Identification of structural features of heparin required for inhibition of herpes simplex virus type 1 binding.
Binding of HSV-1 to cells is mediated by interactions of virion glycoproteins gC and/or gB with heparin sulfate (HS) glycosaminoglycans on cell surface proteoglycans. HS and the related glycosaminoglycan, heparin, comprise a family of heterogeneous carbohydrates composed of long, unbranched polysaccharides modified, for example, by sulfations and acetylations. To define the specific features of HS important for viral binding, we took advantage of the structural similarities between heparin and cell surface HS and compared the ability of chemically modified heparin compounds to inhibit the binding of viral particles to the cell surface and subsequent plaque formation. Because binding presumably involves multiple, complex interactions between both known heparin-binding glycoproteins, gC and gB, and cell surface HS, we compared the effects of modified heparin compounds on the binding and subsequent plaque formation of wild-type and gC-negative strains of HSV-1 and, in select cases, the binding of gB-negative virus to cells. We identified specific structural features of heparin essential for the inhibition of viral binding. For example, both N-sulfation and 6-O-sulfation must be important determinants since desulfation of heparin at these sites abolished or decreased the antiviral activity of heparin. Moreover, we found that the antiviral activity of heparin was independent of its anticoagulant activity. Carboxyl-reduced and 2,3-O-desulfated heparin selectively inhibited binding of gC-positive viruses (wild-type or a gB-negative strain) to cells, but had little or no inhibitory effect on binding and subsequent plaque formation for a gC-deletion virus. These results suggest that gC and gB interact with different structural features of HS.
Herold
B C
BC
University of Chicago, Section of Pediatric Infectious Diseases, Illinois 60637-1470.
Gerber
S I
SI
Polonsky
T
T
Belval
B J
BJ
Shaklee
P N
PN
Holme
K
K
D000818:Animals; D002236:Carbohydrate Conformation; D002240:Carbohydrate Sequence; D002460:Cell Line; D002462:Cell Membrane / Q000187:drug effects / Q000821:virology; D002522:Chlorocebus aethiops; D004305:Dose-Response Relationship, Drug; D006493:Heparin / Q000031:analogs & derivatives / Q000737:chemistry / Q000494:pharmacology*; D018259:Herpesvirus 1, Human / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007700:Kinetics; D008969:Molecular Sequence Data; D013329:Structure-Activity Relationship; D014709:Vero Cells; D010948:Viral Plaque Assay; D014771:Virion / Q000187:drug effects / Q000502:physiology
D006493:Heparin