• We are sorry, but NCBI web applications do not support your browser and may not function properly. More information
Logo of jvirolPermissionsJournals.ASM.orgJournalJV ArticleJournal InfoAuthorsReviewers
J Virol. Feb 1994; 68(2): 834–845.
PMCID: PMC236520

Herpes simplex virus glycoproteins E and I facilitate cell-to-cell spread in vivo and across junctions of cultured cells.

Abstract

Herpes simplex virus (HSV) glycoproteins E and I (gE and gI) can act as a receptor for the Fc domain of immunoglobulin G (IgG). To examine the role of HSV IgG Fc receptor in viral pathogenesis, rabbits and mice were infected by the corneal route with HSV gE- or gI- mutants. Wild-type HSV-1 produced large dendritic lesions in the corneal epithelium and subsequent stromal disease leading to viral encephalitis, whereas gE- and gI- mutant viruses produced microscopic punctate or small dendritic lesions in the epithelium and no corneal disease or encephalitis. These differences were not related to the ability of the gE-gI oligomer to bind IgG because the differences were observed before the appearance of anti-HSV IgG and in mice, in which IgG binds to the Fc receptor poorly or not at all. Mutant viruses produced small plaques on monolayers of normal human fibroblasts and epithelial cells. Replication of gE- and gI- mutant viruses in human fibroblasts were normal, and the rates of entry of mutant and wild-type viruses into fibroblasts were similar; however, spread of gE- and gI- mutant viruses from cell to cell was significantly slower than that of wild-type HSV-1. In experiments in which fibroblast monolayers were infected with low multiplicities of virus and multiple rounds of infection occurred, the presence of neutralizing antibodies in the culture medium caused the yields of mutant viruses to drop dramatically, whereas there was a lesser effect on the production of wild-type HSV. It appears that cell-to-cell transmission of wild-type HSV-1 occurs by at least two mechanisms: (i) release of virus from cells and entry of extracellular virus into a neighboring cell and (ii) transfer of virus across cell junctions in a manner resistant to neutralizing antibodies. Our results suggest that gE- and gI- mutants are defective in the latter mechanism of spread, suggesting the possibility that the gE-gI complex facilitates virus transfer across cell junctions, a mode of spread which may predominate in some tissues. It is ironic that the gE-gI complex, usually considered an IgG Fc receptor, may, through its ability to mediate cell-to-cell spread, actually protect HSV from IgG in a manner different than previously thought.

Full text

Full text is available as a scanned copy of the original print version. Get a printable copy (PDF file) of the complete article (3.3M), or click on a page image below to browse page by page. Links to PubMed are also available for Selected References.

Images in this article

Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Adler R, Glorioso JC, 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. [PMC free article] [PubMed]
  • Baines JD, 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. [PMC free article] [PubMed]
  • Baines JD, 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. [PMC free article] [PubMed]
  • 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. [PMC free article] [PubMed]
  • Brown SM, Ritchie DA, Subak-Sharpe JH. Genetic studies with herpes simplex virus type 1. The isolation of temperature-sensitive mutants, their arrangement into complementation groups and recombination analysis leading to a linkage map. J Gen Virol. 1973 Mar;18(3):329–346. [PubMed]
  • Bzik DJ, Fox BA, DeLuca NA, Person S. Nucleotide sequence specifying the glycoprotein gene, gB, of herpes simplex virus type 1. Virology. 1984 Mar;133(2):301–314. [PubMed]
  • Cai WH, 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. [PMC free article] [PubMed]
  • Campadelli-Fiume G, Arsenakis M, Farabegoli F, Roizman B. Entry of herpes simplex virus 1 in BJ cells that constitutively express viral glycoprotein D is by endocytosis and results in degradation of the virus. J Virol. 1988 Jan;62(1):159–167. [PMC free article] [PubMed]
  • Card JP, Whealy ME, Robbins AK, Enquist LW. 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. [PMC free article] [PubMed]
  • Carter C, Easty DL. Experimental ulcerative herpetic keratitis. I. Systemic immune responses and resistance to corneal infection. Br J Ophthalmol. 1981 Feb;65(2):77–81. [PMC free article] [PubMed]
  • Centifanto-Fitzgerald YM, Yamaguchi T, Kaufman HE, Tognon M, Roizman B. Ocular disease pattern induced by herpes simplex virus is genetically determined by a specific region of viral DNA. J Exp Med. 1982 Feb 1;155(2):475–489. [PMC free article] [PubMed]
  • Dowler KW, Veltri RW. 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. [PubMed]
  • Eisenberg RJ, Long D, Ponce de Leon M, Matthews JT, Spear PG, Gibson MG, Lasky LA, Berman P, Golub E, Cohen GH. Localization of epitopes of herpes simplex virus type 1 glycoprotein D. J Virol. 1985 Feb;53(2):634–644. [PMC free article] [PubMed]
  • Eisenberg RJ, Ponce de Leon M, Friedman HM, Fries LF, Frank MM, Hastings JC, Cohen GH. Complement component C3b binds directly to purified glycoprotein C of herpes simplex virus types 1 and 2. Microb Pathog. 1987 Dec;3(6):423–435. [PubMed]
  • 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. [PMC free article] [PubMed]
  • Frank I, Friedman HM. 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. [PMC free article] [PubMed]
  • Friedman HM, Cohen GH, Eisenberg RJ, Seidel CA, Cines DB. Glycoprotein C of herpes simplex virus 1 acts as a receptor for the C3b complement component on infected cells. Nature. 1984 Jun 14;309(5969):633–635. [PubMed]
  • Fuller AO, Santos RE, Spear PG. Neutralizing antibodies specific for glycoprotein H of herpes simplex virus permit viral attachment to cells but prevent penetration. J Virol. 1989 Aug;63(8):3435–3443. [PMC free article] [PubMed]
  • Goldstein DJ, Weller SK. An ICP6::lacZ insertional mutagen is used to demonstrate that the UL52 gene of herpes simplex virus type 1 is required for virus growth and DNA synthesis. J Virol. 1988 Aug;62(8):2970–2977. [PMC free article] [PubMed]
  • Gompels U, Minson A. The properties and sequence of glycoprotein H of herpes simplex virus type 1. Virology. 1986 Sep;153(2):230–247. [PubMed]
  • Graham FL, van der Eb AJ. A new technique for the assay of infectivity of human adenovirus 5 DNA. Virology. 1973 Apr;52(2):456–467. [PubMed]
  • Hanke T, Graham FL, Lulitanond V, Johnson DC. Herpes simplex virus IgG Fc receptors induced using recombinant adenovirus vectors expressing glycoproteins E and I. Virology. 1990 Aug;177(2):437–444. [PubMed]
  • Heine JW, Honess RW, Cassai E, Roizman B. Proteins specified by herpes simplex virus. XII. The virion polypeptides of type 1 strains. J Virol. 1974 Sep;14(3):640–651. [PMC free article] [PubMed]
  • Hendricks RL, Epstein RJ, Tumpey T. The effect of cellular immune tolerance to HSV-1 antigens on the immunopathology of HSV-1 keratitis. Invest Ophthalmol Vis Sci. 1989 Jan;30(1):105–115. [PubMed]
  • Hendricks RL, Janowicz M, Tumpey TM. Critical role of corneal Langerhans cells in the CD4- but not CD8-mediated immunopathology in herpes simplex virus-1-infected mouse corneas. J Immunol. 1992 Apr 15;148(8):2522–2529. [PubMed]
  • Hendricks RL, Tumpey TM. Contribution of virus and immune factors to herpes simplex virus type I-induced corneal pathology. Invest Ophthalmol Vis Sci. 1990 Oct;31(10):1929–1939. [PubMed]
  • Hendricks RL, Tumpey TM. Concurrent regeneration of T lymphocytes and susceptibility to HSV-1 corneal stromal disease. Curr Eye Res. 1991;10 (Suppl):47–53. [PubMed]
  • Hendricks RL, Tumpey TM, Finnegan A. IFN-gamma and IL-2 are protective in the skin but pathologic in the corneas of HSV-1-infected mice. J Immunol. 1992 Nov 1;149(9):3023–3028. [PubMed]
  • Herold BC, WuDunn D, Soltys N, Spear PG. 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 Mar;65(3):1090–1098. [PMC free article] [PubMed]
  • Highlander SL, Dorney DJ, Gage PJ, Holland TC, Cai W, Person S, Levine M, Glorioso JC. Identification of mar mutations in herpes simplex virus type 1 glycoprotein B which alter antigenic structure and function in virus penetration. J Virol. 1989 Feb;63(2):730–738. [PMC free article] [PubMed]
  • Highlander SL, Sutherland SL, Gage PJ, Johnson DC, Levine M, Glorioso JC. Neutralizing monoclonal antibodies specific for herpes simplex virus glycoprotein D inhibit virus penetration. J Virol. 1987 Nov;61(11):3356–3364. [PMC free article] [PubMed]
  • Holt GD, Krivan HC, Gasic GJ, Ginsburg V. Antistasin, an inhibitor of coagulation and metastasis, binds to sulfatide (Gal(3-SO4) beta 1-1Cer) and has a sequence homology with other proteins that bind sulfated glycoconjugates. J Biol Chem. 1989 Jul 25;264(21):12138–12140. [PubMed]
  • HUANG AS, WAGNER RR. PENETRATION OF HERPES SIMPLEX VIRUS INTO HUMAN EPIDERMOID CELLS. Proc Soc Exp Biol Med. 1964 Aug-Sep;116:863–869. [PubMed]
  • Huszar D, Beharry S, Bacchetti S. Herpes simplex virus-induced ribonucleotide reductase: development of antibodies specific for the enzyme. J Gen Virol. 1983 Jun;64(Pt 6):1327–1335. [PubMed]
  • Hutchinson L, Browne H, Wargent V, Davis-Poynter N, Primorac S, Goldsmith K, Minson AC, Johnson DC. 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 Apr;66(4):2240–2250. [PMC free article] [PubMed]
  • Johansson PJ, Myhre EB, Blomberg J. Specificity of Fc receptors induced by herpes simplex virus type 1: comparison of immunoglobulin G from different animal species. J Virol. 1985 Nov;56(2):489–494. [PMC free article] [PubMed]
  • Johnson DC, Burke RL, Gregory T. Soluble forms of herpes simplex virus glycoprotein D bind to a limited number of cell surface receptors and inhibit virus entry into cells. J Virol. 1990 Jun;64(6):2569–2576. [PMC free article] [PubMed]
  • Johnson DC, Frame MC, Ligas MW, Cross AM, Stow ND. 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. [PMC free article] [PubMed]
  • Johnson DC, Ligas MW. 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. [PMC free article] [PubMed]
  • Johnson RM, Spear PG. Herpes simplex virus glycoprotein D mediates interference with herpes simplex virus infection. J Virol. 1989 Feb;63(2):819–827. [PMC free article] [PubMed]
  • Ligas MW, Johnson DC. 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. [PMC free article] [PubMed]
  • Litwin V, Jackson W, Grose C. Receptor properties of two varicella-zoster virus glycoproteins, gpI and gpIV, homologous to herpes simplex virus gE and gI. J Virol. 1992 Jun;66(6):3643–3651. [PMC free article] [PubMed]
  • 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. [PMC free article] [PubMed]
  • 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. [PubMed]
  • McGeoch DJ, Dolan A, Donald S, Rixon FJ. Sequence determination and genetic content of the short unique region in the genome of herpes simplex virus type 1. J Mol Biol. 1985 Jan 5;181(1):1–13. [PubMed]
  • Meignier B, Longnecker R, Mavromara-Nazos P, Sears AE, Roizman B. Virulence of and establishment of latency by genetically engineered deletion mutants of herpes simplex virus 1. Virology. 1988 Jan;162(1):251–254. [PubMed]
  • Metcalf JF, Hamilton DS, Reichert RW. Herpetic keratitis in athymic (nude) mice. Infect Immun. 1979 Dec;26(3):1164–1171. [PMC free article] [PubMed]
  • Metcalf JF, Michaelis BA. Herpetic keratitis in inbred mice. Invest Ophthalmol Vis Sci. 1984 Oct;25(10):1222–1225. [PubMed]
  • Minson AC, Hodgman TC, Digard P, Hancock DC, Bell SE, Buckmaster EA. 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 Jun;67(Pt 6):1001–1013. [PubMed]
  • Navarro D, Paz P, Pereira L. Domains of herpes simplex virus I glycoprotein B that function in virus penetration, cell-to-cell spread, and cell fusion. Virology. 1992 Jan;186(1):99–112. [PubMed]
  • Neidhardt H, Schröder CH, Kaerner HC. Herpes simplex virus type 1 glycoprotein E is not indispensable for viral infectivity. J Virol. 1987 Feb;61(2):600–603. [PMC free article] [PubMed]
  • 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. [PMC free article] [PubMed]
  • Rajcáni J, Herget U, Kaerner HC. 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]
  • Roop C, Hutchinson L, Johnson DC. 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. [PMC free article] [PubMed]
  • Sears AE, McGwire BS, Roizman B. Infection of polarized MDCK cells with herpes simplex virus 1: two asymmetrically distributed cell receptors interact with different viral proteins. Proc Natl Acad Sci U S A. 1991 Jun 15;88(12):5087–5091. [PMC free article] [PubMed]
  • Smiley JR, Fong BS, Leung WC. Construction of a double-jointed herpes simplex viral DNA molecule: inverted repeats are required for segment inversion, and direct repeats promote deletions. Virology. 1981 Aug;113(1):345–362. [PubMed]
  • Smiley JR, Johnson DC, Pizer LI, Everett RD. 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. [PMC free article] [PubMed]
  • Stulting RD, Kindle JC, Nahmias AJ. Patterns of herpes simplex keratitis in inbred mice. Invest Ophthalmol Vis Sci. 1985 Oct;26(10):1360–1367. [PubMed]
  • Wander AH, Centifanto YM, Kaufman HE. Strain specificity of clinical isolates of herpes simplex virus. Arch Ophthalmol. 1980 Aug;98(8):1458–1461. [PubMed]
  • Weber PC, Levine M, Glorioso JC. Rapid identification of nonessential genes of herpes simplex virus type 1 by Tn5 mutagenesis. Science. 1987 May 1;236(4801):576–579. [PubMed]
  • 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. [PMC free article] [PubMed]
  • Zuckermann FA, Mettenleiter TC, Schreurs C, Sugg N, Ben-Porat T. Complex between glycoproteins gI and gp63 of pseudorabies virus: its effect on virus replication. J Virol. 1988 Dec;62(12):4622–4626. [PMC free article] [PubMed]

Articles from Journal of Virology are provided here courtesy of American Society for Microbiology (ASM)

Formats:

Related citations in PubMed

See reviews...See all...

Cited by other articles in PMC

See all...

Links

  • Cited in Books
    Cited in Books
    PubMed Central articles cited in books
  • MedGen
    MedGen
    Related information in MedGen
  • PubMed
    PubMed
    PubMed citations for these articles

Recent Activity

Your browsing activity is empty.

Activity recording is turned off.

Turn recording back on

See more...