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 glycop roteins gC and/or gB with heparan sulfate (HS) glycosaminoglycans on c ell surface proteoglycans. HS and the related glycosaminoglycan, hepar in, comprise a family of heterogeneous carbohydrates composed of long, unbranched polysaccharides modified, for example, by sulfations and a cetylations. To define the specific features of HS important for viral binding, we took advantage of the structural similarities between hep arin and cell surface HS and compared the ability of chemically modifi ed heparin compounds to inhibit the binding of viral particles to the cell surface and subsequent plaque formation. Because binding presumab ly 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 p laque 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, w e 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-negetive strain) to cells, but had little or no inhibitory effect o n binding and subsequent plaque formation for a go-deletion virus. The se results suggest that go and gB interact with different structural f eatures of HS. (C) 1995 Academic Press, Inc.