The proposed research project will test the hypothesis that herpes simplex virus type 1 (HSV-1) and herpes simplex virus type 2 (HSV-2) recognize different structural features of heparan sulfate glycosaminoglycans (HSGAGs) as receptors for binding to cells. Although HSV-1 and HSV-2 both bind to HSGAGs, these two serotypes do not exhibit complete competition for cell receptors, and they have different affinities for certain cell types. These findings support the notion that HSV-1 and HSV-2 interact with different subpopulations of HSGAGs. Modified heparin compounds will be used to define various structural features of HSGAGs important for binding of HSV-1 and HSV-2 cells. In addition, Phase I will focus on the interactions of specific glycoproteins with HSGAGs. Glycoproteins C and B (gC and gB) can mediate the binding of HSV to cells by interacting with heparan sulfate (HS). Preliminary data suggest, however, that the individual glycoproteins, gC and gB, interact with different structural components of HS. By studying the ability of modified heparins to inhibit the binding of specific glycoproteins to cells, structural features of HS important for interactions with gC and gB of both HSV-1 and HSV-2 will be determined. Mutant viral strains deficient in gC or gB, as well as purified glycoproteins will be used in these studies. Similarly, the specific domains within the individual glycoproteins important for binding to HS will be identified using, for example, site-directed mutagenesis. The initial focus will be gC-1. Possible aims of studies for Phase II include the mapping of the heparin binding domains of other glycoproteins important in viral attachment and/or defining the structural features of HSGAGs with which HSV-2 heparin-binding glycoproteins interact. Furthermore, the potential role of heparin fragments or analogues as an approach to antiviral therapy will be examined. Together these approaches should allow for determination of the specific regions within both the receptor (HS) and anti-receptor (glycoproteins) important for binding of HSV-1 and HSV-2 cells. This hopefully will lead to a better understanding of tissue tropism and the spectrum of biologic disease caused by the two serotypes, and may allow for the development of new therapeutic modalities.
