ENTRY OF HERPES SIMPLEX VIRUS INTO CELLS

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The ultimate objective of studies proposed here is to define the mechanism or mechanisms by which herpes simplex virus (HSV) invades a cell so as to initiate viral gene expression. Current efforts are directed toward identifying and characterizing cell surface components that influence HSV binding to cells and entry and also toward defining functional domains of the HSV glycoproteins that mediate HSV binding and entry. HSV makes its initial contact with cells by binding to glycosaminoglycan (GAG) chains of cell surface proteoglycans (PGs). The virion glycoprotein gC is principally responsible for this binding whereas other virion glycoproteins (gB, gD, gH and gL) are required for penetration. Most cultured cells are susceptible to HSV infection. One exception is the Chinese hamster ovary (CHO) cell line, which is partially resistant to entry of some HSV strains, such as HSV-1(KOS), but is fully susceptible to others. To better define the cell surface components that influence HSV binding and entry, we intend (i) to identify specific PGs that can serve as receptor (at least in part through their GAG chains) for HSV binding to cells; (ii) to explore further some preliminary evidence that GAGs may activate penetration of HSV, as well as serve as receptors for virus binding and (iii) to identify human genes that can render wild-type and mutant CHO cells susceptible to infection by strains of HSV to which the cells are resistant. To better define functional domains of HSV glycoproteins that mediate HSV infection, we intend to (iv) to isolate and characterize the genetic alterations of HSV mutants that exhibit altered specificity for cell binding; (v) to produce recombinant forms of the HSV glycoproteins that mediate virus binding, in order to explore the cell surface expression and distribution of ligands recognized by the viral glycoproteins with wild-type and altered specificity and (v) to determine which gene or genes of a virus that is competent to infect CHO cells must be transferred to HSV-1(KOS) in order to render HSV-1(KOS) competent for infection, thus identifying variable HSV genes that exhibit cell type- dependence in their ability to mediate viral entry. The results of these studies should better define the cell surface PGs to which HSV binds and the functional domains of viral glycoproteins that mediate the binding. In addition, other cell surface components required for HSV entry may be identified and viral genes that govern entry in a cell-specific fashion will be identified. The information and probes developed during the course of this study will permit a more thorough investigation, then is now possible, of some of the key determinants of HSV pathogenesis. Novel antiviral drugs and therapeutic or prophylactic strategies could result from better understanding the mechanism of cell invasion by HSV.