Inhibition of vesicular stomatitis virus replication by Δ12-prostaglandin J 2 is regulated at two separate levels and is associated with induction of stress protein synthesis

Abstract

Δ 12-Prostaglandin J 2 ( Δ 12-PGJ 2), a naturally occurring dehydration product of prostaglandin D 2, is shown to suppress the replication of vesicular stomatitis virus (VSV) in two different epithelial monkey cell lines. A significant delay in the virus-induced cytopathic effect and a dramatic inhibition of virus production can be obtained at doses which do not inhibit protein synthesis in uninfected cells, and induce the synthesis of heat shock proteins (HSPs) in both uninfected and VSV-infected cells. Δ 12-PGJ 2 is shown to block VSV replication at two separate levels in the early and late phase of the virus replication cycle. Treatment started soon after VSV infection greatly suppresses viral (but not cellular) protein synthesis and prevents the virus-induced shut-off of host cell protein synthesis. This effect is accompanied by the induction of HSP synthesis. Δ 12-PGJ 2-treatment in a late phase of the virus replication cycle, when all virus proteins have been synthesized, still causes a dramatic block of infectious virus production. This block is accompanied by a decrease in [ 3H]glucosamine incorporation into the virus glycoprotein G, at concentrations which do not alter glucosamine uptake by the cells, suggesting that a defect in virus protein glycosylation could be responsible for the antiviral activity. Finally, Δ 12-PGJ 2 causes a decrease of glucosamine incorporation into at least two host cell polypeptides, while the majority of cellular proteins are unaffected and glycosylation of a 47 kDa cellular protein is strongly induced. These selective alterations of protein glycosylation suggest that Δ 12-PGJ 2 affects a specific group of glycosylated proteins. The finding that cyclopentenone prostaglandins act on different events during the virus cycle explains the effectiveness of these compounds in controlling the replication of different types of viruses and presents an attractive new approach to antiviral chemotherapy.