling Creates an F-Actin-Depleted Zone in the Virological Synapse. J Virol. 2009;83:11341–11355. doi: 10.1128/JVI.01440-09. [DOI] [PMC free article] [PubMed] [Google Scholar]
  59. Vasiliver-Shamis G, Tuen M, Wu T W, Starr T, Cameron T O, Thomson R, Kaur G, Liu J, Visciano M L, Li H, Kumar R, Ansari R, Han D P, Cho M W, Dustin M L, Hioe C E. Human immunodeficiency virus type 1 envelope gp120 induces a stop signal and virological synapse formation in noninfected CD4+ T cells. J Virol. 2008;82:9445–9457. doi: 10.1128/JVI.00835-08. [DOI] [PMC free article] [PubMed] [Google Scholar]
  60. Vorster P J, Guo J, Yoder A, Wang W, Zheng Y, Xu X, Yu D, Spear M, Wu Y. LIM kinase 1 modulates cortical actin and CXCR4 cycling and is activated by HIV-1 to initiate viral infection. J Biol Chem. 2011;286:12554–12564. doi: 10.1074/jbc.M110.182238. [DOI] [PMC free article] [PubMed] [Google Scholar]
  61. De Vries E, Tscherne D M, Wienholts M J, Cobos-Jiménez V, Scholte F, García-Sastre A, Rottier PJM, de Haan C A M. Dissection of the Influenza A Virus Endocytic Routes Reveals Macropinocytosis as an Alternative Entry Pathway. PLoS Pathog. 2011;7:e1001329. doi: 10.1371/journal.ppat.1001329. [DOI] [PMC free article] [PubMed] [Google Scholar]
  62. Wakimoto H, Shimodo M, Satoh Y, Kitagawa Y, Takeuchi K, Gotoh B, Itoh M. F-Actin Modulates Measles Virus Cell-Cell Fusion and Assembly by Altering the Interaction between the Matrix Protein and the Cytoplasmic Tail of Hemagglutinin. J Virol. 2013;87:1974–1984. doi: 10.1128/JVI.02371-12. [DOI] [PMC free article] [PubMed] [Google Scholar]
  63. Welch M D, Way M. Arp2/3-Mediated Actin-Based Motility: A Tail of Pathogen Abuse. Cell Host Microbe. 2013;14:242–255. doi: 10.1016/j.chom.2013.08.011. [DOI] [PMC free article] [PubMed] [Google Scholar]
  64. Wen X, Ding L, Wang J-J, Qi M, Hammonds J, Chu H, Chen X, Hunter E, Spearman P. J Virol. 2014. ROCK1 and LIM Kinase Modulate Retrovirus Particle Release and Cell-Cell Transmission Events. [DOI] [PMC free article] [PubMed] [Google Scholar]
  65. Xiang Y, Zheng K, Zhong M, Chen J, Wang X, Wang Q, Wang S, Ren Z, Fan J, Wang Y. Ubiquitin-proteasome-dependent slingshot 1 downregulation in neuronal cells inactivates cofilin to facilitate HSV-1 replication. Virology. 2014;449:88–95. doi: 10.1016/j.virol.2013.11.011. [DOI] [PubMed] [Google Scholar]
  66. Yoder A, Yu D, Dong L, Iyer S R, Xu X, Kelly J, Liu J, Wang W, Vorster P J, Agulto L, Stephany D A, Cooper J N, Marsh J W, Wu Y. HIV envelope-CXCR4 signaling activates cofilin to overcome cortical actin restriction in resting CD4 T cells. Cell. 2008;134:782–792. doi: 10.1016/j.cell.2008.06.036. [DOI] [PMC free article] [PubMed] [Google Scholar]
  67. Zheng K, Xiang Y, Wang Q, Jin F, Chen M, Ma K, Ren Z, Wang Y. Calcium-signal facilitates herpes simplex virus type 1 nuclear transport through slingshot 1 and calpain-1 activation. Virus Res. 2014;188C:32–37. doi: 10.1016/j.virusres.2014.03.016. [DOI] [PubMed] [Google Scholar]
  68. Zheng K, Xiang Y, Wang X, Wang Q, Zhong M, Wang S, Wang X, Fan J, Kitazato K, Wang Y. Epidermal growth factor receptor-PI3K signaling controls cofilin activity to facilitate herpes simplex virus 1 entry into neuronal cells. mBio. 2014;5:e00958–00913. doi: 10.1128/mBio.00958-13. [DOI] [PMC free article] [PubMed] [Google Scholar]

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