Pathogenicity of Glycoprotein C-Negative Herpes Simplex Virus Type 1 in Herpetic Keratitis

  • Yasushi Toh
  • Yasufumi Hidaka
  • Yuji Kumano
  • Hiroko Minagawa
  • Ryoichi Mori
Part of the Frontiers of Virology book series (FRVIROLOGY, volume 3)


Recurrent stromal keratitis induced by herpes simplex virus (HSV) type 1 is one of the most important problems in herpetic ocular diseases and has been considered to represent the host’s immunopathologic response to the virus. In the pathogenicity of this disease, glycoprotein C (gC) of HSV-1 has been shown to be essential, because it is reported as immunodominant antigen to induce HSVspecific memory cytotoxic T lymphocytes. gC also functions as a receptor of complement C3b and has been thought to play an important role in natural infection of HSV. Recently, we isolated HSV-1 strains from a patient with recurrent herpetic keratitis. Interestingly, these viruses were shown to be gCnegative by using two different anti-HSV-1, gC-specific monoclonal antibodies. The clinical isolation of the gC-negative HSV strain is an extremely rare event. Molecular analyses of the gC-negative phenotype of these HSV-1 strains revealed that a premature termination of the translation due to a point mutation of the nucleotide occurred in the mid portion of the gC open reading frame and consequently, a truncated, immature gC molecule lacking the transmembrane domain was secreted to the extracellular fluid. We also demonstrated the important role of gC in protection of the virion envelope against complement-mediated damage, by using the gC-positive recombinant viruses derived from one of these clinical isolates. It is thus expected that these rare HSV-1 strains will provide us with valuable information concerning the in vivo functions of gC, especially in ocular disease. The requirement of gC in herpetic stromal keratitis is also discussed.


Herpes Simplex Virus Type Herpetic Keratitis Acute Retinal Necrosis Stromal Keratitis Herpetic Stromal Keratitis 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.


  1. Atherton SS, Kanter MY, Streilein JW (1991) ACAID requires early replication of HSV in the injected eye. Curr Eye Res 10: 75–80PubMedCrossRefGoogle Scholar
  2. Blacklaws BA, Nash AA, Darby G (1987) Specificity of the immune response of mice to herpes simplex virus glycoprotein G and D constitutively expressed on L cell lines. J Gen Virol 68: 1103–1114PubMedCrossRefGoogle Scholar
  3. Boisjoly HM, Woog JJ, Pavan-Langston D, Park N-H (I 984) Prophylactic topical cyclosporine in experimental herpetic stromal keratitis. Arch Ophthalmol 102: 1804–1807Google Scholar
  4. Brawman-Mintzer O, Mondino BJ, Mayer FJ (1988) The complement system in sclera. Invest Ophthalmol Vis Sci 29: 1756–1758PubMedGoogle Scholar
  5. Friedman HM, Glorioso JC, Cohen GH, Hastings JC, Harris SL, Eisenberg RJ (1986) Binding of complement component C3b to glycoprotein gC of herpes simplex virus type 1: mapping of gC-binding sites and demonstration of conserved C3b binding in low-passage clinical isolates. J Virol 60: 470–475PubMedGoogle Scholar
  6. Frink RJ, Eisenberg R, Cohen G, Wagner EK (1983) Detailed analysis of the portion of the herpes simplex virus type 1 genome encoding glycoprotein C. J Virol 45: 634–647PubMedGoogle Scholar
  7. Glorioso J, Schroder CH, Kumel G, Szczesiul M, Levine M (1984) Immunogenicity of herpes simplex virus glycoprotein gC and gB and their role in protective immunity. J Virol 50: 805–812PubMedGoogle Scholar
  8. Glorioso J, Kees U, Kumel G, Kirschner H, Krammer PH (1985) Identification of herpes simplex virus type 1 (HSV-1) glycoprotein gC as the immunodominant antigen for HSV-1specific memory cytotoxic T lymphocytes. J Immunol 135: 575–582PubMedGoogle Scholar
  9. Harris SL, Frank I, Yee A, Cohen GH, Eisenberg RJ, Friedman HM (1990) Glycoprotein C of herpes simplex virus type 1 prevents complement-mediated cell lysis and virus neutralization. J Infect Dis 162: 331–337PubMedCrossRefGoogle Scholar
  10. Hemady R, Opremcak EM, Zaltas M, Berger A, Foster CS (1989) Herpes simplex virus type-1 strain influence on chorioretinal disease patterns following intracameral inoculation in Igh-1 disparate mice. Invest Ophthalmol Vis Sci 30: 1750–1757PubMedGoogle Scholar
  11. Hendricks RL, Tao MSP, Glorioso JP (1989) Alteration in the antigenic structure of two major HSV-1 glycoproteins, gC and gB, influence immune regulation and susceptibility to murine herpes keratitis. J Immunol 142: 263–269PubMedGoogle Scholar
  12. Hidaka Y, Sakuma S, Kumano Y, Minagawa H, Mori R (1990) Characterization of glycorprotein C-negative mutants of herpes simplex virus type 1 isolated from a patient with keratitis. Arch Virol 113: 195–207PubMedCrossRefGoogle Scholar
  13. Hidaka Y, Sakai Y, Toh Y, Mori R (1991) Glycoprotein C of herpes simplex virus type 1 is essential for the virus to evade antibody-independent complement-mediated virus inactivation and lysis of virus-infected cells. J Gen Virol 72: 915–921PubMedCrossRefGoogle Scholar
  14. Holland TC, Sandri-Goldin RM, Holland LE, Marlin SD, Levine M, Glorioso JC (1983) Physical mapping of the mutation in an antigenic variant of herpes simplex virus type 1 by use of an immunoreactive plaque assay. J Virol 46: 649–652PubMedGoogle Scholar
  15. Johnson RM, Lancki KW, Fitch FW, Spear PG (1990) Herpes simplex virus glycoprotein D is recognized as antigen by CD4’ and CD8’ T lymphocytes from infected mice: characterization of T cell clones. J Immunol 145: 702–710PubMedGoogle Scholar
  16. Kawana T, Suzuki R, Hashido M, Sugase M, Sakaoka H, Kurata T (1991) Detection rate of herpes simplex virus type 1 unreactive to the monoclonal antibody ( MicroTrak) among genital herpes patients (in Japanese ). Clin Virol 19: 376–380Google Scholar
  17. Kumano Y, Yamamoto M, Inomata H, Sakuma S, Hidaka Y, Minagawa H, Mori R (1990) Recurrent herpetic keratitis: failure to detect herpes simplex virus infection using the Syva MicroTrakTM HSV1/HSV2 direct specimen identification/typing test. Ophthalmolgia 201: 169–173CrossRefGoogle Scholar
  18. Lewis ML, Culbertson WW, Post MJD, Miller D, Kokame GT, Dix RD (1989) Herpes simplex virus type 1. A cause of the acute retinal necrosis syndrome. Ophthalmolgia 96: 875–878Google Scholar
  19. Liu Y, Sakai Y, Minagawa H, Toh Y, Ishibashi T, Inomata H, Mori R (1993) Induction of bilateral retinal necrosis in mice by unilateral intracameral inoculation of a glycoproteinC deficient clinical isolate of herpes simplex virus type 1. Arch Virol 129: 105–118PubMedCrossRefGoogle Scholar
  20. Martin S, Courtney RJ, Fowler G, Rouse BT (1988) Herpes simplex virus type 1-specific cytotoxic T lymphocytes recognize virus nonstructural proteins. J Virol 62: 2265–2273PubMedGoogle Scholar
  21. Martin S, Cantin E, Rouse BT (1989) Evaluation of antiviral immunity using vaccinia virus recombinants expressing cloned genes for herpes simplex virus type 1 glycoproteins. J Gen Virol 70: 1359–1370PubMedCrossRefGoogle Scholar
  22. Metcalf JF, Hamilton DS, Reichert RW (1979) Herpetic keratitis in athymic (nude) mice. Infect Immun 26: 1164–1171PubMedGoogle Scholar
  23. Mondiano BJ, Ratajczak HV, Goldberg DB, Schanzlin DJ, Brown SI (1980) Alternate and classical pathway components of complements in the normal cornea. Arch Ophthalmol 98: 346–349CrossRefGoogle Scholar
  24. Roizman G, Sears AE (1990) Herpes simplex viruses and their replication. In: Fields BN, Knipe DM, Chanock RM, Hirsch MS, Melnick JL, Monath TP, Roizman B (eds) Virology 2nd edn. Raven, New York, pp 1795–1841Google Scholar
  25. Rosenthal KL, Smiley JR, South S, Johnson DC (1987) Cells expressing herpes simplex virus glycoprotein gC but not gB, gD, gE are recognized by murine virus-specific cytotoxic T lymphocytes. J Virol 61: 2438–2447PubMedGoogle Scholar
  26. Russell PG, Nasisse MP, Larsen HS, Rouse BT (1984) Role of T-lymphocytes in the pathogenesis of herpetic stromal keratitis. Invest Ophthalmol Vis Sci 25: 938–944PubMedGoogle Scholar
  27. Spear PG (1985) Glycoproteins specified by herpes simplex virus. In: Roizman B (ed) The herpesviruses 3. Plenum, New York, pp 315–356CrossRefGoogle Scholar
  28. Toh Y, Tanaka S, Liu Y, Hidaka Y, Mori R (1993) Molecular characterization of naturally occurring glycoprotein C-negative herpes simplex virus type 1. Arch Virol 129: 119–130PubMedCrossRefGoogle Scholar
  29. Witmer LA, Rosenthal KL, Graham FL, Friedman HM, Yee A, Johnson DC (1990) Cytotoxic T lymphocytes specific for herpes simplex virus ( HSV) studied using adenovirus vectors expressing HSV glycoproteins. J Virol 71: 387–396Google Scholar
  30. Wu C-TB, Levine M, Homa F, Highlander SL, Glorioso JC (1990) Characterization of the antigenic structure of herpes simplex virus type 1 glycoprotein C through DNA sequence analysis of monoclonal antibody-resistant mutants. J Virol 64: 856–863PubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 1994

Authors and Affiliations

  • Yasushi Toh
    • 1
  • Yasufumi Hidaka
    • 1
  • Yuji Kumano
    • 1
  • Hiroko Minagawa
    • 1
  • Ryoichi Mori
    • 1
  1. 1.Department of Virology, Faculty of MedicineKyushu UniversityFukuoka, 812Japan

Personalised recommendations