Response of Vascular Cells to Herpes Simplex Virus (HSV) Infection

Abstract

We have demonstrated that endothelial (EC) and smooth muscle cells (SMC) support replication of several human viruses, including HSV-1 and HSV-2 (Ziaie,et al., 1986; Lashgari, et aL, 1987). HSV infection of EC leads to induction of Fc and C3b receptors and to increased granulocyte adherence to EC. Infection of EC or SMC with HSV-1 or HSV-2 suppresses host-cell protein and proteoglycan synthesis (Ziaie,et al, 1986; Lashgari, et al., 1987; Kaner, et al.,1990). The rate of suppression (2–6 hrs. post-infection) is virus dose dependent and varies with the specific host protein: fibronectin > types I, III and IV collagen > von Willebrand Factor > thrombospondin > actin, and tubulin. The reduction in specific host protein synthesis correlates with reduced steady-state levels of mRNA in infected cells (Brinker, et al., 1990; London,et al., 1990). The early phase (2–4 hrs. post-infection) of suppression of host-cell protein synthesis is virion dependent and independent of new viral protein synthesis. Clinical studies have shown that lithium salts prevent recurrence of HSV infections in humans. In vitro studies have suggested that lithium prevents viral DNA replication. Since early suppression of host-cell protein synthesis is mediated by a virion-associated function, we studied the effect of lithium chloride (LiCl) on protein synthesis and host, as well as viral mRNA levels, in HSV-1 infected EC. In the presence of LiCl, host-cell protein synthesis was maintained for a number of host proteins compared to cultures without LiCl. The ability of LiCl to maintain host protein synthesis in HSV-infected EC depended on virus dose, LiCl concentration (30mM > 20mM > 10mM) and varied with the host protein, i.e. the synthesis was more pronounced for thrombospondin and plasminogen activator inhibitor-1 than for fibronectin or collagen type IV (Ziaie and Kefalides, 1989). LiCl was must effective when added from 0–3 hrs. post-infection. The degree of synthesis of a given protein correlated with an increase in the level of its corresponding mRNA. Although immediate-early proteins of HSV were synthesized, the synthesis of early and late HSV peptides was suppressed. Both the synthesis of HSV DNA polymerase protein and its corresponding mRNA level were totally suppressed in the infected EC treated with LiCl. This resulted in complete suppression of production of infectious HSV particles. (Supported by NIH Grants AR20553, HL29492 and AR07490).