Skip to main content
SpringerLink
Log in

Infection of Cells by Alphaviruses

  • Chapter
  • First Online:
Book cover Viral Molecular Machines

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 726))

Abstract

It is widely accepted that alphaviruses enter cells by a process involving endocytosis and low-pH-mediated virus membrane–cell membrane fusion. This model and the data supporting it have received extensive and numerous reviews. The major points presented in support of this model are summarized briefly herein. It is the primary objective of this review to present an alternative mechanism describing the penetration of cells by alphaviruses which does not involve endocytosis or exposure to acid environment. The data supporting this model are summarized in detail.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 219.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  • Anthony RP, Paredes AM, Brown DT (1992) Disulfide bonds are essential for the stability of the Sindbis virus envelope. Virology 190(1):330–336

    Article  PubMed  CAS  Google Scholar 

  • Belnap DM, Filman DJ, Trus BL, Cheng N, Booy FP, Conway JF, Curry S, Hiremath CN, Tsang SK, Steven AC, Hogle JM (2000) Molecular tectonic model of virus structural transitions: the putative cell entry states of poliovirus. J Virol 74(3):1342–1354

    Article  PubMed  CAS  Google Scholar 

  • Brown DT, Condreay LD (1986) Replication of alphaviruses in mosquito cells. In: Schlesinger MJ (ed) The Togaviridae and Flaviviridae. New York, Plenum Publishing Corporation, pp 171–207

    Google Scholar 

  • Brown DT, Waite MRF, Pfefferkorn ER (1972) Morphology and morphogenesis of Sindbis virus as seen with freeze-etching techniques. J Virol 10:534–536

    Google Scholar 

  • Bullough PA, Hughson FM, Skehel JJ, Wiley DC (1994) Structure of influenza haemagglutinin at the pH of membrane fusion. Nature 371(6492):37–43

    Article  PubMed  CAS  Google Scholar 

  • Carleton M, Brown DT (1996) Disulfide bridge-mediated folding of Sindbis virus glycoproteins. J Virol 70(8):5541–5547

    PubMed  CAS  Google Scholar 

  • Carleton M, Lee H, Mulvey M, Brown DT (1997) Role of glycoprotein PE2 in formation and maturation of the Sindbis virus spike. J Virol 71(2):1558–1566

    PubMed  CAS  Google Scholar 

  • Clayton RB (1964) The utilization of sterols by insects. J Lipid Res 5:3–19

    CAS  Google Scholar 

  • Cleverley D, Geller H, Lenard J (1997) Characterization of cholesterol-free insect cells infectible by baculoviruses: effects of cholesterol on VSV fusion and infectivity and on cytotoxicity induced by influenza M2 protein. Exp Cell Res 233(2):288–296

    Article  PubMed  CAS  Google Scholar 

  • Coombs K, Mann E, Edwards J, Brown DT (1981) Effects of chloroquine and cytochalasin B on the infection of cells by Sindbis virus and vesicular stomatitis virus. J Virol 37(3):1060–1065

    PubMed  CAS  Google Scholar 

  • Coombs K, Brown B, Brown DT (1984) Evidence for a change in capsid morphology during Sindbis virus envelopment. Virus Res 1(4):297–302

    Article  PubMed  CAS  Google Scholar 

  • Crider BP, Xie XS, Stone DK (1994) Bafilomycin inhibits proton flow through the H+ channel of vacuolar proton pumps. J Biol Chem 269(26):17379–17381

    PubMed  CAS  Google Scholar 

  • Dhileepan K, Azuolas JK, Gibson CA (1996) Evidence of vertical transmission of Ross River and Sindbis viruses (Togaviridae: Alphavirus) by mosquitoes (Diptera: Culicidae) in southeastern Australia. J Med Entomol 33(1):180–182

    PubMed  CAS  Google Scholar 

  • Eckert DM, Kim PS (2001) Mechanisms of viral membrane fusion and its inhibition. Annu Rev Biochem 70:777–810

    Article  PubMed  CAS  Google Scholar 

  • Edwards J, Brown DT (1986) Sindbis virus-mediated cell fusion from without is a two-step event. J Gen Virol 67(Pt 2):377–380

    Article  PubMed  Google Scholar 

  • Edwards J, Brown DT (1991) Sindbis virus infection of a Chinese hamster ovary cell mutant defective in the acidification of endosomes. Virology 182(1):28–33

    Article  PubMed  CAS  Google Scholar 

  • Ferreira DF, Santo MP, Rebello MA, Rebello MC (2000) Weak bases affect late stages of Mayaro virus replication cycle in vertebrate cells. J Med Microbiol 49(4):313–318

    PubMed  CAS  Google Scholar 

  • Ferreira DF, Hernandez R, Horton M, Brown DT (2003) Morphological variants of Sindbis virus produced by a mutation in the capsid protein. Virology 307(1):54–66

    Article  PubMed  CAS  Google Scholar 

  • Flynn DC, Meyer WJ, Mackenzie JM Jr, Johnston RE (1990) A conformational change in Sindbis virus glycoproteins E1 and E2 is detected at the plasma membrane as a consequence of early virus-cell interaction. J Virol 64(8):3643–3653

    PubMed  CAS  Google Scholar 

  • Fulhorst CF, Hardy JL, Eldridge BF, Presser SB, Reeves WC (1994) Natural vertical transmission of western equine encephalomyelitis virus in mosquitoes. Science 263(5147):676–678

    Article  PubMed  CAS  Google Scholar 

  • Gibbons DL, Reilly B, Ahn A, Vaney MC, Vigouroux A, Rey FA, Kielian M (2004) Purification and crystallization reveal two types of interactions of the fusion protein homotrimer of Semliki Forest virus. J Virol 78(7):3514–3523

    Article  PubMed  CAS  Google Scholar 

  • Glomb-Reinmund S, Kielian M (1998) The role of low pH and disulfide shuffling in the entry and fusion of Semliki Forest virus and Sindbis virus. Virology 248(2):372–381

    Article  PubMed  CAS  Google Scholar 

  • Hafer A, Whittlesey R, Brown DT, Hernandez R (2009) Differential incorporation of cholesterol by Sindbis virus grown in mammalian or insect cells. J Virol 83:9113–9121

    Article  PubMed  CAS  Google Scholar 

  • Hase T, Summers PL, Cohen WH (1989a) A comparative study of entry modes into C6/36 cells by Semliki Forest and Japanese encephalitis viruses. Arch Virol 108(1–2):101–114

    Article  PubMed  CAS  Google Scholar 

  • Hase T, Summers PL, Eckels KH (1989b) Flavivirus entry into cultured mosquito cells and human peripheral blood monocytes. Arch Virol 104(1–2):129–143

    Article  PubMed  CAS  Google Scholar 

  • He L, Piper A, Meilleur F, Myles DA, Hernandez R, Brown DT, Heller WT (2010) The structure of Sindbis virus produced from vertebrate and invertebrate hosts determined by small-angle neutron scattering. J Virol 84:5270–5276

    Article  PubMed  CAS  Google Scholar 

  • Helenius A (1984) Semliki Forest virus penetration from endosomes: a morphological study. Biol Cell 51(2):181–185

    PubMed  CAS  Google Scholar 

  • Helenius A, Marsh M (1982) Endocytosis of enveloped animal viruses. Ciba Found Symp 92:59–76

    PubMed  CAS  Google Scholar 

  • Helenius A, Morein B, Fries E, Simons K, Robinson P, Schirrmacher V, Terhorst C, Strominger JL (1978) Human (HLA-A and HLA-B) and murine (H-2K and H-2D) histocompatibility antigens are cell surface receptors for Semliki Forest virus. Proc Natl Acad Sci USA 75(8):3846–3850

    Article  PubMed  CAS  Google Scholar 

  • Helenius A, Kartenbeck J, Simons K, Fries E (1980) On the entry of Semliki Forest virus into BHK-21 cells. J Cell Biol 84:404–420

    Article  PubMed  CAS  Google Scholar 

  • Helenius A, Marsh M, White J (1982) Inhibition of Semliki forest virus penetration by lysosomotropic weak bases. J Gen Virol 58(Pt 1):47–61

    Article  PubMed  CAS  Google Scholar 

  • Hernandez R, Lee H, Nelson C, Brown DT (2000) A single deletion in the membrane-proximal region of the Sindbis virus glycoprotein E2 endodomain blocks virus assembly. J Virol 74(9):4220–4228

    Article  PubMed  CAS  Google Scholar 

  • Hernandez R, Luo T, Brown DT (2001) Exposure to low pH is not required for penetration of mosquito cells by Sindbis virus. J Virol 75(4):2010–2013

    Article  PubMed  CAS  Google Scholar 

  • Hernandez R, Sinodis C, Horton M, Ferreira D, Yang C, Brown DT (2003) Deletions in the transmembrane domain of a Sindbis virus glycoprotein alter virus infectivity, stability, and host range. J Virol 77(23):12710–12719

    Article  PubMed  CAS  Google Scholar 

  • Hernandez R, Ferreira D, Sinodis C, Litton K, Brown DT (2005) Single amino acid insertions at the junction of the Sindbis virus E2 transmembrane domain and endodomain disrupt virus envelopment and alter infectivity. J Virol 79(12):7682–7697

    Article  PubMed  CAS  Google Scholar 

  • Hernandez R et al (2006) Sindbis virus: propagation, quantification and storage. In: Coico R et al (eds) Current protocols in microbiology, vol 1. Wiley, New York, p 15B.1

    Google Scholar 

  • Hunt SR, Hernandez R et al. (2011) Role of the vacuolar-ATPase in Sindbis virus infection. Journal of virology 85(3):1257–1266

    Article  PubMed  CAS  Google Scholar 

  • Johnston RE, Wan K, Bose HR (1974) Homologous interference induced by Sindbis virus. J Virol 14(5):1076–1082

    PubMed  CAS  Google Scholar 

  • Kielian M (1995) Membrane fusion and the alphavirus life cycle. Adv Virus Res 45:113–151

    Article  PubMed  CAS  Google Scholar 

  • Kielian MC, Helenius A (1984) Role of cholesterol in fusion of Semliki Forest virus with membranes. J Virol 52(1):281–283

    PubMed  CAS  Google Scholar 

  • Kielian M, Jungerwirth S (1990) Mechanisms of enveloped virus entry into cells. Mol Biol Med 7(1):17–31

    PubMed  CAS  Google Scholar 

  • Kielian M, Rey FA (2006) Virus membrane-fusion proteins: more than one way to make a hairpin. Nat Rev Microbiol 4(1):67–76

    Article  PubMed  CAS  Google Scholar 

  • Kielian MC, Keranen S, Kaariainen L, Helenius A (1984) Membrane fusion mutants of Semliki Forest virus. J Cell Biol 98(1):139–145

    Article  PubMed  CAS  Google Scholar 

  • Klimstra WB, Ryman KD, Johnston RE (1998) Adaptation of Sindbis virus to BHK cells selects for use of heparan sulfate as an attachment receptor. J Virol 72(9):7357–7366

    PubMed  CAS  Google Scholar 

  • Klimstra WB, Nangle EM, Smith MS, Yurochko AD, Ryman KD (2003) DC-SIGN and L-SIGN can act as attachment receptors for alphaviruses and distinguish between mosquito cell- and mammalian cell-derived viruses. J Virol 77(22):12022–12032

    Article  PubMed  CAS  Google Scholar 

  • Koschinski A, Wengler G, Repp H (2003) The membrane proteins of flaviviruses form ion-permeable pores in the target membrane after fusion: identification of the pores and analysis of their possible role in virus infection. J Gen Virol 84(Pt 7):1711–1721

    Article  PubMed  CAS  Google Scholar 

  • Lanzrein M, Weingart R, Kempf C (1993) pH-dependent pore formation in Semliki forest virus-infected Aedes albopictus cells. Virology 193(1):296–302

    Article  PubMed  CAS  Google Scholar 

  • Lee S, Owen KE, Choi HK, Lee H, Lu G, Wengler G, Brown DT, Rossmann MG, Kuhn RJ (1996) Identification of a protein binding site on the surface of the alphavirus nucleocapsid and its implication in virus assembly. Structure 4(5):531–541

    Article  PubMed  CAS  Google Scholar 

  • Li L, Jose J et al. (2010) Structural changes of envelope proteins during alphavirus fusion. Nature 468(7324): 705–708

    Article  PubMed  CAS  Google Scholar 

  • Liu N, Brown DT (1993a) Phosphorylation dephosphorylation events play critical roles in Sindbis virus maturation. Virology 196:703–711

    Article  PubMed  CAS  Google Scholar 

  • Liu N, Brown DT (1993b) Transient translocation of the cytoplasmic (endo) domain of a type I membrane glycoprotein into cellular membranes. J Cell Biol 120(4):877–883

    Article  PubMed  CAS  Google Scholar 

  • Lu YE, Cassese T, Kielian M (1999) The cholesterol requirement for Sindbis virus entry and exit and characterization of a spike protein region involved in cholesterol dependence. J Virol 73(5):4272–4278

    PubMed  CAS  Google Scholar 

  • Maassen JA, Terhorst C (1981) Identification of a cell-surface protein involved in the binding site of Sindbis virus on human lymphoblastic cell lines using a heterobifunctional cross-linker. Eur J Biochem 115(1):153–158

    Article  PubMed  CAS  Google Scholar 

  • Madan V, Sanz MA, Carrasco L (2005) Requirement of the vesicular system for membrane permeabilization by Sindbis virus. Virology 332:307–315

    Article  PubMed  CAS  Google Scholar 

  • Marsh M, Wellsteed J, Kern H, Harms E, Helenius A (1982) Monensin inhibits Semliki Forest virus penetration into culture cells. Proc Natl Acad Sci USA 79(17):5297–5301

    Article  PubMed  CAS  Google Scholar 

  • Marsh M, Bolzau E, Helenius A (1983) Penetration of Semliki Forest virus from acidic prelysosomal vacuoles. Cell 32(3):931–940

    Article  PubMed  CAS  Google Scholar 

  • Mitsuhashi J, Nakasone S, Horie Y (1983) Sterol-free eukaryotic cells from continuous cell lines of insects. Cell Biol Int Rep 7(12):1057–1062

    Article  PubMed  CAS  Google Scholar 

  • Mukhopadhyay S, Zhang W, Gabler S, Chipman PR, Strauss EG, Strauss JH, Baker TS, Kuhn RJ, Rossmann MG (2006) Mapping the structure and function of the E1 and E2 glycoproteins in alphaviruses. Structure 14(1):63–73

    Article  PubMed  CAS  Google Scholar 

  • Mulvey M, Brown DT (1994) Formation and rearrangement of disulfide bonds during maturation of the Sindbis virus E1 glycoprotein. J Virol 68(2):805–812

    PubMed  CAS  Google Scholar 

  • Mulvey M, Brown DT (1995) Involvement of the molecular chaperone BiP in maturation of Sindbis virus envelope glycoproteins. J Virol 69(3):1621–1627

    PubMed  CAS  Google Scholar 

  • Mulvey M, Brown DT (1996) Assembly of the Sindbis virus spike protein complex. Virology 219(1):125–132

    Article  PubMed  CAS  Google Scholar 

  • Oldstone MB, Tishon A, Dutko FJ, Kennedy SI, Holland JJ, Lampert PW (1980) Does the major histocompatibility complex serve as a specific receptor for Semliki Forest virus? J Virol 34(1):256–265

    PubMed  CAS  Google Scholar 

  • Omar A, Koblet H (1988) Semliki Forest virus particles containing only E1 envelope glycoprotein are infectious and can induce cell-cell fusion. Virology 166:17–23

    Article  PubMed  CAS  Google Scholar 

  • Paredes AM, Brown DT, Rothnagel R, Chiu W, Schoepp RJ, Johnston RE, Prasad BV (1993) Three-dimensional structure of a membrane-containing virus. Proc Natl Acad Sci USA 90(19):9095–9099

    Article  PubMed  CAS  Google Scholar 

  • Paredes AM, Ferreira D, Horton M, Saad A, Tsuruta H, Johnston R, Klimstra W, Ryman K, Hernandez R, Chiu W, Brown DT (2004) Conformational changes in Sindbis virions resulting from exposure to low pH and interactions with cells suggest that cell penetration may occur at the cell surface in the absence of membrane fusion. Virology 324(2):373–386

    Article  PubMed  CAS  Google Scholar 

  • Pletnev SV, Zhang W, Mukhopadhyay S, Fisher BR, Hernandez R, Brown DT, Baker TS, Rossmann MG, Kuhn RJ (2001) Locations of carbohydrate sites on alphavirus glycoproteins show that E1 forms an icosahedral scaffold. Cell 105(1):127–136

    Article  PubMed  CAS  Google Scholar 

  • Ren J, Ding T, Zhang W, Song J, Ma W (2007) Does Japanese encephalitis virus share the same cellular receptor with other mosquito-borne flaviviruses on the C6/36 mosquito cells? Virol J 4:83

    Article  PubMed  Google Scholar 

  • Schlesinger RW (1971) Some speculations on the possible role of arthropods in the evolution of arboviruses. Curr Top Microbiol Immunol 55:241–245

    PubMed  CAS  Google Scholar 

  • Skehel JJ, Wiley DC (2000) Receptor binding and membrane fusion in virus entry: the influenza hemagglutinin. Annu Rev Biochem 69:531–569

    Article  PubMed  CAS  Google Scholar 

  • Skehel JJ, Bizebard T, Bullough PA, Hughson FM, Knossow M, Steinhauer DA, Wharton SA, Wiley DC (1995) Membrane fusion by influenza hemagglutinin. Cold Spring Harb Symp Quant Biol 60:573–580

    Article  PubMed  CAS  Google Scholar 

  • Smit JM, Li G, Schoen P, Corver J, Bittman R, Lin KC, Wilschut J (2002) Fusion of alphaviruses with liposomes is a non-leaky process. FEBS Lett 521(1–3):62–66

    Article  PubMed  CAS  Google Scholar 

  • Strauss JH, Strauss EG (1994) The alphaviruses: gene expression, replication, and evolution. Micro Rev 58:491–562

    CAS  Google Scholar 

  • Ubol S, Griffin DE (1991) Identification of a putative alphavirus receptor on mouse neural cells. J Virol 65(12):6913–6921

    PubMed  CAS  Google Scholar 

  • Voss JE, Vaney MC et al. (2010) Glycoprotein organization of Chikungunya virus particles revealed by X-ray crystallography. Nature 468(7324):709–712

    Article  PubMed  CAS  Google Scholar 

  • Wang KS, Kuhn RJ, Strauss EG, Ou S, Strauss JH (1992) High-affinity laminin receptor is a receptor for Sindbis virus in mammalian cells. J Virol 66(8):4992–5001

    PubMed  CAS  Google Scholar 

  • Weinstein DB (1979) A single-step adsoption method for romoval of lipiproteins and preparation of cholesterol-free serum. Circulation 59–60(supplement II-54), abstract 204

    Google Scholar 

  • Wengler G, Koschinski A, Dreyer F (2003) Entry of alphaviruses at the plasma membrane converts the viral surface proteins into an ion-permeable pore that can be detected by electrophysiological analyses of whole-cell membrane currents. J Gen Virol 84(Pt 1):173–181

    Article  PubMed  CAS  Google Scholar 

  • Wengler G, Koschinski A, Repp H (2004) During entry of alphaviruses, the E1 glycoprotein molecules probably form two separate populations that generate either a fusion pore or ion-permeable pores. J Gen Virol 85(Pt 6):1695–1701

    Article  PubMed  CAS  Google Scholar 

  • White J, Helenius A (1980) pH-dependent fusion between the Semliki Forest virus membrane and lipsoomes. Proc Natl Acad Sci USA 77(6):3273–3277

    Article  PubMed  CAS  Google Scholar 

  • White J, Kartenbeck J, Helenius A (1980) Fusion of Semliki Forest virus with the plasma membrane can be induced by low pH. J Cell Biol 87:264–272

    Article  PubMed  CAS  Google Scholar 

  • Whitehurst CB, Soderblom EJ, West ML, Hernandez R, Goshe MB, Brown DT (2007) Location and role of free cysteinyl residues in the Sindbis virus E1 and E2 glycoproteins. J Virol 81(12):6231–6240

    Article  PubMed  CAS  Google Scholar 

  • Zhang W, Mukhopadhyay S, Pletnev SV, Baker TS, Kuhn RJ, Rossmann MG (2002) Placement of the structural proteins in Sindbis virus. J Virol 76(22):11645–11658

    Article  PubMed  CAS  Google Scholar 

  • Zhang W, Heil M, Kuhn RJ, Baker TS (2005) Heparin binding sites on Ross River virus revealed by electron cryo-microscopy. Virology 332(2):511–518

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

Dennis Brown and Raquel Hernandez are supported by “The Foundation for Research” Carson City, NV. The authors thank Sabrina Hunt for editing this manuscript.

Author information

Authors and Affiliations

  1. Department of Molecular and Structural Biochemistry, North Carolina State University, 128 Polk Hall, Campus, 7622, Raleigh, NC, 27695, USA

    Dennis T. Brown & Raquel Hernandez

Authors
  1. Dennis T. Brown
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Raquel Hernandez
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dennis T. Brown .

Editor information

Editors and Affiliations

  1. Dept. Biological Sciences, Purdue University, W. State St. 915, West Lafayette, 47907-2054, Indiana, USA

    Michael G. Rossmann

  2. Dept. Biology, Catholic University of America, Washington, 20064, District of Columbia, USA

    Venigalla B. Rao

Rights and permissions

Reprints and permissions

Copyright information

© 2012 Springer Science+Business Media, LLC

About this chapter

Cite this chapter

Brown, D.T., Hernandez, R. (2012). Infection of Cells by Alphaviruses. In: Rossmann, M., Rao, V. (eds) Viral Molecular Machines. Advances in Experimental Medicine and Biology, vol 726. Springer, Boston, MA. https://doi.org/10.1007/978-1-4614-0980-9_8

Download citation

Publish with us

Policies and ethics

Search

Navigation