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First Impressions—the Potential of Altering Initial Host-Virus Interactions for Rational Design of Herpesvirus Vaccine Vectors

  • Recent Developments in Anti-viral Vaccines (K Kousoulas and P Rider, Section Editors)
  • Published:
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Abstract

Purpose of Review

The earliest host-virus interactions occur during virus attachment and entry into cells. These initial steps in the virus lifecycle influence the outcome of infection beyond delivery of the viral genome into the cell. Herpesviruses alter host signaling pathways and processes during attachment and entry to facilitate virus infection and modulate innate immune responses. We suggest in this review that understanding these early events may inform the rational design of therapeutic and prevention strategies for herpesvirus infection, as well as the engineering of viral vectors for immunotherapy purposes.

Recent Findings

Recent reports demonstrate that modulation of herpes simplex virus type-1 (HSV-1) entry results in unexpected enhancement of anti-viral immune responses.

Summary

A variety of evidence suggests that herpesviruses promote specific cellular signaling responses that facilitate viral replication after binding to cell surfaces, as well as during virus entry. Of particular interest is the ability of the virus to alter innate immune responses through these cellular signaling events. Uncovering the underlying immune evasion strategies may lead to the design of live-attenuated vaccines that can generate robust and protective anti-viral immune responses against herpesviruses. These adjuvant properties may be extended to a variety of heterologous antigens expressed by herpesviral vectors.

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References

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Roizman B, Knipe D, Whitley RJ. Herpes simplex viruses. In: HP KDM, editor. Fields Virology. 6th ed. Philadelphia: Lippincott Williams & Wilkins; 2013. p. 1823–97.

    Google Scholar 

  2. Looker KJ, Magaret AS, May MT, Turner KM, Vickerman P, Gottlieb SL, et al. Global and regional estimates of prevalent and incident herpes simplex virus type 1 infections in 2012. PLoS One. 2015;10(10):e0140765. https://doi.org/10.1371/journal.pone.0140765.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  3. Looker KJ, Magaret AS, Turner KM, Vickerman P, Gottlieb SL, Newman LM. Global estimates of prevalent and incident herpes simplex virus type 2 infections in 2012. PLoS One. 2015;10(1):e114989. https://doi.org/10.1371/journal.pone.0114989.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  4. Pottage JC Jr, Kessler HA. Herpes simplex virus resistance to acyclovir: clinical relevance. Infect Agents Dis. 1995;4(3):115–24.

    CAS  PubMed  Google Scholar 

  5. Castelo-Soccio L, Bernardin R, Stern J, Goldstein SA, Kovarik C. Successful treatment of acyclovir-resistant herpes simplex virus with intralesional cidofovir. Arch Dermatol. 2010;146(2):124–6. https://doi.org/10.1001/archdermatol.2009.363.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Kemble G, Spaete R. Herpes simplex vaccines. In: Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, Whitley R, et al., editors. Human herpesviruses: biology, therapy, and immunoprophylaxis. Cambridge: Cambridge University Press; 2007. http://www.ncbi.nlm.nih.gov/pubmed/21348132.

  7. Stanfield B, Kousoulas KG. Herpes simplex vaccines: prospects of live-attenuated HSV vaccines to combat genital and ocular infections. Curr Clin Microbiol Rep. 2015;2(3):125–36. https://doi.org/10.1007/s40588-015-0020-4.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Gianni T, Leoni V, Chesnokova LS, Hutt-Fletcher LM, Campadelli-Fiume G. Alphavbeta3-integrin is a major sensor and activator of innate immunity to herpes simplex virus-1. Proc Natl Acad Sci U S A. 2012;109(48):19792–7. https://doi.org/10.1073/pnas.1212597109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Paludan SR, Bowie AG, Horan KA, Fitzgerald KA. Recognition of herpesviruses by the innate immune system. Nat Rev Immunol. 2011;11(2):143–54. https://doi.org/10.1038/nri2937.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Casiraghi C, Gianni T, Campadelli-Fiume G. Alphavbeta3 integrin boosts the innate immune response elicited in epithelial cells through plasma membrane and endosomal toll-like receptors. J Virol. 2016;90(8):4243–8. https://doi.org/10.1128/JVI.03175-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Cai M, Li M, Wang K, Wang S, Lu Q, Yan J, et al. The herpes simplex virus 1-encoded envelope glycoprotein B activates NF-kappaB through the toll-like receptor 2 and MyD88/TRAF6-dependent signaling pathway. PLoS One. 2013;8(1):e54586. https://doi.org/10.1371/journal.pone.0054586.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Kim M, Osborne NR, Zeng W, Donaghy H, McKinnon K, Jackson DC, et al. Herpes simplex virus antigens directly activate NK cells via TLR2, thus facilitating their presentation to CD4 T lymphocytes. J Immunol. 2012;188(9):4158–70. https://doi.org/10.4049/jimmunol.1103450.

    Article  CAS  PubMed  Google Scholar 

  13. Holm CK, Jensen SB, Jakobsen MR, Cheshenko N, Horan KA, Moeller HB, et al. Virus-cell fusion as a trigger of innate immunity dependent on the adaptor STING. Nat Immunol. 2012;13(8):737–43. https://doi.org/10.1038/ni.2350.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Stevenson EV, Collins-McMillen D, Kim JH, Cieply SJ, Bentz GL, Yurochko AD. HCMV reprogramming of infected monocyte survival and differentiation: a goldilocks phenomenon. Viruses. 2014;6(2):782–807. https://doi.org/10.3390/v6020782.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  15. Yurochko AD. Human cytomegalovirus modulation of signal transduction. Curr Top Microbiol Immunol. 2008;325:205–20.

    CAS  PubMed  Google Scholar 

  16. Kurt-Jones EA, Orzalli MH, Knipe DM. Innate immune mechanisms and herpes simplex virus infection and disease. Adv Anat Embryol Cell Biol. 2017;223:49–75. https://doi.org/10.1007/978-3-319-53168-7_3.

    Article  PubMed  Google Scholar 

  17. McCormick AL, Mocarski ES Jr. Viral modulation of the host response to infection. In: Arvin A, Campadelli-Fiume G, Mocarski E, Moore PS, Roizman B, Whitley R, et al., editors. Human Herpesviruses: Biology, Therapy, and Immunoprophylaxis. Cambridge: Cambridge University Press; 2007. http://www.ncbi.nlm.nih.gov/pubmed/21348102.

  18. Medici MA, Sciortino MT, Perri D, Amici C, Avitabile E, Ciotti M, et al. Protection by herpes simplex virus glycoprotein D against Fas-mediated apoptosis: role of nuclear factor kappaB. J Biol Chem. 2003;278(38):36059–67. https://doi.org/10.1074/jbc.M306198200.

    Article  CAS  PubMed  Google Scholar 

  19. Liu X, Fitzgerald K, Kurt-Jones E, Finberg R, Knipe DM. Herpesvirus tegument protein activates NF-kappaB signaling through the TRAF6 adaptor protein. Proc Natl Acad Sci U S A. 2008;105(32):11335–9. https://doi.org/10.1073/pnas.0801617105.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Campadelli-Fiume G, Collins-McMillen D, Gianni T, Yurochko AD. Integrins as herpesvirus receptors and mediators of the host signalosome. Annu Rev Virol. 2016;3(1):215–36. https://doi.org/10.1146/annurev-virology-110615-035618.

    Article  CAS  PubMed  Google Scholar 

  21. Chan G, Nogalski MT, Stevenson EV, Yurochko AD. Human cytomegalovirus induction of a unique signalsome during viral entry into monocytes mediates distinct functional changes: a strategy for viral dissemination. J Leukoc Biol. 2012;92(4):743–52. https://doi.org/10.1189/jlb.0112040.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Azab W, Osterrieder K. Initial contact: the first steps in herpesvirus entry. Adv Anat Embryol Cell Biol. 2017;223:1–27. https://doi.org/10.1007/978-3-319-53168-7_1.

    Article  PubMed  Google Scholar 

  23. Eisenberg RJ, Atanasiu D, Cairns TM, Gallagher JR, Krummenacher C, Cohen GH. Herpes virus fusion and entry: a story with many characters. Viruses. 2012;4(5):800–32. https://doi.org/10.3390/v4050800.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  24. Heldwein EE, Krummenacher C. Entry of herpesviruses into mammalian cells. Cell Mol Life Sci. 2008;65(11):1653–68. https://doi.org/10.1007/s00018-008-7570-z.

    Article  CAS  PubMed  Google Scholar 

  25. Turner A, Bruun B, Minson T, Browne H. 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(1):873–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Ruyechan WT, Morse LS, Knipe DM, Roizman B. Molecular genetics of herpes simplex virus. II. Mapping of the major viral glycoproteins and of the genetic loci specifying the social behavior of infected cells. J Virol. 1979;29(2):677–97.

    CAS  PubMed  PubMed Central  Google Scholar 

  27. Dolter KE, Ramaswamy R, Holland TC. Syncytial mutations in the herpes simplex virus type 1 gK (UL53) gene occur in two distinct domains. J Virol. 1994;68(12):8277–81.

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Bond VC, Person S, Warner SC. The isolation and characterization of mutants of herpes simplex virus type 1 that induce cell fusion. J Gen Virol. 1982;61(Pt 2):245–54. https://doi.org/10.1099/0022-1317-61-2-245.

    Article  CAS  PubMed  Google Scholar 

  29. Read GS, Person S, Keller PM. Genetic studies of cell fusion induced by herpes simplex virus type 1. J Virol. 1980;35(1):105–13.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Pogue-Geile KL, Spear PG. The single base pair substitution responsible for the Syn phenotype of herpes simplex virus type 1, strain MP. Virology. 1987;157(1):67–74. https://doi.org/10.1016/0042-6822(87)90314-X.

    Article  CAS  PubMed  Google Scholar 

  31. Avitabile E, Lombardi G, Gianni T, Capri M, Campadelli-Fiume G. Coexpression of UL20p and gK inhibits cell-cell fusion mediated by herpes simplex virus glycoproteins gD, gH-gL, and wild-type gB or an endocytosis-defective gB mutant and downmodulates their cell surface expression. J Virol. 2004;78(15):8015–25. https://doi.org/10.1128/JVI.78.15.8015-8025.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Agelidis AM, Shukla D. Cell entry mechanisms of HSV: what we have learned in recent years. Futur Virol. 2015;10(10):1145–54. https://doi.org/10.2217/fvl.15.85.

    Article  CAS  Google Scholar 

  33. Nicola AV, Hou J, Major EO, Straus SE. Herpes simplex virus type 1 enters human epidermal keratinocytes, but not neurons, via a pH-dependent endocytic pathway. J Virol. 2005;79(12):7609–16. https://doi.org/10.1128/JVI.79.12.7609-7616.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Clement C, Tiwari V, Scanlan PM, Valyi-Nagy T, Yue BY, Shukla D. A novel role for phagocytosis-like uptake in herpes simplex virus entry. J Cell Biol. 2006;174(7):1009–21. https://doi.org/10.1083/jcb.200509155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Gianni T, Salvioli S, Chesnokova LS, Hutt-Fletcher LM, Campadelli-Fiume G. Alphavbeta6- and alphavbeta8-integrins serve as interchangeable receptors for HSV gH/gL to promote endocytosis and activation of membrane fusion. PLoS Pathog. 2013;9(12):e1003806. https://doi.org/10.1371/journal.ppat.1003806.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  36. Nicola AV, Straus SE. Cellular and viral requirements for rapid endocytic entry of herpes simplex virus. J Virol. 2004;78(14):7508–17. https://doi.org/10.1128/JVI.78.14.7508-7517.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Nicola AV. Herpesvirus entry into host cells mediated by endosomal low pH. Traffic. 2016;17(9):965–75. https://doi.org/10.1111/tra.12408.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Azab W, Gramatica A, Herrmann A, Osterrieder N. Binding of alphaherpesvirus glycoprotein H to surface alpha4beta1-integrins activates calcium-signaling pathways and induces phosphatidylserine exposure on the plasma membrane. MBio. 2015;6(5):e01552–15. https://doi.org/10.1128/mBio.01552-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  39. Ryckman BJ, Jarvis MA, Drummond DD, Nelson JA, Johnson DC. 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):710–22. https://doi.org/10.1128/JVI.80.2.710-722.2006.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Archer MA, Brechtel TM, Davis LE, Parmar RC, Hasan MH, Tandon R. Inhibition of endocytic pathways impacts cytomegalovirus maturation. Sci Rep. 2017;7:46069. https://doi.org/10.1038/srep46069.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Oxford KL, Strelow L, Yue Y, Chang WL, Schmidt KA, Diamond DJ, et al. Open reading frames carried on UL/b' are implicated in shedding and horizontal transmission of rhesus cytomegalovirus in rhesus monkeys. J Virol. 2011;85(10):5105–14. https://doi.org/10.1128/JVI.02631-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Spear PG. Herpes simplex virus: receptors and ligands for cell entry. Cell Microbiol. 2004;6(5):401–10. https://doi.org/10.1111/j.1462-5822.2004.00389.x.

    Article  CAS  PubMed  Google Scholar 

  43. Shukla D, Liu J, Blaiklock P, Shworak NW, Bai X, Esko JD, et al. A novel role for 3-O-sulfated heparan sulfate in herpes simplex virus 1 entry. Cell. 1999;99(1):13–22. https://doi.org/10.1016/S0092-8674(00)80058-6.

    Article  CAS  PubMed  Google Scholar 

  44. Montgomery RI, Warner MS, Lum BJ, Spear PG. Herpes simplex virus-1 entry into cells mediated by a novel member of the TNF/NGF receptor family. Cell. 1996;87(3):427–36. https://doi.org/10.1016/S0092-8674(00)81363-X.

    Article  CAS  PubMed  Google Scholar 

  45. Cocchi F, Menotti L, Mirandola P, Lopez M, Campadelli-Fiume G. The ectodomain of a novel member of the immunoglobulin subfamily related to the poliovirus receptor has the attributes of a bona fide receptor for herpes simplex virus types 1 and 2 in human cells. J Virol. 1998;72(12):9992–10002.

    CAS  PubMed  PubMed Central  Google Scholar 

  46. Geraghty RJ, Krummenacher C, Cohen GH, Eisenberg RJ, Spear PG. Entry of alphaherpesviruses mediated by poliovirus receptor-related protein 1 and poliovirus receptor. Science. 1998;280(5369):1618–20. https://doi.org/10.1126/science.280.5369.1618.

    Article  CAS  PubMed  Google Scholar 

  47. Satoh T, Arii J, Suenaga T, Wang J, Kogure A, Uehori J, et al. PILRalpha is a herpes simplex virus-1 entry coreceptor that associates with glycoprotein B. Cell. 2008;132(6):935–44. https://doi.org/10.1016/j.cell.2008.01.043.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  48. Arii J, Goto H, Suenaga T, Oyama M, Kozuka-Hata H, Imai T, et al. Non-muscle myosin IIA is a functional entry receptor for herpes simplex virus-1. Nature. 2010;467(7317):859–62. https://doi.org/10.1038/nature09420.

    Article  CAS  PubMed  Google Scholar 

  49. Suenaga T, Satoh T, Somboonthum P, Kawaguchi Y, Mori Y, Arase H. Myelin-associated glycoprotein mediates membrane fusion and entry of neurotropic herpesviruses. Proc Natl Acad Sci U S A. 2010;107(2):866–71. https://doi.org/10.1073/pnas.0913351107.

    Article  CAS  PubMed  Google Scholar 

  50. Taylor JM, Lin E, Susmarski N, Yoon M, Zago A, Ware CF, et al. Alternative entry receptors for herpes simplex virus and their roles in disease. Cell Host Microbe. 2007;2(1):19–28. https://doi.org/10.1016/j.chom.2007.06.005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Di Giovine P, Settembre EC, Bhargava AK, Luftig MA, Lou H, Cohen GH, et al. Structure of herpes simplex virus glycoprotein D bound to the human receptor nectin-1. PLoS Pathog. 2011;7(9):e1002277. https://doi.org/10.1371/journal.ppat.1002277.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  52. Carfi A, Willis SH, Whitbeck JC, Krummenacher C, Cohen GH, Eisenberg RJ, et al. Herpes simplex virus glycoprotein D bound to the human receptor HveA. Mol Cell. 2001;8(1):169–79. https://doi.org/10.1016/S1097-2765(01)00298-2.

    Article  CAS  PubMed  Google Scholar 

  53. Cheshenko N, Liu W, Satlin LM, Herold BC. Multiple receptor interactions trigger release of membrane and intracellular calcium stores critical for herpes simplex virus entry. Mol Biol Cell. 2007;18(8):3119–30. https://doi.org/10.1091/mbc.E07-01-0062.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Shui JW, Kronenberg M. HVEM: an unusual TNF receptor family member important for mucosal innate immune responses to microbes. Gut Microbes. 2013;4(2):146–51. https://doi.org/10.4161/gmic.23443.

    Article  PubMed  PubMed Central  Google Scholar 

  55. Steinberg MW, Cheung TC, Ware CF. The signaling networks of the herpesvirus entry mediator (TNFRSF14) in immune regulation. Immunol Rev. 2011;244(1):169–87. https://doi.org/10.1111/j.1600-065X.2011.01064.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Murphy TL, Murphy KM. Slow down and survive: enigmatic immunoregulation by BTLA and HVEM. Annu Rev Immunol. 2010;28(1):389–411. https://doi.org/10.1146/annurev-immunol-030409-101202.

    Article  CAS  PubMed  Google Scholar 

  57. Cheung TC, Steinberg MW, Oborne LM, Macauley MG, Fukuyama S, Sanjo H, et al. Unconventional ligand activation of herpesvirus entry mediator signals cell survival. Proc Natl Acad Sci U S A. 2009;106(15):6244–9. https://doi.org/10.1073/pnas.0902115106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Lasaro MO, Tatsis N, Hensley SE, Whitbeck JC, Lin SW, Rux JJ, et al. Targeting of antigen to the herpesvirus entry mediator augments primary adaptive immune responses. Nat Med. 2008;14(2):205–12. https://doi.org/10.1038/nm1704.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  59. Sciortino MT, Medici MA, Marino-Merlo F, Zaccaria D, Giuffre-Cuculletto M, Venuti A, et al. Involvement of gD/HVEM interaction in NF-kB-dependent inhibition of apoptosis by HSV-1 gD. Biochem Pharmacol. 2008;76(11):1522–32. https://doi.org/10.1016/j.bcp.2008.07.030.

    Article  CAS  PubMed  Google Scholar 

  60. Edwards RG, Longnecker R. Herpesvirus entry mediator and ocular herpesvirus infection: more than meets the eye. J Virol. 2017;91(13):e00115–7. https://doi.org/10.1128/JVI.00115-17.

    Article  PubMed  PubMed Central  Google Scholar 

  61. Karaba AH, Kopp SJ, Longnecker R. Herpesvirus entry mediator is a serotype specific determinant of pathogenesis in ocular herpes. Proc Natl Acad Sci U S A. 2012;109(50):20649–54. https://doi.org/10.1073/pnas.1216967109.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Karaba AH, Kopp SJ, Longnecker R. Herpesvirus entry mediator and nectin-1 mediate herpes simplex virus 1 infection of the murine cornea. J Virol. 2011;85(19):10041–7. https://doi.org/10.1128/JVI.05445-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Feire AL, Roy RM, Manley K, Compton T. The glycoprotein B disintegrin-like domain binds beta 1 integrin to mediate cytomegalovirus entry. J Virol. 2010;84(19):10026–37. https://doi.org/10.1128/JVI.00710-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  64. Garrigues HJ, Rubinchikova YE, Dipersio CM, Rose TM. Integrin alphaVbeta3 binds to the RGD motif of glycoprotein B of Kaposi’s sarcoma-associated herpesvirus and functions as an RGD-dependent entry receptor. J Virol. 2008;82(3):1570–80. https://doi.org/10.1128/JVI.01673-07.

    Article  CAS  PubMed  Google Scholar 

  65. Leoni V, Gianni T, Salvioli S, Campadelli-Fiume G. Herpes simplex virus glycoproteins gH/gL and gB bind Toll-like receptor 2, and soluble gH/gL is sufficient to activate NF-kappaB. J Virol. 2012;86(12):6555–62. https://doi.org/10.1128/JVI.00295-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Fournier N, Chalus L, Durand I, Garcia E, Pin JJ, Churakova T, et al. FDF03, a novel inhibitory receptor of the immunoglobulin superfamily, is expressed by human dendritic and myeloid cells. J Immunol. 2000;165(3):1197–209. https://doi.org/10.4049/jimmunol.165.3.1197.

    Article  CAS  PubMed  Google Scholar 

  67. Wang J, Shiratori I, Uehori J, Ikawa M, Arase H. Neutrophil infiltration during inflammation is regulated by PILRalpha via modulation of integrin activation. Nat Immunol. 2013;14(1):34–40. https://doi.org/10.1038/ni.2456.

    Article  CAS  PubMed  Google Scholar 

  68. Parry C, Bell S, Minson T, Browne H. Herpes simplex virus type 1 glycoprotein H binds to alphavbeta3 integrins. J Gen Virol. 2005;86(Pt 1):7–10. https://doi.org/10.1099/vir.0.80567-0.

    Article  CAS  PubMed  Google Scholar 

  69. Cheshenko N, Trepanier JB, Gonzalez PA, Eugenin EA, Jacobs WR Jr, Herold BC. Herpes simplex virus type 2 glycoprotein H interacts with integrin alphavbeta3 to facilitate viral entry and calcium signaling in human genital tract epithelial cells. J Virol. 2014;88(17):10026–38. https://doi.org/10.1128/JVI.00725-14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  70. Cheshenko N, Trepanier JB, Stefanidou M, Buckley N, Gonzalez P, Jacobs W, et al. HSV activates Akt to trigger calcium release and promote viral entry: novel candidate target for treatment and suppression. FASEB J. 2013;27(7):2584–99. https://doi.org/10.1096/fj.12-220285.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. Cheshenko N, Del Rosario B, Woda C, Marcellino D, Satlin LM, Herold BC. Herpes simplex virus triggers activation of calcium-signaling pathways. J Cell Biol. 2003;163(2):283–93. https://doi.org/10.1083/jcb.200301084.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  72. Gianni T, Massaro R, Campadelli-Fiume G. Dissociation of HSV gL from gH by alphavbeta6- or alphavbeta8-integrin promotes gH activation and virus entry. Proc Natl Acad Sci U S A. 2015;112(29):E3901–10. https://doi.org/10.1073/pnas.1506846112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Gianni T, Campadelli-Fiume G. The epithelial alphavbeta3-integrin boosts the MYD88-dependent TLR2 signaling in response to viral and bacterial components. PLoS Pathog. 2014;10(11):e1004477. https://doi.org/10.1371/journal.ppat.1004477.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  74. Gianni T, Campadelli-Fiume G. AlphaVbeta3-integrin relocalizes nectin1 and routes herpes simplex virus to lipid rafts. J Virol. 2012;86(5):2850–5. https://doi.org/10.1128/JVI.06689-11.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  75. Iversen MB, Reinert LS, Thomsen MK, Bagdonaite I, Nandakumar R, Cheshenko N, et al. An innate antiviral pathway acting before interferons at epithelial surfaces. Nat Immunol. 2016;17(2):150–8. https://doi.org/10.1038/ni.3319.

    Article  CAS  PubMed  Google Scholar 

  76. Tiwari V, Shukla D. Phosphoinositide 3 kinase signalling may affect multiple steps during herpes simplex virus type-1 entry. J Gen Virol. 2010;91(Pt 12):3002–9. https://doi.org/10.1099/vir.0.024166-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. MacLeod IJ, Minson T. Binding of herpes simplex virus type-1 virions leads to the induction of intracellular signalling in the absence of virus entry. PLoS One. 2010;5(3):e9560. https://doi.org/10.1371/journal.pone.0009560.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  78. Liu X, Cohen JI. The role of PI3K/Akt in human herpesvirus infection: from the bench to the bedside. Virology. 2015;479-480:568–77. https://doi.org/10.1016/j.virol.2015.02.040.

    Article  CAS  PubMed  Google Scholar 

  79. Zheng K, Xiang Y, Wang X, Wang Q, Zhong M, Wang S, et al. Epidermal growth factor receptor-PI3K signaling controls cofilin activity to facilitate herpes simplex virus 1 entry into neuronal cells. MBio. 2014;5(1):e00958–13. https://doi.org/10.1128/mBio.00958-13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  80. Mostowy S, Shenoy AR. The cytoskeleton in cell-autonomous immunity: structural determinants of host defence. Nat Rev Immunol. 2015;15(9):559–73. https://doi.org/10.1038/nri3877.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Fukazawa A, Alonso C, Kurachi K, Gupta S, Lesser CF, McCormick BA, et al. GEF-H1 mediated control of NOD1 dependent NF-kappaB activation by Shigella effectors. PLoS Pathog. 2008;4(11):e1000228. https://doi.org/10.1371/journal.ppat.1000228.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  82. Keestra AM, Winter MG, Auburger JJ, Frassle SP, Xavier MN, Winter SE, et al. Manipulation of small rho GTPases is a pathogen-induced process detected by NOD1. Nature. 2013;496(7444):233–7. https://doi.org/10.1038/nature12025.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Dunn W, Chou C, Li H, Hai R, Patterson D, Stolc V, et al. Functional profiling of a human cytomegalovirus genome. Proc Natl Acad Sci U S A. 2003;100(24):14223–8. https://doi.org/10.1073/pnas.2334032100.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  84. Wang D, Shenk T. Human cytomegalovirus virion protein complex required for epithelial and endothelial cell tropism. Proc Natl Acad Sci U S A. 2005;102(50):18153–8. https://doi.org/10.1073/pnas.0509201102.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  85. Hai R, Chu A, Li H, Umamoto S, Rider P, Liu F. Infection of human cytomegalovirus in cultured human gingival tissue. Virol J. 2006;3(1):84. https://doi.org/10.1186/1743-422X-3-84.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  86. Borza CM, Hutt-Fletcher LM. Alternate replication in B cells and epithelial cells switches tropism of Epstein-Barr virus. Nat Med. 2002;8(6):594–9. https://doi.org/10.1038/nm0602-594.

    Article  CAS  PubMed  Google Scholar 

  87. Jambunathan N, Charles AS, Subramanian R, Saied AA, Naderi M, Rider P, et al. Deletion of a predicted beta-sheet domain within the amino terminus of herpes simplex virus glycoprotein K conserved among alphaherpesviruses prevents virus entry into neuronal axons. J Virol. 2015;90(5):2230–9. https://doi.org/10.1128/JVI.02468-15.

    Article  PubMed  CAS  Google Scholar 

  88. Li G, Nguyen CC, Ryckman BJ, Britt WJ, Kamil JPA. Viral regulator of glycoprotein complexes contributes to human cytomegalovirus cell tropism. Proc Natl Acad Sci U S A. 2015;112(14):4471–6. https://doi.org/10.1073/pnas.1419875112.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  89. Li G, Kamil JP. Viral regulation of cell tropism in human cytomegalovirus. J Virol. 2015;90(2):626–9. https://doi.org/10.1128/JVI.01500-15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  90. Mori Y. Recent topics related to human herpesvirus 6 cell tropism. Cell Microbiol. 2009;11(7):1001–6. https://doi.org/10.1111/j.1462-5822.2009.01312.x.

    Article  CAS  PubMed  Google Scholar 

  91. Hutt-Fletcher LM, Lake CM. Two Epstein-Barr virus glycoprotein complexes. Curr Top Microbiol Immunol. 2001;258:51–64.

    CAS  PubMed  Google Scholar 

  92. Sathiyamoorthy K, Hu YX, Mohl BS, Chen J, Longnecker R, Jardetzky TS. Structural basis for Epstein-Barr virus host cell tropism mediated by gp42 and gHgL entry glycoproteins. Nat Commun. 2016;7:13557. https://doi.org/10.1038/ncomms13557.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  93. Saied AA, Chouljenko VN, Subramanian R, Kousoulas KGA. Replication competent HSV-1(McKrae) with a mutation in the amino-terminus of glycoprotein K (gK) is unable to infect mouse trigeminal ganglia after cornea infection. Curr Eye Res. 2014;39(6):596–603. https://doi.org/10.3109/02713683.2013.855238.

    Article  CAS  PubMed  Google Scholar 

  94. Chouljenko VN, Iyer AV, Chowdhury S, Kim J, Kousoulas KG. The herpes simplex virus type 1 UL20 protein and the amino terminus of glycoprotein K (gK) physically interact with gB. J Virol. 2010;84(17):8596–606. https://doi.org/10.1128/JVI.00298-10.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Chowdhury S, Chouljenko VN, Naderi M, Kousoulas KG. The amino terminus of herpes simplex virus 1 glycoprotein K is required for virion entry via the paired immunoglobulin-like type-2 receptor alpha. J Virol. 2013;87(6):3305–13. https://doi.org/10.1128/JVI.02982-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  96. Wang K, Kappel JD, Canders C, Davila WF, Sayre D, Chavez M, et al. A herpes simplex virus 2 glycoprotein D mutant generated by bacterial artificial chromosome mutagenesis is severely impaired for infecting neuronal cells and infects only Vero cells expressing exogenous HVEM. J Virol. 2012;86(23):12891–902. https://doi.org/10.1128/JVI.01055-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  97. Hansen SG, Sacha JB, Hughes CM, Ford JC, Burwitz BJ, Scholz I, et al. Cytomegalovirus vectors violate CD8+ T cell epitope recognition paradigms. Science. 2013;340(6135):1237874. https://doi.org/10.1126/science.1237874.

    Article  PubMed  CAS  Google Scholar 

  98. Barouch DH, Picker LJ. Novel vaccine vectors for HIV-1. Nat Rev Microbiol. 2014;12(11):765–71. https://doi.org/10.1038/nrmicro3360.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  99. Wussow F, Yue Y, Martinez J, Deere JD, Longmate J, Herrmann A, et al. A vaccine based on the rhesus cytomegalovirus UL128 complex induces broadly neutralizing antibodies in rhesus macaques. J Virol. 2013;87(3):1322–32. https://doi.org/10.1128/JVI.01669-12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Wussow F, Chiuppesi F, Martinez J, Campo J, Johnson E, Flechsig C, et al. Human cytomegalovirus vaccine based on the envelope gH/gL pentamer complex. PLoS Pathog. 2014;10(11):e1004524. https://doi.org/10.1371/journal.ppat.1004524.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  101. Zhou G, Roizman B. Construction and properties of a herpes simplex virus 1 designed to enter cells solely via the IL-13alpha2 receptor. Proc Natl Acad Sci U S A. 2006;103(14):5508–13. https://doi.org/10.1073/pnas.0601258103.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  102. Zhou G, Ye GJ, Debinski W, Roizman B. Engineered herpes simplex virus 1 is dependent on IL13Ralpha 2 receptor for cell entry and independent of glycoprotein D receptor interaction. Proc Natl Acad Sci U S A. 2002;99(23):15124–9. https://doi.org/10.1073/pnas.232588699.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Campadelli-Fiume G, Petrovic B, Leoni V, Gianni T, Avitabile E, Casiraghi C, et al. Retargeting strategies for oncolytic herpes simplex viruses. Viruses. 2016;8(3):63. https://doi.org/10.3390/v8030063.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  104. Gambini E, Reisoli E, Appolloni I, Gatta V, Campadelli-Fiume G, Menotti L, et al. Replication-competent herpes simplex virus retargeted to HER2 as therapy for high-grade glioma. Mol Ther. 2012;20(5):994–1001. https://doi.org/10.1038/mt.2012.22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Nanni P, Gatta V, Menotti L, De Giovanni C, Ianzano M, Palladini A, et al. Preclinical therapy of disseminated HER-2(+) ovarian and breast carcinomas with a HER-2-retargeted oncolytic herpesvirus. PLoS Pathog. 2013;9(1):e1003155. https://doi.org/10.1371/journal.ppat.1003155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Gatta V, Petrovic B, Campadelli-Fiume G. The engineering of a novel ligand in gH confers to HSV an expanded tropism independent of gD activation by its receptors. PLoS Pathog. 2015;11(5):e1004907. https://doi.org/10.1371/journal.ppat.1004907.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  107. Leoni V, Gatta V, Palladini A, Nicoletti G, Ranieri D, Dall'Ora M, et al. Systemic delivery of HER2-retargeted oncolytic-HSV by mesenchymal stromal cells protects from lung and brain metastases. Oncotarget. 2015;6(33):34774–87. https://doi.org/10.18632/oncotarget.5793.

    Article  PubMed  PubMed Central  Google Scholar 

  108. Leoni V, Gatta V, Casiraghi C, Nicosia A, Petrovic B, Campadelli-Fiume GA. Strategy for cultivation of retargeted oncolytic herpes simplex viruses in non-cancer cells. J Virol. 2017;91(10):e00067–17. https://doi.org/10.1128/JVI.00067-17.

    Article  PubMed  PubMed Central  Google Scholar 

  109. Petrovic B, Gianni T, Gatta V, Campadelli-Fiume G. Insertion of a ligand to HER2 in gB retargets HSV tropism and obviates the need for activation of the other entry glycoproteins. PLoS Pathog. 2017;13(4):e1006352. https://doi.org/10.1371/journal.ppat.1006352.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  110. Petro CD, Weinrick B, Khajoueinejad N, Burn C, Sellers R, Jacobs WR Jr, et al. HSV-2 DeltagD elicits FcgammaR-effector antibodies that protect against clinical isolates. JCI Insight. 2016;1(12) https://doi.org/10.1172/jci.insight.88529.

  111. Boukhvalova M, McKay J, Mbaye A, Sanford-Crane H, Blanco JC, Huber A, et al. Efficacy of the herpes simplex virus 2 (HSV-2) glycoprotein D/AS04 vaccine against genital HSV-2 and HSV-1 infection and disease in the cotton rat Sigmodon Hispidus model. J Virol. 2015;89(19):9825–40. https://doi.org/10.1128/JVI.01387-15.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  112. • Petro C, Gonzalez PA, Cheshenko N, Jandl T, Khajoueinejad N, Benard A, et al. Herpes simplex type 2 virus deleted in glycoprotein D protects against vaginal, skin and neural disease. elife. 2015;4:e06054. This manuscript demonstrates the efficaciousness of a gD deficient HSV-2 vaccine is due to ADCC.

    Article  PubMed Central  CAS  Google Scholar 

  113. Royer DJ, Carr MM, Gurung HR, Halford WP, Carr DJJ. The neonatal fc receptor and complement fixation facilitate prophylactic vaccine-mediated humoral protection against viral infection in the ocular mucosa. J Immunol. 2017;199(5):1898–911. https://doi.org/10.4049/jimmunol.1700316.

    Article  CAS  PubMed  Google Scholar 

  114. • Wang K, Goodman KN, Li DY, Raffeld M, Chavez M, Cohen JI. A herpes simplex virus 2 (HSV-2) gD mutant impaired for neural tropism is superior to an HSV-2 gD subunit vaccine to protect animals from challenge with HSV-2. J Virol. 2015;90(1):562–574. This report demonstrates the utility of a stable mutation in HSV-2 abrogating binding of gD to nectin-1 provides protection of mice from lethal HSV-2 challenge. https://doi.org/10.1128/JVI.01845-15.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  115. MacLean CA, Efstathiou S, Elliott ML, Jamieson FE, McGeoch DJ. Investigation of herpes simplex virus type 1 genes encoding multiply inserted membrane proteins. J Gen Virol. 1991;72(Pt 4):897–906. https://doi.org/10.1099/0022-1317-72-4-897.

    Article  CAS  PubMed  Google Scholar 

  116. Melancon JM, Foster TP, Kousoulas KG. Genetic analysis of the herpes simplex virus type 1 (HSV-1) UL20 protein domains involved in cytoplasmic virion envelopment and virus-induced cell fusion. J Virol. 2004;78(14):7329–43. https://doi.org/10.1128/JVI.78.14.7329-7343.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  117. Baines JD, Ward PL, Campadelli-Fiume G, Roizman B. The UL20 gene of herpes simplex virus 1 encodes a function necessary for viral egress. J Virol. 1991;65(12):6414–24.

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Bzik DJ, Fox BA, DeLuca NA, Person S. 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(1):185–90. https://doi.org/10.1016/0042-6822(84)90022-9.

    Article  CAS  PubMed  Google Scholar 

  119. Pellett PE, Kousoulas KG, Pereira L, Roizman B. Anatomy of the herpes simplex virus 1 strain F glycoprotein B gene: primary sequence and predicted protein structure of the wild type and of monoclonal antibody-resistant mutants. J Virol. 1985;53(1):243–53.

    CAS  PubMed  PubMed Central  Google Scholar 

  120. Bond VC, Person S. Fine structure physical map locations of alterations that affect cell fusion in herpes simplex virus type 1. Virology. 1984;132(2):368–76. https://doi.org/10.1016/0042-6822(84)90042-4.

    Article  CAS  PubMed  Google Scholar 

  121. Debroy C, Pederson N, Person S. Nucleotide sequence of a herpes simplex virus type 1 gene that causes cell fusion. Virology. 1985;145(1):36–48. https://doi.org/10.1016/0042-6822(85)90199-0.

    Article  CAS  PubMed  Google Scholar 

  122. Hutchinson L, Goldsmith K, Snoddy D, Ghosh H, Graham FL, Johnson DC. Identification and characterization of a novel herpes simplex virus glycoprotein, gK, involved in cell fusion. J Virol. 1992;66(9):5603–9.

    CAS  PubMed  PubMed Central  Google Scholar 

  123. Pogue-Geile KL, Lee GT, Shapira SK, Spear PG. Fine mapping of mutations in the fusion-inducing MP strain of herpes simplex virus type 1. Virology. 1984;136(1):100–9. https://doi.org/10.1016/0042-6822(84)90251-4.

    Article  CAS  PubMed  Google Scholar 

  124. Kim IJ, Chouljenko VN, Walker JD, Kousoulas KG. Herpes simplex virus 1 glycoprotein M and the membrane-associated protein UL11 are required for virus-induced cell fusion and efficient virus entry. J Virol. 2013;87(14):8029–37. https://doi.org/10.1128/JVI.01181-13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Foster TP, Chouljenko VN, Kousoulas KG. Functional and physical interactions of the herpes simplex virus type 1 UL20 membrane protein with glycoprotein K. J Virol. 2008;82(13):6310–23. https://doi.org/10.1128/JVI.00147-08.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Foster TP, Melancon JM, Baines JD, Kousoulas KG. The herpes simplex virus type 1 UL20 protein modulates membrane fusion events during cytoplasmic virion morphogenesis and virus-induced cell fusion. J Virol. 2004;78(10):5347–57. https://doi.org/10.1128/JVI.78.10.5347-5357.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Melancon JM, Luna RE, Foster TP, Kousoulas KG. Herpes simplex virus type 1 gK is required for gB-mediated virus-induced cell fusion, while neither gB and gK nor gB and UL20p function redundantly in virion de-envelopment. J Virol. 2005;79(1):299–313. https://doi.org/10.1128/JVI.79.1.299-313.2005.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Rider PJF, Naderi M, Bergeron S, Chouljenko VN, Brylinski M, Kousoulas KG. Cysteines and N-glycosylation sites conserved among all alphaherpesviruses regulate membrane fusion in herpes simplex virus type 1 infection. J Virol. 2017;91(21):e00873–17. https://doi.org/10.1128/JVI.00873-17.

    Article  PubMed  Google Scholar 

  129. • Stanfield BA, Stahl J, Chouljenko VN, Subramanian R, Charles AS, Saied AA, et al. A single intramuscular vaccination of mice with the HSV-1 VC2 virus with mutations in the glycoprotein K and the membrane protein UL20 confers full protection against lethal intravaginal challenge with virulent HSV-1 and HSV-2 strains. PLoS One. 2014;9(10):e109890. This manuscript demonstrates efficacy of an HSV-1 vaccine which possesses a mutation in gK that affects neuronal tropism against both HSV-1 and HSV-2 challenge in a mouse model. https://doi.org/10.1371/journal.pone.0109890.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  130. Stanfield BA, Pahar B, Chouljenko VN, Veazey R, Kousoulas KG. Vaccination of rhesus macaques with the live-attenuated HSV-1 vaccine VC2 stimulates the proliferation of mucosal T cells and germinal center responses resulting in sustained production of highly neutralizing antibodies. Vaccine. 2017;35(4):536–43. https://doi.org/10.1016/j.vaccine.2016.12.018.

    Article  CAS  PubMed  Google Scholar 

  131. Musarrat F, Jambunathan N, Rider PJF, Chouljenko VN, Kousoulas KG. The Amino-terminus of HSV-1 Glycoprotein K (gK) is Required for gB Binding to Akt, Release of Intracellular Calcium and Fusion of the Viral Envelope with Plasma Membranes. J Virol. 2018. https://doi.org/10.1128/JVI.01842-17.

  132. Murphy JE, Padilla BE, Hasdemir B, Cottrell GS, Bunnett NW. Endosomes: a legitimate platform for the signaling train. Proc Natl Acad Sci U S A. 2009;106(42):17615–22. https://doi.org/10.1073/pnas.0906541106.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Gleeson PA. The role of endosomes in innate and adaptive immunity. Semin Cell Dev Biol. 2014;31:64–72. https://doi.org/10.1016/j.semcdb.2014.03.002.

    Article  CAS  PubMed  Google Scholar 

  134. Brubaker SW, Bonham KS, Zanoni I, Kagan JC. Innate immune pattern recognition: a cell biological perspective. Annu Rev Immunol. 2015;33(1):257–90. https://doi.org/10.1146/annurev-immunol-032414-112240.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

We regret that the important works of many of our colleagues were outside the scope of this review and were thus unable to be discussed. We would like to thank Rhonda Cardin for the comments and critical reading of the manuscript. The work was supported by the LSU Division of Biotechnology and Molecular Medicine, by a Governor’s Biotechnology Initiative Grant (KGK) and Cores of the Center for Experimental Infectious Disease Research (CEIDR) supported by the NIH:NIGMS Grant P30GM110670.

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  1. Division of Biotechnology and Molecular Medicine and Department of Pathobiological Sciences, School of Veterinary Medicine, Louisiana State University, Baton Rouge, LA, USA

    Paul J. F. Rider, Farhana Musarrat, Rafiq Nabi, Shan Naidu & Konstantin G. Kousoulas

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Dr. Kousoulas declares a pending patent for vaccines against genital herpes simplex infections (United States Patent Application 20170266275 pending).

Paul J.F. Rider, Farhana Musarrat, Rafiq Nabi, and Shan Naidu declare that they have no conflict of interest.

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This article is part of the Topical Collection on Recent Developments in Anti-viral Vaccines

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Rider, P.J.F., Musarrat, F., Nabi, R. et al. First Impressions—the Potential of Altering Initial Host-Virus Interactions for Rational Design of Herpesvirus Vaccine Vectors. Curr Clin Micro Rpt 5, 55–65 (2018). https://doi.org/10.1007/s40588-018-0082-1

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