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. 1995 Nov;69(11):7087–7098. doi: 10.1128/jvi.69.11.7087-7098.1995

Glycoproteins E and I facilitate neuron-to-neuron spread of herpes simplex virus.

K S Dingwell 1, L C Doering 1, D C Johnson 1
PMCID: PMC189628  PMID: 7474128

Abstract

Two herpes simplex virus (HSV) glycoproteins E and I (gE and gI) form a heterooligomer which acts as an Fc receptor and also facilitates cell-to-cell spread of virus in epithelial tissues and between certain cultured cells. By contrast, gE-gI is not required for infection of cells by extracellular virus. HSV glycoproteins gD and gJ are encoded by neighboring genes, and gD is required for both virus entry into cells and cell-to-cell spread, whereas gJ has not been shown to influence these processes. Since HSV infects neurons and apparently spreads across synaptic junctions, it was of interest to determine whether gD, gE, gI and gJ are also important for interneuronal transfer of virus. We tested the roles of these glycoproteins in neuron-to-neuron transmission of HSV type 1 (HSV-1) by injecting mutant viruses unable to express these glycoproteins into the vitreous body of the rat eye. The spread of virus infection was measured in neuron-rich layers of the retina and in the major retinorecipient areas of the brain. Wild-type HSV-1 and a gJ- mutant spread rapidly between synaptically linked retinal neurons and efficiently infected major retinorecipient areas of the brain. gD mutants, derived from complementing cells, infected only a few neurons and did not spread in the retina or brain. Mutants unable to express gE or gI were markedly restricted in their ability to spread within the retina, produced 10-fold-less virus in the retina, and spread inefficiently to the brain. Furthermore, when compared with wild-type HSV-1, gE- and gI- mutants spread inefficiently from cell to cell in cultures of neurons derived from rat trigeminal ganglia. Together, our results suggest that the gE-gI heterooligomer is required for efficient neuron-to-neuron transmission through synaptically linked neuronal pathways.

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Selected References

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  1. Adler R., Glorioso J. C., Cossman J., Levine M. Possible role of Fc receptors on cells infected and transformed by herpesvirus: escape from immune cytolysis. Infect Immun. 1978 Aug;21(2):442–447. doi: 10.1128/iai.21.2.442-447.1978. [DOI] [PMC free article] [PubMed] [Google Scholar]
  2. Babic N., Mettenleiter T. C., Flamand A., Ugolini G. Role of essential glycoproteins gII and gp50 in transneuronal transfer of pseudorabies virus from the hypoglossal nerves of mice. J Virol. 1993 Jul;67(7):4421–4426. doi: 10.1128/jvi.67.7.4421-4426.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Baines J. D., Roizman B. The UL10 gene of herpes simplex virus 1 encodes a novel viral glycoprotein, gM, which is present in the virion and in the plasma membrane of infected cells. J Virol. 1993 Mar;67(3):1441–1452. doi: 10.1128/jvi.67.3.1441-1452.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Baines J. D., Roizman B. The open reading frames UL3, UL4, UL10, and UL16 are dispensable for the replication of herpes simplex virus 1 in cell culture. J Virol. 1991 Feb;65(2):938–944. doi: 10.1128/jvi.65.2.938-944.1991. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Balan P., Davis-Poynter N., Bell S., Atkinson H., Browne H., Minson T. An analysis of the in vitro and in vivo phenotypes of mutants of herpes simplex virus type 1 lacking glycoproteins gG, gE, gI or the putative gJ. J Gen Virol. 1994 Jun;75(Pt 6):1245–1258. doi: 10.1099/0022-1317-75-6-1245. [DOI] [PubMed] [Google Scholar]
  6. Bell S., Cranage M., Borysiewicz L., Minson T. Induction of immunoglobulin G Fc receptors by recombinant vaccinia viruses expressing glycoproteins E and I of herpes simplex virus type 1. J Virol. 1990 May;64(5):2181–2186. doi: 10.1128/jvi.64.5.2181-2186.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Brunetti C. R., Burke R. L., Hoflack B., Ludwig T., Dingwell K. S., Johnson D. C. Role of mannose-6-phosphate receptors in herpes simplex virus entry into cells and cell-to-cell transmission. J Virol. 1995 Jun;69(6):3517–3528. doi: 10.1128/jvi.69.6.3517-3528.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  8. Cai W. H., Gu B., Person S. Role of glycoprotein B of herpes simplex virus type 1 in viral entry and cell fusion. J Virol. 1988 Aug;62(8):2596–2604. doi: 10.1128/jvi.62.8.2596-2604.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Card J. P., Rinaman L., Lynn R. B., Lee B. H., Meade R. P., Miselis R. R., Enquist L. W. Pseudorabies virus infection of the rat central nervous system: ultrastructural characterization of viral replication, transport, and pathogenesis. J Neurosci. 1993 Jun;13(6):2515–2539. doi: 10.1523/JNEUROSCI.13-06-02515.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Card J. P., Whealy M. E., Robbins A. K., Enquist L. W. Pseudorabies virus envelope glycoprotein gI influences both neurotropism and virulence during infection of the rat visual system. J Virol. 1992 May;66(5):3032–3041. doi: 10.1128/jvi.66.5.3032-3041.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Card J. P., Whealy M. E., Robbins A. K., Moore R. Y., Enquist L. W. Two alpha-herpesvirus strains are transported differentially in the rodent visual system. Neuron. 1991 Jun;6(6):957–969. doi: 10.1016/0896-6273(91)90236-s. [DOI] [PubMed] [Google Scholar]
  12. Cook M. L., Stevens J. G. Pathogenesis of herpetic neuritis and ganglionitis in mice: evidence for intra-axonal transport of infection. Infect Immun. 1973 Feb;7(2):272–288. doi: 10.1128/iai.7.2.272-288.1973. [DOI] [PMC free article] [PubMed] [Google Scholar]
  13. DeVries S. H., Baylor D. A. Synaptic circuitry of the retina and olfactory bulb. Cell. 1993 Jan;72 (Suppl):139–149. doi: 10.1016/s0092-8674(05)80033-9. [DOI] [PubMed] [Google Scholar]
  14. Dingwell K. S., Brunetti C. R., Hendricks R. L., Tang Q., Tang M., Rainbow A. J., Johnson D. C. Herpes simplex virus glycoproteins E and I facilitate cell-to-cell spread in vivo and across junctions of cultured cells. J Virol. 1994 Feb;68(2):834–845. doi: 10.1128/jvi.68.2.834-845.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  15. Dotti C. G., Simons K. Polarized sorting of viral glycoproteins to the axon and dendrites of hippocampal neurons in culture. Cell. 1990 Jul 13;62(1):63–72. doi: 10.1016/0092-8674(90)90240-f. [DOI] [PubMed] [Google Scholar]
  16. Dowler K. W., Veltri R. W. In vitro neutralization of HSV-2: inhibition by binding of normal IgG and purified Fc to virion Fc receptor (FcR). J Med Virol. 1984;13(3):251–259. doi: 10.1002/jmv.1890130307. [DOI] [PubMed] [Google Scholar]
  17. Ejercito P. M., Kieff E. D., Roizman B. Characterization of herpes simplex virus strains differing in their effects on social behaviour of infected cells. J Gen Virol. 1968 May;2(3):357–364. doi: 10.1099/0022-1317-2-3-357. [DOI] [PubMed] [Google Scholar]
  18. Enquist L. W., Dubin J., Whealy M. E., Card J. P. Complementation analysis of pseudorabies virus gE and gI mutants in retinal ganglion cell neurotropism. J Virol. 1994 Aug;68(8):5275–5279. doi: 10.1128/jvi.68.8.5275-5279.1994. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Forrester A., Farrell H., Wilkinson G., Kaye J., Davis-Poynter N., Minson T. Construction and properties of a mutant of herpes simplex virus type 1 with glycoprotein H coding sequences deleted. J Virol. 1992 Jan;66(1):341–348. doi: 10.1128/jvi.66.1.341-348.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Frank I., Friedman H. M. A novel function of the herpes simplex virus type 1 Fc receptor: participation in bipolar bridging of antiviral immunoglobulin G. J Virol. 1989 Nov;63(11):4479–4488. doi: 10.1128/jvi.63.11.4479-4488.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Hanke T., Graham F. L., Lulitanond V., Johnson D. C. Herpes simplex virus IgG Fc receptors induced using recombinant adenovirus vectors expressing glycoproteins E and I. Virology. 1990 Aug;177(2):437–444. doi: 10.1016/0042-6822(90)90507-n. [DOI] [PubMed] [Google Scholar]
  22. Hutchinson L., Johnson D. C. Herpes simplex virus glycoprotein K promotes egress of virus particles. J Virol. 1995 Sep;69(9):5401–5413. doi: 10.1128/jvi.69.9.5401-5413.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  23. Jacobs L., Mulder W. A., Van Oirschot J. T., Gielkens A. L., Kimman T. G. Deleting two amino acids in glycoprotein gI of pseudorabies virus decreases virulence and neurotropism for pigs, but does not affect immunogenicity. J Gen Virol. 1993 Oct;74(Pt 10):2201–2206. doi: 10.1099/0022-1317-74-10-2201. [DOI] [PubMed] [Google Scholar]
  24. Johnson D. C., Frame M. C., Ligas M. W., Cross A. M., Stow N. D. Herpes simplex virus immunoglobulin G Fc receptor activity depends on a complex of two viral glycoproteins, gE and gI. J Virol. 1988 Apr;62(4):1347–1354. doi: 10.1128/jvi.62.4.1347-1354.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Johnson D. C., Ligas M. W. Herpes simplex viruses lacking glycoprotein D are unable to inhibit virus penetration: quantitative evidence for virus-specific cell surface receptors. J Virol. 1988 Dec;62(12):4605–4612. doi: 10.1128/jvi.62.12.4605-4612.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  26. Kaneko A. Physiology of the retina. Annu Rev Neurosci. 1979;2:169–191. doi: 10.1146/annurev.ne.02.030179.001125. [DOI] [PubMed] [Google Scholar]
  27. Kimman T. G., de Wind N., Oei-Lie N., Pol J. M., Berns A. J., Gielkens A. L. Contribution of single genes within the unique short region of Aujeszky's disease virus (suid herpesvirus type 1) to virulence, pathogenesis and immunogenicity. J Gen Virol. 1992 Feb;73(Pt 2):243–251. doi: 10.1099/0022-1317-73-2-243. [DOI] [PubMed] [Google Scholar]
  28. Kristensson K., Lycke E., Röyttä M., Svennerholm B., Vahlne A. Neuritic transport of herpes simplex virus in rat sensory neurons in vitro. Effects of substances interacting with microtubular function and axonal flow [nocodazole, taxol and erythro-9-3-(2-hydroxynonyl)adenine]. J Gen Virol. 1986 Sep;67(Pt 9):2023–2028. doi: 10.1099/0022-1317-67-9-2023. [DOI] [PubMed] [Google Scholar]
  29. Kristensson K., Lycke E., Sjöstrand J. Spread of herpes simplex virus in peripheral nerves. Acta Neuropathol. 1971;17(1):44–53. doi: 10.1007/BF00684740. [DOI] [PubMed] [Google Scholar]
  30. Kristensson K., Nennesmo L., Persson L., Lycke E. Neuron to neuron transmission of herpes simplex virus. Transport of virus from skin to brainstem nuclei. J Neurol Sci. 1982 Apr;54(1):149–156. doi: 10.1016/0022-510x(82)90227-1. [DOI] [PubMed] [Google Scholar]
  31. Kritas S. K., Pensaert M. B., Mettenleiter T. C. Role of envelope glycoproteins gI, gp63 and gIII in the invasion and spread of Aujeszky's disease virus in the olfactory nervous pathway of the pig. J Gen Virol. 1994 Sep;75(Pt 9):2319–2327. doi: 10.1099/0022-1317-75-9-2319. [DOI] [PubMed] [Google Scholar]
  32. Ligas M. W., Johnson D. C. A herpes simplex virus mutant in which glycoprotein D sequences are replaced by beta-galactosidase sequences binds to but is unable to penetrate into cells. J Virol. 1988 May;62(5):1486–1494. doi: 10.1128/jvi.62.5.1486-1494.1988. [DOI] [PMC free article] [PubMed] [Google Scholar]
  33. Linden R., Perry V. H. Massive retinotectal projection in rats. Brain Res. 1983 Aug 1;272(1):145–149. doi: 10.1016/0006-8993(83)90371-2. [DOI] [PubMed] [Google Scholar]
  34. Longnecker R., Chatterjee S., Whitley R. J., Roizman B. Identification of a herpes simplex virus 1 glycoprotein gene within a gene cluster dispensable for growth in cell culture. Proc Natl Acad Sci U S A. 1987 Jun;84(12):4303–4307. doi: 10.1073/pnas.84.12.4303. [DOI] [PMC free article] [PubMed] [Google Scholar]
  35. Longnecker R., Roizman B. Clustering of genes dispensable for growth in culture in the S component of the HSV-1 genome. Science. 1987 May 1;236(4801):573–576. doi: 10.1126/science.3033823. [DOI] [PubMed] [Google Scholar]
  36. Longnecker R., Roizman B. Generation of an inverting herpes simplex virus 1 mutant lacking the L-S junction a sequences, an origin of DNA synthesis, and several genes including those specifying glycoprotein E and the alpha 47 gene. J Virol. 1986 May;58(2):583–591. doi: 10.1128/jvi.58.2.583-591.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  37. McGeoch D. J. Evolutionary relationships of virion glycoprotein genes in the S regions of alphaherpesvirus genomes. J Gen Virol. 1990 Oct;71(Pt 10):2361–2367. doi: 10.1099/0022-1317-71-10-2361. [DOI] [PubMed] [Google Scholar]
  38. McLean J. H., Shipley M. T., Bernstein D. I. Golgi-like, transneuronal retrograde labelling with CNS injections of herpes simplex virus type 1. Brain Res Bull. 1989 May;22(5):867–881. doi: 10.1016/0361-9230(89)90032-4. [DOI] [PubMed] [Google Scholar]
  39. Neidhardt H., Schröder C. H., Kaerner H. C. Herpes simplex virus type 1 glycoprotein E is not indispensable for viral infectivity. J Virol. 1987 Feb;61(2):600–603. doi: 10.1128/jvi.61.2.600-603.1987. [DOI] [PMC free article] [PubMed] [Google Scholar]
  40. Norgren R. B., Jr, Lehman M. N. Retrograde transneuronal transport of herpes simplex virus in the retina after injection in the superior colliculus, hypothalamus and optic chiasm. Brain Res. 1989 Feb 13;479(2):374–378. doi: 10.1016/0006-8993(89)91644-2. [DOI] [PubMed] [Google Scholar]
  41. Norgren R. B., Jr, McLean J. H., Bubel H. C., Wander A., Bernstein D. I., Lehman M. N. Anterograde transport of HSV-1 and HSV-2 in the visual system. Brain Res Bull. 1992 Mar;28(3):393–399. doi: 10.1016/0361-9230(92)90038-y. [DOI] [PubMed] [Google Scholar]
  42. Peeters B., Pol J., Gielkens A., Moormann R. Envelope glycoprotein gp50 of pseudorabies virus is essential for virus entry but is not required for viral spread in mice. J Virol. 1993 Jan;67(1):170–177. doi: 10.1128/jvi.67.1.170-177.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  43. Peeters B., de Wind N., Hooisma M., Wagenaar F., Gielkens A., Moormann R. Pseudorabies virus envelope glycoproteins gp50 and gII are essential for virus penetration, but only gII is involved in membrane fusion. J Virol. 1992 Feb;66(2):894–905. doi: 10.1128/jvi.66.2.894-905.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  44. Penfold M. E., Armati P., Cunningham A. L. Axonal transport of herpes simplex virions to epidermal cells: evidence for a specialized mode of virus transport and assembly. Proc Natl Acad Sci U S A. 1994 Jul 5;91(14):6529–6533. doi: 10.1073/pnas.91.14.6529. [DOI] [PMC free article] [PubMed] [Google Scholar]
  45. Rajcáni J., Herget U., Kaerner H. C. Spread of herpes simplex virus (HSV) strains SC16, ANG, ANGpath and its glyC minus and GlyE minus mutants in DBA-2 mice. Acta Virol. 1990 Aug;34(4):305–320. [PubMed] [Google Scholar]
  46. Rodieck R. W. Visual pathways. Annu Rev Neurosci. 1979;2:193–225. doi: 10.1146/annurev.ne.02.030179.001205. [DOI] [PubMed] [Google Scholar]
  47. Roop C., Hutchinson L., Johnson D. C. A mutant herpes simplex virus type 1 unable to express glycoprotein L cannot enter cells, and its particles lack glycoprotein H. J Virol. 1993 Apr;67(4):2285–2297. doi: 10.1128/jvi.67.4.2285-2297.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  48. Ruyechan W. T., Morse L. S., Knipe D. M., 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 Feb;29(2):677–697. doi: 10.1128/jvi.29.2.677-697.1979. [DOI] [PMC free article] [PubMed] [Google Scholar]
  49. Simmons A., Tscharke D., Speck P. The role of immune mechanisms in control of herpes simplex virus infection of the peripheral nervous system. Curr Top Microbiol Immunol. 1992;179:31–56. doi: 10.1007/978-3-642-77247-4_3. [DOI] [PubMed] [Google Scholar]
  50. Smiley J. R., Johnson D. C., Pizer L. I., Everett R. D. The ICP4 binding sites in the herpes simplex virus type 1 glycoprotein D (gD) promoter are not essential for efficient gD transcription during virus infection. J Virol. 1992 Feb;66(2):623–631. doi: 10.1128/jvi.66.2.623-631.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]
  51. Ugolini G., Kuypers H. G., Simmons A. Retrograde transneuronal transfer of herpes simplex virus type 1 (HSV 1) from motoneurones. Brain Res. 1987 Oct 6;422(2):242–256. doi: 10.1016/0006-8993(87)90931-0. [DOI] [PubMed] [Google Scholar]
  52. Ugolini G., Kuypers H. G., Strick P. L. Transneuronal transfer of herpes virus from peripheral nerves to cortex and brainstem. Science. 1989 Jan 6;243(4887):89–91. doi: 10.1126/science.2536188. [DOI] [PubMed] [Google Scholar]
  53. Vahlne A., Nyström B., Sandberg M., Hamberger A., Lycke E. Attachment of herpes simplex virus to neurons and glial cells. J Gen Virol. 1978 Aug;40(2):359–371. doi: 10.1099/0022-1317-40-2-359. [DOI] [PubMed] [Google Scholar]
  54. Weber P. C., Levine M., Glorioso J. C. Rapid identification of nonessential genes of herpes simplex virus type 1 by Tn5 mutagenesis. Science. 1987 May 1;236(4801):576–579. doi: 10.1126/science.3033824. [DOI] [PubMed] [Google Scholar]
  55. Whealy M. E., Card J. P., Robbins A. K., Dubin J. R., Rziha H. J., Enquist L. W. Specific pseudorabies virus infection of the rat visual system requires both gI and gp63 glycoproteins. J Virol. 1993 Jul;67(7):3786–3797. doi: 10.1128/jvi.67.7.3786-3797.1993. [DOI] [PMC free article] [PubMed] [Google Scholar]
  56. York I. A., Roop C., Andrews D. W., Riddell S. R., Graham F. L., Johnson D. C. A cytosolic herpes simplex virus protein inhibits antigen presentation to CD8+ T lymphocytes. Cell. 1994 May 20;77(4):525–535. doi: 10.1016/0092-8674(94)90215-1. [DOI] [PubMed] [Google Scholar]
  57. Zsak L., Zuckermann F., Sugg N., Ben-Porat T. Glycoprotein gI of pseudorabies virus promotes cell fusion and virus spread via direct cell-to-cell transmission. J Virol. 1992 Apr;66(4):2316–2325. doi: 10.1128/jvi.66.4.2316-2325.1992. [DOI] [PMC free article] [PubMed] [Google Scholar]

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