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J Virol. Jun 1996; 70(6): 3461–3469.
PMCID: PMC190219

Differences in the susceptibility of herpes simplex virus types 1 and 2 to modified heparin compounds suggest serotype differences in viral entry.


Although heparan sulfate (HS) serves as an initial receptor for the binding of both herpes simplex virus type 1 (HSV-1) and HSV-2 to cell surfaces, the two serotypes differ in epidemiology, cell tropism, and ability to compete for viral receptors in vitro. These observations are not necessarily contradictory and can be explained if the two serotypes recognize different structural features of HS. To compare the specific features of HS important for the binding and infection of HSV-1 and HSV-2, we took advantage of structural similarities between heparin and cell surface HS and compared the abilities of chemically modified heparin compounds to inhibit plaque formation. We found that the antiviral activity of heparin for both serotypes was independent of anticoagulant activity. Moreover, specific negatively charged regions of the polysaccharide, including N sulfations and the carboxyl groups, are key structural features for interactions of both HSV-1 and HSV-2 with cell surfaces since N desulfation or carboxyl reduction abolished heparin's antiviral activity. In contrast, 6-O sulfations and 2-,3-O sulfations are important determinants primarily for HSV- 1 infection. The O-desulfated heparins had little or no inhibitory effect on HSV-1 infection but inhibited HSV-2 infection. Using a series of intertypic recombinant mutant viruses, we found that susceptibility to O-desulfated heparins can be transferred to HSV-1 by the gene for glycoprotein C of HSV-2 (gC-2). This supports the notion that the envelope glycoproteins of HSV-1 and HSV-2 interact with different affinities for different structural features of heparin. To determine if the modified heparin compounds inhibited plaque formation by competing with cell surface HS for viral attachment, binding studies were also performed. As anticipated, most compounds inhibited binding and plaque formation in parallel. However, several compounds inhibited the binding of HSV-1 to cells during the initial attachment period at 4 degrees C; this inhibitory effect was reversed when the cells and inoculum were shifted to 37 degrees C. This temperature-dependent differential response to modified heparin compounds was evident primarily when glycoprotein C of HSV-1 (gC-1) was present in the virion envelope. Minimal temperature-dependent differences were seen for HSV-1 with gC-1 deleted and for HSV-2. These results suggest differences in the interactions of HSV-1 and HSV-2 with cell surface HS that may influence cell tropism.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Bae J, Desai UR, Pervin A, Caldwell EE, Weiler JM, Linhardt RJ. Interaction of heparin with synthetic antithrombin III peptide analogues. Biochem J. 1994 Jul 1;301(Pt 1):121–129. [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]
  • Campadelli-Fiume G, Stirpe D, Boscaro A, Avitabile E, Foá-Tomasi L, Barker D, Roizman B. Glycoprotein C-dependent attachment of herpes simplex virus to susceptible cells leading to productive infection. Virology. 1990 Sep;178(1):213–222. [PubMed]
  • Cassai EN, Sarmiento M, Spear PG. Comparison of the virion proteins specified by herpes simplex virus types 1 and 2. J Virol. 1975 Nov;16(5):1327–1331. [PMC free article] [PubMed]
  • Compton T, Nowlin DM, Cooper NR. Initiation of human cytomegalovirus infection requires initial interaction with cell surface heparan sulfate. Virology. 1993 Apr;193(2):834–841. [PubMed]
  • Conley AJ, Knipe DM, Jones PC, Roizman B. Molecular genetics of herpes simplex virus. VII. Characterization of a temperature-sensitive mutant produced by in vitro mutagenesis and defective in DNA synthesis and accumulation of gamma polypeptides. J Virol. 1981 Jan;37(1):191–206. [PMC free article] [PubMed]
  • David G. Integral membrane heparan sulfate proteoglycans. FASEB J. 1993 Aug;7(11):1023–1030. [PubMed]
  • Ejercito PM, Kieff ED, 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. [PubMed]
  • Fernandes J, Tang D, Leone G, Lee PW. Binding of reovirus to receptor leads to conformational changes in viral capsid proteins that are reversible upon virus detachment. J Biol Chem. 1994 Jun 24;269(25):17043–17047. [PubMed]
  • Flynn DC, Meyer WJ, Mackenzie JM, Jr, Johnston RE. A conformational change in Sindbis virus glycoproteins E1 and E2 is detected at the plasma membrane as a consequence of early virus-cell interaction. J Virol. 1990 Aug;64(8):3643–3653. [PMC free article] [PubMed]
  • Flynn SJ, Ryan P. A heterologous heparin-binding domain can promote functional attachment of a pseudorabies virus gC mutant to cell surfaces. J Virol. 1995 Feb;69(2):834–839. [PMC free article] [PubMed]
  • Fuller AO, Lee WC. Herpes simplex virus type 1 entry through a cascade of virus-cell interactions requires different roles of gD and gH in penetration. J Virol. 1992 Aug;66(8):5002–5012. [PMC free article] [PubMed]
  • Gerber SI, Belval BJ, Herold BC. Differences in the role of glycoprotein C of HSV-1 and HSV-2 in viral binding may contribute to serotype differences in cell tropism. Virology. 1995 Dec 1;214(1):29–39. [PubMed]
  • Gruenheid S, Gatzke L, Meadows H, Tufaro F. Herpes simplex virus infection and propagation in a mouse L cell mutant lacking heparan sulfate proteoglycans. J Virol. 1993 Jan;67(1):93–100. [PMC free article] [PubMed]
  • Habuchi H, Suzuki S, Saito T, Tamura T, Harada T, Yoshida K, Kimata K. Structure of a heparan sulphate oligosaccharide that binds to basic fibroblast growth factor. Biochem J. 1992 Aug 1;285(Pt 3):805–813. [PMC free article] [PubMed]
  • Haywood AM. Virus receptors: binding, adhesion strengthening, and changes in viral structure. J Virol. 1994 Jan;68(1):1–5. [PMC free article] [PubMed]
  • Herold BC, Gerber SI, Polonsky T, Belval BJ, Shaklee PN, Holme K. Identification of structural features of heparin required for inhibition of herpes simplex virus type 1 binding. Virology. 1995 Feb 1;206(2):1108–1116. [PubMed]
  • Herold BC, Spear PG. Neomycin inhibits glycoprotein C (gC)-dependent binding of herpes simplex virus type 1 to cells and also inhibits postbinding events in entry. Virology. 1994 Aug 15;203(1):166–171. [PubMed]
  • Herold BC, Visalli RJ, Susmarski N, Brandt CR, Spear PG. Glycoprotein C-independent binding of herpes simplex virus to cells requires cell surface heparan sulphate and glycoprotein B. J Gen Virol. 1994 Jun;75(Pt 6):1211–1222. [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]
  • Holland TC, Sandri-Goldin RM, Holland LE, Marlin SD, Levine M, Glorioso JC. Physical mapping of the mutation in an antigenic variant of herpes simplex virus type 1 by use of an immunoreactive plaque assay. J Virol. 1983 May;46(2):649–652. [PMC free article] [PubMed]
  • Ishihara M, Shaklee PN, Yang Z, Liang W, Wei Z, Stack RJ, Holme K. Structural features in heparin which modulate specific biological activities mediated by basic fibroblast growth factor. Glycobiology. 1994 Aug;4(4):451–458. [PubMed]
  • Jackson RL, Busch SJ, Cardin AD. Glycosaminoglycans: molecular properties, protein interactions, and role in physiological processes. Physiol Rev. 1991 Apr;71(2):481–539. [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, 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]
  • Karger A, Mettenleiter TC. Glycoproteins gIII and gp50 play dominant roles in the biphasic attachment of pseudorabies virus. Virology. 1993 Jun;194(2):654–664. [PubMed]
  • Kari B, Gehrz R. A human cytomegalovirus glycoprotein complex designated gC-II is a major heparin-binding component of the envelope. J Virol. 1992 Mar;66(3):1761–1764. [PMC free article] [PubMed]
  • Kari B, Gehrz R. Structure, composition and heparin binding properties of a human cytomegalovirus glycoprotein complex designated gC-II. J Gen Virol. 1993 Feb;74(Pt 2):255–264. [PubMed]
  • Kiefer MC, Stephans JC, Crawford K, Okino K, Barr PJ. Ligand-affinity cloning and structure of a cell surface heparan sulfate proteoglycan that binds basic fibroblast growth factor. Proc Natl Acad Sci U S A. 1990 Sep;87(18):6985–6989. [PMC free article] [PubMed]
  • Kieff ED, Bachenheimer SL, Roizman B. Size, composition, and structure of the deoxyribonucleic acid of herpes simplex virus subtypes 1 and 2. J Virol. 1971 Aug;8(2):125–132. [PMC free article] [PubMed]
  • Kjellén L, Lindahl U. Proteoglycans: structures and interactions. Annu Rev Biochem. 1991;60:443–475. [PubMed]
  • Langeland N, Holmsen H, Lillehaug JR, Haarr L. Evidence that neomycin inhibits binding of herpes simplex virus type 1 to the cellular receptor. J Virol. 1987 Nov;61(11):3388–3393. [PMC free article] [PubMed]
  • Langeland N, Moore LJ, Holmsen H, Haarr L. Interaction of polylysine with the cellular receptor for herpes simplex virus type 1. J Gen Virol. 1988 Jun;69(Pt 6):1137–1145. [PubMed]
  • Langeland N, Oyan AM, Marsden HS, Cross A, Glorioso JC, Moore LJ, Haarr L. Localization on the herpes simplex virus type 1 genome of a region encoding proteins involved in adsorption to the cellular receptor. J Virol. 1990 Mar;64(3):1271–1277. [PMC free article] [PubMed]
  • Liang XP, Babiuk LA, van Drunen Littel-van den Hurk S, Fitzpatrick DR, Zamb TJ. Bovine herpesvirus 1 attachment to permissive cells is mediated by its major glycoproteins gI, gIII, and gIV. J Virol. 1991 Mar;65(3):1124–1132. [PMC free article] [PubMed]
  • Lindahl U, Kjellén L. Heparin or heparan sulfate--what is the difference? Thromb Haemost. 1991 Jul 12;66(1):44–48. [PubMed]
  • Lindahl U, Thunberg L, Bäckström G, Riesenfeld J, Nordling K, Björk I. Extension and structural variability of the antithrombin-binding sequence in heparin. J Biol Chem. 1984 Oct 25;259(20):12368–12376. [PubMed]
  • Lycke E, Johansson M, Svennerholm B, Lindahl U. Binding of herpes simplex virus to cellular heparan sulphate, an initial step in the adsorption process. J Gen Virol. 1991 May;72(Pt 5):1131–1137. [PubMed]
  • McClain DS, Fuller AO. Cell-specific kinetics and efficiency of herpes simplex virus type 1 entry are determined by two distinct phases of attachment. Virology. 1994 Feb;198(2):690–702. [PubMed]
  • Mettenleiter TC, Zsak L, Zuckermann F, Sugg N, Kern H, Ben-Porat T. Interaction of glycoprotein gIII with a cellular heparinlike substance mediates adsorption of pseudorabies virus. J Virol. 1990 Jan;64(1):278–286. [PMC free article] [PubMed]
  • Neyts J, Snoeck R, Schols D, Balzarini J, Esko JD, Van Schepdael A, De Clercq E. Sulfated polymers inhibit the interaction of human cytomegalovirus with cell surface heparan sulfate. Virology. 1992 Jul;189(1):48–58. [PubMed]
  • Okazaki K, Matsuzaki T, Sugahara Y, Okada J, Hasebe M, Iwamura Y, Ohnishi M, Kanno T, Shimizu M, Honda E, et al. BHV-1 adsorption is mediated by the interaction of glycoprotein gIII with heparinlike moiety on the cell surface. Virology. 1991 Apr;181(2):666–670. [PubMed]
  • Oyan AM, Dolter KE, Langeland N, Goins WF, Glorioso JC, Haarr L, Crumpacker CS. Resistance of herpes simplex virus type 2 to neomycin maps to the N-terminal portion of glycoprotein C. J Virol. 1993 May;67(5):2434–2441. [PMC free article] [PubMed]
  • Sawitzky D, Hampl H, Habermehl KO. Comparison of heparin-sensitive attachment of pseudorabies virus (PRV) and herpes simplex virus type 1 and identification of heparin-binding PRV glycoproteins. J Gen Virol. 1990 May;71(Pt 5):1221–1225. [PubMed]
  • Schreurs C, Mettenleiter TC, Zuckermann F, Sugg N, Ben-Porat T. Glycoprotein gIII of pseudorabies virus is multifunctional. J Virol. 1988 Jul;62(7):2251–2257. [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]
  • Shieh MT, Spear PG. Herpesvirus-induced cell fusion that is dependent on cell surface heparan sulfate or soluble heparin. J Virol. 1994 Feb;68(2):1224–1228. [PMC free article] [PubMed]
  • Shieh MT, WuDunn D, Montgomery RI, Esko JD, Spear PG. Cell surface receptors for herpes simplex virus are heparan sulfate proteoglycans. J Cell Biol. 1992 Mar;116(5):1273–1281. [PMC free article] [PubMed]
  • Spivak-Kroizman T, Lemmon MA, Dikic I, Ladbury JE, Pinchasi D, Huang J, Jaye M, Crumley G, Schlessinger J, Lax I. Heparin-induced oligomerization of FGF molecules is responsible for FGF receptor dimerization, activation, and cell proliferation. Cell. 1994 Dec 16;79(6):1015–1024. [PubMed]
  • Svennerholm B, Jeansson S, Vahlne A, Lycke E. Involvement of glycoprotein C (gC) in adsorption of herpes simplex virus type 1 (HSV-1) to the cell. Arch Virol. 1991;120(3-4):273–279. [PubMed]
  • Swain MA, Peet RW, Galloway DA. Characterization of the gene encoding herpes simplex virus type 2 glycoprotein C and comparison with the type 1 counterpart. J Virol. 1985 Feb;53(2):561–569. [PMC free article] [PubMed]
  • Tal-Singer R, Peng C, Ponce De Leon M, Abrams WR, Banfield BW, Tufaro F, Cohen GH, Eisenberg RJ. Interaction of herpes simplex virus glycoprotein gC with mammalian cell surface molecules. J Virol. 1995 Jul;69(7):4471–4483. [PMC free article] [PubMed]
  • Turnbull JE, Fernig DG, Ke Y, Wilkinson MC, Gallagher JT. Identification of the basic fibroblast growth factor binding sequence in fibroblast heparan sulfate. J Biol Chem. 1992 May 25;267(15):10337–10341. [PubMed]
  • Vahlne A, Svennerholm B, Lycke E. Evidence for herpes simplex virus type-selective receptors on cellular plasma membranes. J Gen Virol. 1979 Jul;44(1):217–225. [PubMed]
  • Vahlne A, Svennerholm B, Sandberg M, Hamberger A, Lycke E. Differences in attachment between herpes simplex type 1 and type 2 viruses to neurons and glial cells. Infect Immun. 1980 Jun;28(3):675–680. [PMC free article] [PubMed]
  • WuDunn D, Spear PG. Initial interaction of herpes simplex virus with cells is binding to heparan sulfate. J Virol. 1989 Jan;63(1):52–58. [PMC free article] [PubMed]
  • Yayon A, Klagsbrun M, Esko JD, Leder P, Ornitz DM. Cell surface, heparin-like molecules are required for binding of basic fibroblast growth factor to its high affinity receptor. Cell. 1991 Feb 22;64(4):841–848. [PubMed]
  • Zsak L, Sugg N, Ben-Porat T, Robbins AK, Whealy ME, Enquist LW. The gIII glycoprotein of pseudorabies virus is involved in two distinct steps of virus attachment. J Virol. 1991 Aug;65(8):4317–4324. [PMC free article] [PubMed]
  • Zuckermann F, Zsak L, Reilly L, Sugg N, Ben-Porat T. Early interactions of pseudorabies virus with host cells: functions of glycoprotein gIII. J Virol. 1989 Aug;63(8):3323–3329. [PMC free article] [PubMed]

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