Skip to main content

Entry of Herpesviruses into Cells: The Enigma Variations

  • Chapter
Viral Entry into Host Cells

Part of the book series: Advances in Experimental Medicine and Biology ((AEMB,volume 790))

Abstract

The entry of herpesviruses into their target cells is complex at many levels. Virus entry proceeds by a succession of interactions between viral envelope glycoproteins and molecules on the cell membrane. The process is divided into distinct steps: attachment to the cell surface, interaction with a specific entry receptor, internalization of the particle (optional and cell specific), and membrane fusion. Several viral envelope glycoproteins are involved in one or several of these steps. The most conserved entry glycoproteins in the herpesvirus family (gB, gH/gL) are involved in membrane fusion. Around this functional core, herpesviruses have a variety of receptor binding glycoproteins, which interact with cell surface proteins often from different families. This interaction activates and controls the actual fusion machinery. Interactions with cellular receptors and between viral glycoproteins have to be tightly coordinated and regulated to guarantee successful entry. Although additional entry receptors for herpesviruses continue to be identified, the molecular interactions between viral glycoproteins remain mostly enigmatic. This chapter will review our current understanding of the molecular interactions that occur during herpesvirus entry from attachment to fusion. Particular emphasis will be placed on structure-based representation of receptor binding as a trigger of fusion during herpes simplex virus entry.

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

Access this chapter

Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 129.00
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 169.99
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

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. Roizman B, Pellett PE. The family herpesviridae: A brief introduction. In: Knipe DM, Howley PM, eds. Fields Virology. 4th ed. Philadelphia: Lippincott, Willams and Wilkins, 2001:2381–2398.

    Google Scholar 

  2. Mettenleiter TC. Pathogenesis of neurotropic herpesviruses: Role of viral glycoproteins in neuroinvasion and transneuronal spread. Virus Res 2003; 92(2): 197–206.

    Article  PubMed  CAS  Google Scholar 

  3. Cole NL, Grose C. Membrane fusion mediated by herpesvirus glycoproteins: The paradigm of varicella-zoster virus. Rev Med Virol 2003; 13(4):207–222.

    Article  PubMed  CAS  Google Scholar 

  4. Speck P, Haan KM, Longnecker R. Epstein-Barr virus entry into cells. Virology 2000; 277(1): 1–5.

    Article  PubMed  CAS  Google Scholar 

  5. Spear PG, Longnecker R. Herpesvirus entry: An update. J Virol Methods 2003; 77(19): 10179–10185.

    Article  CAS  Google Scholar 

  6. Campadelli-Fiume G, Cocchi F, Menotti L et al. The novel receptors that mediate the entry of herpes simplex viruses and animal alphaherpesviruses into cells. Rev Med Virol 2000; 10(5):305–319.

    Article  PubMed  CAS  Google Scholar 

  7. Compton T. Receptors and immune sensors: The complex entry path of human cytomegalovirus. Trends Cell Biol 2004; 14(1):5–8.

    Article  PubMed  CAS  Google Scholar 

  8. Grunewald K, Desai P, Winkler DC et al. Three-dimensional structure of herpes simplex virus from cryo-electron tomography. Science 2003; 302:1396–1398.

    Article  PubMed  CAS  Google Scholar 

  9. Gianni T, Martelli PL, Casadio R et al. The ectodomain of herpes simplex virus glycoprotein H contains a membrane alpha-helix with attributes of an internal fusion peptide, positionally conserved in the herpesviridae family. J Virol 2005; 79(5):2931–2940.

    Article  PubMed  CAS  Google Scholar 

  10. Lopper M, Compton T. Disulfide bond configuration of human cytomegalovirus glycoprotein B. J Virol 2002; 76(12):6073–6082.

    Article  PubMed  CAS  Google Scholar 

  11. Galdiero S, Falanga A, Vitiello M et al. Fusogenic domains in herpes simplex virus type 1 glycoprotein H. J Biol Chem 2005; 280:28632–28643.

    Article  PubMed  CAS  Google Scholar 

  12. Foster TP, Melancon JM, Kousoulas KG. An alpha-Helical domain within the carboxyl terminus of Herpes simplex virus type 1 (HSV-1) glycoprotein B (gB) is associated with cell fusion and resistance to heparin inhibition of cell fusion. Virology 2001; 287(1): 18–29.

    Article  PubMed  CAS  Google Scholar 

  13. Bzik DJ, Fox BA, DeLuca NA et al. Nucleotide sequence of a region of the herpes simplex virus type 1 gB glycoprotein gene: Mutations affecting rate of virus entry and cell fusion. Virology 1984; 137:185–190.

    Article  PubMed  CAS  Google Scholar 

  14. Gage PJ, Levine M, Glorioso JC. Syncytium-inducing mutations localize to two discrete regions within the cytoplasmic domain of herpes simplex virus type 1 glycoprotein B. J Virol 1993; 67:2191–2201.

    PubMed  CAS  Google Scholar 

  15. Engel JP, Boyer EP, Goodman JL. Two novel single amino acid syncytial mutations in the carboxy-terminus of glycoprotein B of herpes simplex virus type 1 confer a unique pathogenic phenotype. Virology 1993; 192:112–120.

    Article  PubMed  CAS  Google Scholar 

  16. Ruell N, Zago A, Spear PG. Alanine substitution of conserved residues in the cytoplasmic tail of herpes simplex virus gB can enhance or abolish cell fusion activity and viral entry. Virology 2006; 344:17–24.

    Article  CAS  Google Scholar 

  17. Navarro D, Paz P, Tugizov S et al. Glycoprotein B of human cytomegalovirus promotes virion penetration into cells, transmission of infection from cell to cell, and fusion of infected cells. Virology 1993; 197:143–158.

    Article  PubMed  CAS  Google Scholar 

  18. Herold BC, WuDunn D, Soltys N et al. Glycoprotein C of herpes simplex virus type 1 plays a principal role in the adsorption of virus to cells and in infectivity. J Virol 1991; 65:1090–1098.

    PubMed  CAS  Google Scholar 

  19. Shieh MT, WuDunn D, Montgomery RI et al. Cell surface receptors for herpes simplex virus are heparan sulfate proteoglycans. J Cell Biol 1992; 116:1273–1281.

    Article  PubMed  CAS  Google Scholar 

  20. WuDunn D, Spear PG. Initial interaction of herpes simplex virus with cells is binding to heparan sulfate. J Virol 1989; 63:52–58.

    PubMed  CAS  Google Scholar 

  21. Cheshenko N, Herold BC. Glycoprotein B plays a predominant role in mediating herpes simplex virus type 2 attachment and is required for entry and cell-to-cell spread. J Gen Virol 2002; 83(9):2247–2255.

    PubMed  CAS  Google Scholar 

  22. Tal-Singer R, Peng C, Ponce de Leon M et al. Interaction of herpes simplex virus glycoprotein gC with mammalian cell surface molecules. J Virol 1995; 69(7):4471–4483.

    PubMed  CAS  Google Scholar 

  23. Rux AH, Lou H, Lambris JD et al. Kinetic analysis of glycoprotein C of herpes simplex virus types 1 and 2 binding to heparin, heparan sulfate, and complement component C3b. Virology 2002; 294(2):324–332.

    Article  PubMed  CAS  Google Scholar 

  24. Williams RK, Straus SE. Specificity and affinity of binding of herpes simplex virus type 2 glycoprotein B to glycosaminoglycans. J Virol 1997; 71:1375–1380.

    PubMed  CAS  Google Scholar 

  25. Laquerre S, Argnani R, Anderson DB et al. Heparan sulfate proteoglycan binding by herpes simplex virus type 1 glycoproteins B and C, which differ in their contributions to virus attachment, penetration, and cell-to-cell spread. J Virol 1998; 72:6119–6130.

    PubMed  CAS  Google Scholar 

  26. Ligas MW, Johnson DC. A herpes simplex virus mutant in which glycoprotein D sequences are replaced by β-galactosidase sequences binds to but is unable to penetrate into cells. J Virol 1988; 62:1486–1494.

    PubMed  CAS  Google Scholar 

  27. Carfi A, Willis SH, Whitbeck JC et al. Herpes simplex virus glycoprotein D bound to the human receptor HveA. Molecular Cell 2001; 8(1): 169–179.

    Article  PubMed  CAS  Google Scholar 

  28. Spear PG, Eisenberg RJ, Cohen GH. Three classes of cell surface receptors for alphaherpesvirus entry. Virology 2000; 275:1–8.

    Article  PubMed  CAS  Google Scholar 

  29. Geraghty RJ, Krummenacher C, Eisenberg RJ et al. Entry of alphaherpesviruses mediated by poliovirus receptor related protein 1 and poliovirus receptor. Science 1998; 280:1618–1620.

    Article  PubMed  CAS  Google Scholar 

  30. Cocchi F, Menotti L, Mirandola P et al. The ectodomain of a novel member of the immunoglobulin subfamily related to the poliovirus receptor has the attribute of a bona fide receptor for herpes simplex virus types 1 and 2 in human cells. J Virol 1998; 72(12):9992–10002.

    PubMed  CAS  Google Scholar 

  31. Warner MS, Martinez W, Geraghty RJ et al. A cell surface protein with herpesvirus entry activity (HveB) confers susceptibility to infection by herpes simplex virus type 2, mutants of herpes simplex virus type 1 and pseudorabies virus. Virology 1998; 246:179–189.

    Article  PubMed  CAS  Google Scholar 

  32. Lopez M, Cocchi F, Menotti L et al. Nectin2alpha (PRR2alpha or HveB) and nectin2delta are low-efficiency mediators for entry of herpes simplex virus mutants carrying the Leu25Pro substitution in glycoprotein D. J Virol 2000; 74(3):1267–1274.

    Article  PubMed  CAS  Google Scholar 

  33. Milne RSB, Connolly SA, Krummenacher C et al. Porcine HveC, a member of the highly conserved HveC/nectin 1 family, is a functional alphaherpesvirus receptor. Virology 2001; 281:315–328.

    Article  PubMed  CAS  Google Scholar 

  34. Connolly SA, Whitbeck JC, Rux AH et al. Glycoprotein D homologues in herpes simplex virus type 1, pseudorabies virus, and bovine herpes virus type 1 bind directly to human HveC (nectin-1) with different affinities. Virology 2001; 280:7–18.

    Article  PubMed  CAS  Google Scholar 

  35. Shukla D, DalCanto MC, Rowe CL et al. Striking similarity of murine nectin-1α to human nectin-1α (HveC) in sequence and activity as a gD receptor for alphaherpesvirus entry. J Virol 2000; 74:11773–11781.

    Article  PubMed  CAS  Google Scholar 

  36. Montgomery RI, Warner MS, Lum BJ et al. Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell 1996; 87:427–436.

    Article  PubMed  CAS  Google Scholar 

  37. Shukla D, Liu J, Blaiklock P et al. A novel role for 3-O-sulfated heparan sulfate in herpes simplex virus 1 entry. Cell 1999; 99:13–22.

    Article  PubMed  CAS  Google Scholar 

  38. Krummenacher C, Baribaud F, Ponce De Leon M et al. Comparative usage of herpesvirus entry mediator A and nectin-1 by laboratory strains and clinical isolates of herpes simplex virus. Virology 2004; 322(2):286–299.

    Article  PubMed  CAS  Google Scholar 

  39. Mallory S, Sommer M, Arvin AM. Mutational analysis of the role of glycoprotein I in varicella-zoster virus replication and its effects on glycoprotein E conformation and trafficking. J Virol 1997;71(11):8279–8288.

    PubMed  CAS  Google Scholar 

  40. Saldanha CE, Lubinski J, Martin C et al. Herpes simplex virus type 1 glycoprotein E domains involved in virus spread and disease. J Virol 2000; 74(15):6712–6719.

    Article  PubMed  CAS  Google Scholar 

  41. Dingwell KS, Brunetti CR, Hendricks RL et al. Herpes simplex virus glycoproteins E and I facilitate cell-to-cell spread of virus in vivo and across junctions of cultured cells. J Virol 1994; 68:834–845.

    PubMed  CAS  Google Scholar 

  42. Polcicova K, Goldsmith K, Rainish BL et al. The extracellular domain of herpes simplex virus gE is indispensable for efficient cell-to-cell spread: Evidence for gE/gI receptors. J Virol 2005; 79(18): 11990–12001.

    Article  PubMed  CAS  Google Scholar 

  43. Johnson DC, Webb M, Wisner TW et al. Herpes simplex virus gE/gI sorts nascent virions to epithelial cell junctions, promoting virus spread. J Virol 2001; 75(2):821–833.

    Article  PubMed  CAS  Google Scholar 

  44. McMillan TN, Johnson DC. Cytoplasmic domain of herpes simplex virus gE causes accumulation in the trans-Golgi network, a site of virus envelopment and sorting of virions to cell junctions. J Virol 2001; 75(4):1928–1940.

    Article  PubMed  CAS  Google Scholar 

  45. Wang F, Tang W, McGraw HM et al. Herpes simplex virus type 1 glycoprotein e is required for axonal localization of capsid, tegument, and membrane glycoproteins. J Virol 2005; 79(21): 13362–13372.

    Article  PubMed  CAS  Google Scholar 

  46. McGeoch DJ. Evolutionary relationships of virion glycoprotein genes in the S regions of alphaherpesvirus genomes. J Gen Virol 1990; 71:2361–2367.

    Article  PubMed  CAS  Google Scholar 

  47. Farnsworth A, Goldsmith K, Johnson DC. Herpes simplex virus glycoproteins gD and gE/gI serve essential but redundant functions during acquisition of the virion envelope in the cytoplasm. J Virol 2003; 77(15):8481–8494.

    Article  PubMed  CAS  Google Scholar 

  48. Wisner T, Brunetti C, Dingwell K et al. The extracellular domain of herpes simplex virus gE is sufficient for accumulation at cell junctions but not for cell-to-cell spread. J Virol 2000; 74(5):2278–2287.

    Article  PubMed  CAS  Google Scholar 

  49. Krummenacher C, Baribaud I, Eisenberg RJ et al. Cellular localization of nectin-1 and glycoprotein D during herpes simplex virus infection. J Virol 2003; 77(16):8985–8999.

    Article  PubMed  CAS  Google Scholar 

  50. Norrild B, Virtanen I, Lehto VP et al. Accumulation of herpes simplex virus type 1 glycoprotein D in adhesion areas of infected cells. J Gen Virol 1983; 64(11):2499–2503.

    Article  PubMed  CAS  Google Scholar 

  51. Mo C, Schneeberger EE, Arvin AM. Glycoprotein E of varicella-zoster virus enhances cell-cell contact in polarized epithelial cells. J Virol 2000; 74(23):11377–11387.

    Article  PubMed  CAS  Google Scholar 

  52. Dingwell KS, Johnson DC. The herpes simplex virus gE-gI complex facilitates cell-to-cell spread and binds to components of cell junctions. J Virol 1998; 72(11):8933–8942.

    PubMed  CAS  Google Scholar 

  53. Turner A, Bruun B, Minson T et al. Glycoproteins gB, gD, and gHgL of herpes simplex virus type 1 are necessary and sufficient to mediate membrane fusion in a Cos cell transfection system. J Virol 1998; 72:873–875.

    PubMed  CAS  Google Scholar 

  54. Pertel PE, Fridberg A, Parish ML et al. Cell fusion induced by herpes simplex virus glycoproteins gB, gD, and gH-gL requires a gD receptor but not necessarily heparan sulfate. Virology 2001; 279(1):313–324.

    Article  PubMed  CAS  Google Scholar 

  55. Muggeridge MI. Characterization of cell-cell fusion mediated by herpes simplex virus 2 glycoproteins gB, gD, gH and gL in transfected cells. J Gen Virol 2000; 81(8):2017–2027.

    PubMed  CAS  Google Scholar 

  56. Heldwein EE, Lou H, Whitbeck JC et al. Crystal structure of the ectodomain of HSV-1 glycoprotein B reveals an elongated trimer. Turku, Finland: 30th International Herpesvirus Workshop, 2005.

    Google Scholar 

  57. Hutchinson L, Browne H, Wargent V et al. A novel herpes simplex virus glycoprotein, gL, forms a complex with glycoprotein H (gH) and affects normal folding and surface expression of gH. J Virol 1992; 66:2240–2250.

    PubMed  CAS  Google Scholar 

  58. Peng T, Ponce de Leon M, Novotny MJ et al. Structural and antigenic analysis of a truncated form of the herpes simplex virus glycoprotein gH-gL complex. J Virol 1998; 72(7):6092–6103.

    PubMed  CAS  Google Scholar 

  59. Duus KM, Hatfield C, Grose C. Cell surface expression and fusion by the varicella-zoster virus gH:gL glycoprotein complex: Analysis by laser scanning confocal microscopy. Virology 1995; 210(2):429–440.

    Article  PubMed  CAS  Google Scholar 

  60. Bender FC, Whitbeck JC, Lou H et al. Herpes simplex virus glycoprotein B binds to cell surfaces independently of heparan sulfate and blocks virus entry. J Virol 2005; 79(18):11588–11597.

    Article  PubMed  CAS  Google Scholar 

  61. Parry C, Bell S, Minson T et al. Herpes simplex virus type 1 glycoprotein H binds to alphavbeta3 integrins. J Gen Virol 2005; 86(1):7–10.

    Article  PubMed  CAS  Google Scholar 

  62. Jones TR, Lee SW, Johann SV et al. Specific inhibition of human cytomegalovirus glycoprotein B-mediated fusion by a novel thiourea small molecule. J Virol 2004; 78(3): 1289–1300.

    Article  PubMed  CAS  Google Scholar 

  63. Britt WJ, Vugler LG. Processing of the gp55-116 envelope glycoprotein complex (gB) of human cytomegalovirus. J Virol 1989; 63:403–410.

    PubMed  CAS  Google Scholar 

  64. Colman PM, Lawrence MC. The structural biology of type I viral membrane fusion. Nat Rev Mol Cell Biol 2003; 4(4):309–319.

    Article  PubMed  CAS  Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  66. Feire AL, Koss H, Compton T. Cellular integrins function as entry receptors for human cytomegalovirus via a highly conserved disintegrin-like domain. Proc Natl Acad Sci USA 2004; 101(43): 15470–15475.

    Article  PubMed  CAS  Google Scholar 

  67. Wang X, Huong SM, Chiu ML et al. Epidermal growth factor receptor is a cellular receptor for human cytomegalovirus. Nature 2003; 424:456–461.

    Article  PubMed  CAS  Google Scholar 

  68. Wang X, Huang DY, Huong SM et al. Integrin alphavbeta3 is a coreceptor for human cytomegalovirus. Nat Med 2005; 11(5):515–521.

    Article  PubMed  CAS  Google Scholar 

  69. Tugizov S, Navarro D, Paz P et al. Function of human cytomegalovirus glycoprotein B: Syncytium formation in cells constitutively expressing gB is blocked by virus-neutralizing antibodies. Virology 1994;201(2):263–276.

    Article  PubMed  CAS  Google Scholar 

  70. Kinzler ER, Compton T. Characterization of human cytomegalovirus glycoprotein-induced cell-cell fusion. J Virol 2005; 79(12):7827–7837.

    Article  PubMed  CAS  Google Scholar 

  71. Huber MT, Compton T. The human cytomegalovirus UL74 gene encodes the third component of the glycoprotein H-glycoprotein L-containing envelope complex. J Virol 1998; 72(10):8191–8197.

    PubMed  CAS  Google Scholar 

  72. Akkapaiboon P, Mori Y, Sadaoka T et al. Intracellular processing of human herpesvirus 6 glycoproteins Q1 and Q2 into tetrameric complexes expressed on the viral envelope. J Virol 2004; 78(15):7969–7983.

    Article  PubMed  CAS  Google Scholar 

  73. Mori Y, Akkapaiboon P, Yang X et al. The human herpesvirus 6 U100 gene product is the third component of the gH-gL glycoprotein complex on the viral envelope. J Virol 2003; 77(4):2452–2458.

    Article  PubMed  CAS  Google Scholar 

  74. Mori Y, Akkapaiboon P, Yonemoto S et al. Discovery of a second form of tripartite complex containing gH-gL of human herpesvirus 6 and observations on CD46. J Virol 2004; 78(9):4609–4616.

    Article  PubMed  CAS  Google Scholar 

  75. Mori Y, Yang X, Akkapaiboon P et al. Human herpesvirus 6 variant A glycoprotein H-glycoprotein L-glycoprotein Q complex associates with human CD46. J Virol 2003; 77(8):4992–4999.

    Article  PubMed  CAS  Google Scholar 

  76. Santoro F, Greenstone HL, Insinga A et al. Interaction of glycoprotein H of human herpesvirus 6 with the cellular receptor CD46. J Biol Chem 2003; 278(28):25964–25969.

    Article  PubMed  CAS  Google Scholar 

  77. Santoro F, Kennedy PE, Locatelli G et al. CD46 is a cellular receptor for human herpesvirus 6. Cell 1999; 99(7):817–827.

    Article  PubMed  CAS  Google Scholar 

  78. Secchiero P, Sun D, De Vico AL et al. Role of the extracellular domain of human herpesvirus 7 glycoprotein B in virus binding to cell surface heparan sulfate proteoglycans. J Virol 1997; 71(6):4571–4580.

    PubMed  CAS  Google Scholar 

  79. Lusso P, Secchiero P, Crowley RW et al. CD4 is a critical component of the receptor for human herpesvirus 7: Interference with human immunodeficiency virus. Proc Natl Acad Sci USA 1994; 91:3872–3876.

    Article  PubMed  CAS  Google Scholar 

  80. Nemerow GR, Wolfert R, McNaughton ME et al. Identification and characterization of the Epstein-Barr virus receptor on human B lymphocytes and its relationship to the C3d complement receptor (CR2). J Virol 1985; 55(2):347–351.

    PubMed  CAS  Google Scholar 

  81. Tugizov SM, Berline JW, Palefsky JM. Epstein-Barr virus infection of polarized tongue and nasopharyngeal epithelial cells. Nat Med 2003; 9(3):307–314.

    Article  PubMed  CAS  Google Scholar 

  82. Li Q, Spriggs MK, Kovats S et al. Epstein-Barr virus uses HLA class II as a cofactor for infection of B lymphocytes. J Virol 1997; 71(6):4657–4662.

    PubMed  CAS  Google Scholar 

  83. Haan KM, Kwok WW, Longnecker R et al. Epstein-Barr virus entry utilizing HLA-DP or HLA-DQ as a coreceptor. J Virol 2000; 74(5):2451–2444.

    Article  PubMed  CAS  Google Scholar 

  84. Mullen MM, Haan KM, Longnecker R et al. Structure of the Epstein-Barr virus gp42 protein bound to the MHC class II receptor HLA-DR1. Mol Cell 2002; 9(2):375–385.

    Article  PubMed  CAS  Google Scholar 

  85. Wang X, Hutt-Fletcher LM. Epstein-Barr virus lacking glycoprotein gp42 can bind to B cells but is not able to infect. J Virol 1998; 72:158–163.

    PubMed  CAS  Google Scholar 

  86. Li Q, Turk SM, Hutt-Fletcher LM. The Epstein-Barr virus (EBV) BZLF2 gene product associates with the gH and gL homologs of EBV and carries an epitope critical to infection of B cells but not of epithelial cells. J Virol 1995; 69(7):3987–3994.

    PubMed  CAS  Google Scholar 

  87. Borza CM, Morgan AJ, Turk SM et al. Use of gHgL for attachment of Epstein-Barr virus to epithelial cells compromises infection. J Virol 2004; 78(10):5007–5014.

    Article  PubMed  CAS  Google Scholar 

  88. Molesworth SJ, Lake CM, Borza CM et al. Epstein-Barr virus gH is essential for penetration of B cells but also plays a role in attachment of virus to epithelial cells. J Virol 2000; 74(14):6324–6332.

    Article  PubMed  CAS  Google Scholar 

  89. Wang X, Kenyon WJ, Li Q et al. Epstein-Barr virus uses different complexes of glycoproteins gH and gL to infect B lymphocytes and epithelial cells. J Virol 1998; 72(7):5552–5558.

    PubMed  CAS  Google Scholar 

  90. Borza CM, Hutt-Fletcher LM. Alternate replication in B cells and epithelial cells switches tropism of Epstein-Barr virus. Nat Med 2002; 8(6):594–599.

    Article  PubMed  CAS  Google Scholar 

  91. Wang FZ, Akula SM, Pramod NP et al. Human herpesvirus 8 envelope glycoprotein K8.1A interaction with the target cells involves heparan sulfate. J Virol 2001; 75(16):7517–7527.

    Article  PubMed  CAS  Google Scholar 

  92. Birkmann A, Mahr K, Ensser A et al. Cell surface heparan sulfate is a receptor for human herpesvirus 8 and interacts with envelope glycoprotein K8.1. J Virol 2001; 75(23): 11583–11593.

    Article  PubMed  CAS  Google Scholar 

  93. Pertel PE. Human herpesvirus 8 glycoprotein B (gB), gH, and gL can mediate cell fusion. J Virol 2002; 76(9):4390–4400.

    Article  PubMed  CAS  Google Scholar 

  94. Wang FZ, Akula SM, Sharma-Walia N et al. Human herpesvirus 8 envelope glycoprotein B mediates cell adhesion via its RGD sequence. J Virol 2003; 77(5):3131–3147.

    Article  PubMed  CAS  Google Scholar 

  95. Akula SM, Pramod NP, Wang FZ et al. Integrin alpha3beta1 (CD 49c/29) is a cellular receptor for Kaposi’s sarcoma-associated herpesvirus (KSHV/HHV-8) entry into the target cells. Cell 2002; 108(3):407–419.

    Article  PubMed  CAS  Google Scholar 

  96. Kaleeba JAR, Berger EA. Kaposi’s sarcoma-associated herpesvirus fusion-entry receptor: Cystine transporter xCT. Science 2006; 311:1921–1924.

    Article  PubMed  CAS  Google Scholar 

  97. Ryckman BJ, Jarvis MA, Drummond DD et al. Human cytomegalovirus entry into epithelial and endothelial cells depends on genes UL128 to UL150 and occurs by endocytosis and low-pH fusion. J Virol 2006; 80(2):710–722.

    Article  PubMed  CAS  Google Scholar 

  98. Compton T, Nepomuceno RR, Nowlin DM. Human cytomegalovirus penetrates host cells by pH-independent fusion at the cell surface. Virology 1992; 191(1):387–395.

    Article  PubMed  CAS  Google Scholar 

  99. Miller N, Hutt-Fletcher LM. Epstein-Barr virus enters B cells and epithelial cells by different routes. J Virol 1992; 66(6):3409–3414.

    PubMed  CAS  Google Scholar 

  100. Tanner J, Weis J, Fearon D et al. Epstein-Barr virus gp350/220 binding to the B lymphocyte C3d receptor mediates adsorption, capping, and endocytosis. Cell 1987; 50:203–213.

    Article  PubMed  CAS  Google Scholar 

  101. Akula SM, Naranatt PP, Walia NS et al. Kaposi’s sarcoma-associated herpesvirus (human herpesvirus 8) infection of human fibroblast cells occurs through endocytosis. J Virol 2003; 77(14):7978–7990.

    Article  PubMed  CAS  Google Scholar 

  102. Nicola AV, Straus SE. Cellular and viral requirements for rapid endocytic entry of herpes simplex virus. J Virol 2004; 78(14):7508–7517.

    Article  PubMed  CAS  Google Scholar 

  103. Milne RS, Nicola AV, Whitbeck JC et al. Glycoprotein D receptor-dependent, low-pH-independent endocytic entry of herpes simplex virus type 1. J Virol 2005; 79(11):6655–6663.

    Article  PubMed  CAS  Google Scholar 

  104. Nicola AV, McEvoy AM, Straus SE. Roles for endocytosis and low pH in herpes simplex virus entry into HeLa and Chinese hamster ovary cells. J Virol 2003; 77(9):5324–5332.

    Article  PubMed  CAS  Google Scholar 

  105. Wittels M, Spear PG. Penetration of cells by herpes simplex virus does not require a low pH-dependent endocytic pathway. Virus Res 1990; 18:271–290.

    Article  Google Scholar 

  106. Granzow H, Weiland F, Jons A et al. Ultrastructural analysis of the replication cycle of pseudorabies virus in cell culture: A reassessment. J Virol 1997; 71(3):2072–2082.

    PubMed  CAS  Google Scholar 

  107. Long D, Wilcox WC, Abrams WR et al. Disulfide bond structure of glycoprotein D of herpes simplex virus types 1 and 2. J Virol 1992; 66:6668–6685.

    PubMed  CAS  Google Scholar 

  108. Krummenacher C, Supekar VM, Whitbeck JC et al. Structure of HSV gD in the prereceptor binding conformation reveals a mechanism for receptor-mediated activation of virus entry. EMBO J 2005; 24(23):4144–4153.

    Article  PubMed  CAS  Google Scholar 

  109. Chiang HY, Cohen GH, Eisenberg RJ. Identification of functional regions of herpes simplex virus glycoprotein gD by using linker-insertion mutagenesis. J Virol 1994; 68:2529–2543.

    PubMed  CAS  Google Scholar 

  110. Connolly SA, Landsburg DJ, Carfi A et al. Potential nectin-1 binding site on herpes simplex virus glycoprotein D. Journal of Virology 2005; 79(2): 1282–1295.

    Article  PubMed  CAS  Google Scholar 

  111. Terry-Allison T, Montgomery RI, Warner MS et al. Contributions of gD receptors and glycosaminoglycan sulfation to cell fusion mediated by herpes simplex virus 1. Virus Res 2001; 74(1–2):39–45.

    Article  PubMed  CAS  Google Scholar 

  112. Cocchi F, Menotti L, Dubreuil P et al. Cell-to-cell spread of wild-type herpes simplex virus type 1, but not of syncytial strains, is mediated by the immunoglobulin-like receptors that mediate virion entry, nectin1 (PRR1/HveC/HIgR) and nectin2 (PRR2/HveB). J Virol 2000; 74(8):3909–3917.

    Article  PubMed  CAS  Google Scholar 

  113. Shukla D, Spear PG. Herpesviruses and heparan sulfate: An intimate relationship in aid of viral entry. J Clin Invest 2001; 108(4):503–510.

    PubMed  CAS  Google Scholar 

  114. Whitbeck JC, Peng C, Lou H et al. Glycoprotein D of herpes simplex virus (HSV) binds directly to HVEM, a member of the TNFR superfamily and amediator of HSV entry. J Virol 1997; 71(8):6083–6093.

    PubMed  CAS  Google Scholar 

  115. Krummenacher C, Nicola AV, Whitbeck JC et al. Herpes simplex virus glycoprotein D can bind to poliovirus receptor-related protein 1 or herpesvirus entry mediator, two structurally unrelated mediators of virus entry. J Virol 1998; 72:7064–7074.

    PubMed  CAS  Google Scholar 

  116. Liu J, Shriver Z, Pope RM et al. Characterization of a heparan sulfate octasaccharide that binds to herpes simplex virus type 1 glycoprotein D. J Biol Chem 2002; 277(36):33456–33467.

    Article  PubMed  CAS  Google Scholar 

  117. Whitbeck JC, Connolly SA, Willis SH et al. Localization of the gD-binding region of the human herpes simplex virus receptor, HveA. J Virol 2001; 75:171–180.

    Article  PubMed  CAS  Google Scholar 

  118. Connolly SA, Landsburg DJ, Carfi A et al. Structure-based analysis of the herpes simplex virus glycoprotein D binding site present on herpesvirus entry mediator HveA(HVEM). J Virol 2002; 76:10894–10904.

    Article  PubMed  CAS  Google Scholar 

  119. Connolly SA, Landsburg DJ, Carfi A et al. Structure-based mutagenesis of herpes simplex virus glycoprotein D defines three critical regions at the gD/HveA interface. J Virol 2003; 77(14):8127–8140.

    Article  PubMed  CAS  Google Scholar 

  120. Compaan DM, Gonzalez LC, Tom I et al. Attenuating lymphocyte activity: The crystal structure of the BTLA-HVEM complex. J Biol Chem 2005; 280(47):39553–39561.

    Article  PubMed  CAS  Google Scholar 

  121. Mauri DN, Ebner R, Kochel KD et al. LIGHT, a new member of the TNF superfamily, and lymphotoxin (LT) α are ligands for herpesvirus entry mediator (HVEM). Immunity 1998; 8:21–30.

    Article  PubMed  CAS  Google Scholar 

  122. Croft M. The evolving crosstalk between costimulatory and coinhibitory receptors: HVEM-BTLA. Trends Immunol 2005; 26(6):292–294.

    Article  PubMed  CAS  Google Scholar 

  123. Sakisaka T, Takai Y. Biology and pathology of nectins and nectin-like molecules. Curr Opin Cell Biol 2004; 16(5):513–521.

    Article  PubMed  CAS  Google Scholar 

  124. Takai Y, Irie K, Shimizu K et al. Nectins and nectin-like molecules: Roles in cell adhesion, migration, and polarization. Cancer Sci 2003; 94(8):655–667.

    Article  PubMed  CAS  Google Scholar 

  125. Cocchi F, Lopez M, Menotti L et al. The V domain of herpesvirus Ig-like receptor (HIgR) contains a major functional region in herpes simplex virus-1 entry into cells and interacts physically with the viral glycoprotein D. Proc Natl Acad Sci USA 1998; 95:15700–15705.

    Article  PubMed  CAS  Google Scholar 

  126. Krummenacher C, Rux AH, Whitbeck JC et al. The first immunoglobulin-like domain of HveC is sufficient to bind herpes simplex virus gD with full affinity while the third domain is involved in oligomerization of HveC. J Virol 1999; 73:8127–8137.

    PubMed  CAS  Google Scholar 

  127. Krummenacher C, Baribaud I, Ponce de Leon M et al. Localization of a binding site for herpes simplex virus glycoprotein D on the herpesvirus entry mediator C by using anti-receptor monoclonal antibodies. J Virol 2000; 74:10863–10872.

    Article  PubMed  CAS  Google Scholar 

  128. Martinez WM, Spear PG. Amino acid substitutions in the V domain of nectin-1 (HveC) that impair entry activity for herpes simplex virus types 1 and 2 but not for Pseudorabies virus or bovine herpesvirus 1. J Virol 2002; 76(14):7255–7262.

    Article  PubMed  CAS  Google Scholar 

  129. Geraghty RJ, Fridberg A, Krummenacher C et al. Use of chimeric nectin-1(HveC)-related receptors to demonstrate that ability to bind alphaherpesvirus gD is not necessarily sufficient for viral entry. Virology 2001; 285:366–375.

    Article  PubMed  CAS  Google Scholar 

  130. Struyf F, Plate AE, Spear PG. Deletion of the second immunoglobulin-like domain of nectin-1 alters its intracellular processing and localization and ability to mediate entry of herpes simplex virus. J Virol 2005; 79(6):3841–3845.

    Article  PubMed  CAS  Google Scholar 

  131. Manoj S, Jogger CR, Myscofski D et al. Mutations in herpes simplex virus glycoprotein D that prevent cell entry via nectins and alter cell tropism. Proc Natl Acad Sci USA 2004; 101(34): 12414–12421.

    Article  PubMed  CAS  Google Scholar 

  132. Krummenacher C, Baribaud I, Sanzo JF et al. Effects of herpes simplex virus on structure and function of nectin-1/HveC. J Virol 2002; 76(5):2424–2433.

    Article  PubMed  CAS  Google Scholar 

  133. Sakisaka T, Taniguchi T, Nakanishi H et al. Requirement of interaction of nectin-1alpha/HveC with afadin for efficient cell-cell spread of herpes simplex virus type 1. J Virol 2001; 75(10):4734–4743.

    Article  PubMed  CAS  Google Scholar 

  134. Yoon M, Spear PG. Disruption of adherens junctions liberates nectin-1 to serve as receptor for herpes simplex virus and pseudorabies virus entry. J Virol 2002; 76(14):7203–7208.

    Article  PubMed  CAS  Google Scholar 

  135. O’Donnell CD, Tiwari V, Oh MJ et al. A role for heparan sulfate 3-O-sulfotransferase isoform 2 in herpes simplex virus type 1 entry and spread. Virology 2006; 346(2):452–459.

    Article  CAS  Google Scholar 

  136. Tiwari V, O’Donnell CD, Oh MJ et al. A role for 3-O-sulfotransferase isoform-4 in assisting HSV-1 entry and spread. Biochem Biophys Res Commun 2005; 338(2):930–937.

    Article  PubMed  CAS  Google Scholar 

  137. Xu D, Tiwari V, Xia G et al. Characterization of heparan sulphate 3-O-sulphotransferase isoform 6 and its role in assisting the entry of herpes simplex virus type 1. Biochem J 2005; 385(2):451–459.

    Article  PubMed  CAS  Google Scholar 

  138. Xia G, Chen J, Tiwari V et al. Heparan sulfate 3-O-sulfotransferase isoform 5 generates both an antithrombin-binding site and an entry receptor for herpes simplex virus, type 1. J Biol Chem 2002; 277(40):37912–37919.

    Article  PubMed  CAS  Google Scholar 

  139. Akhtar J, Shukla D. Viral entry mechanisms: cellular and viral mediators of herpes simplex virus entry. FEBS J 2009; 276(24):7228–7236.

    Article  PubMed  CAS  Google Scholar 

  140. Milne RSB, Hanna SL, Rux AH et al. Function of herpes simplex virus type 1 gD mutants with different receptor-binding affinities in virus entry and fusion. J Virol 2003; 77(16):8962–8972.

    Article  PubMed  CAS  Google Scholar 

  141. Rux AH, Willis SH, Nicola AV et al. Functional region IV of glycoprotein D from herpes simplex virus modulates glycoprotein binding to the herpes virus entry mediator. J Virol 1998; 72:7091–7098.

    PubMed  CAS  Google Scholar 

  142. Jogger CR, Montgomery RI, Spear PG. Effects of linker-insertion mutations in herpes simplex virus 1 gD on glycoprotein-induced fusion with cells expressing HVEM or nectin-1. Virology 2004;318(1):318–326.

    Article  PubMed  CAS  Google Scholar 

  143. Willis SH, Rux AH, Peng C et al. Examination of the kinetics of herpes simplex virus glycoprotein D binding to the herpesvirus entry mediator, using surface plasmon resonance. J Virol 1998; 72(7):5937–5947.

    PubMed  CAS  Google Scholar 

  144. Minson AC, Hodgman TC, Digard P et al. An analysis of the biological properties of monoclonal antibodies against glycoprotein D of herpes simplex virus and identification of amino acid substitutions that confer resistance to neutralization. J Gen Virol 1986; 67:1001–1013.

    Article  PubMed  CAS  Google Scholar 

  145. Handler CG, Eisenberg RJ, Cohen GH. Oligomeric structure of glycoproteins in herpes simplex virus type 1. J Virol 1996; 70:6067–6075.

    PubMed  CAS  Google Scholar 

  146. Yoon M, Zago A, Shukla D et al. Mutations in the N termini of herpes simplex virus type 1 and 2 gDs alter functional interactions with the entry/fusion receptors HVEM, Nectin-2, and 3-O-sulfated heparan sulfate but not with Nectin-1. J Virol 2003; 77(17):9221–9231.

    Article  PubMed  CAS  Google Scholar 

  147. Whitbeck JC, Muggeridge MI, Rux A et al. The major neutralizing antigenic site on herpes simplex virus glycoprotein D overlaps a receptor-binding domain. J Virol 1999; 73:9879–9890.

    PubMed  CAS  Google Scholar 

  148. Fusco D, Forghieri C, Campadelli-Fiume G. The pro-fusion domain of herpes simplex virus glycoprotein D (gD) interacts with the gD N terminus and is displaced by soluble forms of viral receptors. Proc Natl Acad Sci USA 2005; 102(26):9323–9328.

    Article  PubMed  CAS  Google Scholar 

  149. Zago A, Jogger CR, Spear PG. Use of herpes simplex virus and pseudorabies virus chimeric glycoprotein D molecules to identify regions critical for membrane fusion. Proc Natl Acad Sci USA 2004; 101(50):17498–17503.

    Article  PubMed  CAS  Google Scholar 

  150. Lavillette D, Maurice M, Roche C et al. A proline-rich motif downstream of the receptor binding domain modulates conformation and fusogenicity of murine retroviral envelopes. J Virol 1998;72(12):9955–9965.

    PubMed  CAS  Google Scholar 

  151. Whitbeck JC, Zuo Y, Milne RSB et al. Stable association of herpes simplex virus with target membrane is triggered by low pH in the presence of the gD receptor HVEM. J Virol 2006; 80:3773–3780.

    Article  PubMed  CAS  Google Scholar 

  152. Di Giovine P, Settembre EC, Bhargava AK et al. Structure of herpes simplex virus glycoprotein D bound to the human receptor nectin-1. PLoS Pathog 2011; 7:e1002277.

    Article  PubMed  CAS  Google Scholar 

  153. Kirschner AN, Sorem J, Longnecker R et al. Structure of Epstein-Barr virus glycoprotein 42 suggests a mechanism for triggering receptor-activated virus entry. Structure 2009; 17:223–233.

    Article  PubMed  CAS  Google Scholar 

  154. Backovic M, Longnecker R, Jardetzky TS. Structure of a trimeric variant of the Epstein-Barr virus glycoprotein B. Proc Natl Acad Sci USA 2009; 106:2880–2885.

    Article  PubMed  CAS  Google Scholar 

  155. Heldwein EE, Lou H, Bender FC et al. Crystal structure of glycoprotein B from herpes simplex virus 1. Science 2006; 313:217–220.

    Article  PubMed  CAS  Google Scholar 

  156. Chowdary TK, Cairns TM, Atanasiu D et al. Crystal structure of the conserved herpesvirus fusion regulator complex gH-gL. Nat Struct Mol Biol 2010; 17:882–8.

    Article  PubMed  CAS  Google Scholar 

  157. Backovic M, DuBois RM, Cockburn JJ et al. Structure of a core fragment of glycoprotein H from pseudorabies virus in complex with antibody. Proc Natl Acad Sci USA 2010; 107:22635–22640.

    Article  PubMed  CAS  Google Scholar 

  158. Matsuura H, Kirschner AN, Longnecker R et al. Crystal structure of the Epstein-Barr virus (EBV) glycoprotein H/glycoprotein L (gH/gL) complex. Proc Natl Acad Sci USA 2010; 107:22641–22646.

    Article  PubMed  CAS  Google Scholar 

  159. Heldwein EE, Krummenacher C. Entry of herpesviruses into mammalian cells. Cell Mol Life Sci 2008; 65:1653–1668.

    Article  PubMed  CAS  Google Scholar 

  160. Eisenberg RJ, Atanasiu D, Cairns TM et al. Herpes virus fusion and entry: a story with many characters. Viruses 2012; 4:800–832.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Claude Krummenacher .

Editor information

Editors and Affiliations

Rights and permissions

Reprints and permissions

Copyright information

© 2013 Landes Bioscience and Springer Science+Business Media

About this chapter

Cite this chapter

Krummenacher, C., Carfí, A., Eisenberg, R.J., Cohen, G.H. (2013). Entry of Herpesviruses into Cells: The Enigma Variations. In: Pöhlmann, S., Simmons, G. (eds) Viral Entry into Host Cells. Advances in Experimental Medicine and Biology, vol 790. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-7651-1_10

Download citation

Publish with us

Policies and ethics