The effect of triterpenoid compounds on uninfected and herpes simplex virus-infected cells in culture. I: Effect on cell growth, virus particles and virus replication

Summary The related triterpenoid compounds carbenoxolone sodium (CBX) and cicloxolone sodium (CCX) have been investigated in clinical trials for treatment of herpes simplex virus (HSV) infections. When the drugs were tested in vitro, two dose-related effects on BHK cells became apparent: the rate of cell growth was reduced and the drugs exhibited cytotoxicity at high concentrations. Flow 2002 cells, in contrast, were apparently unaffected by all drug concentrations tested. The effect of up to 3 days incubation with 100 µm-CCX on BHK cells was reversible. The presence of 500 µm-CBX or 300 µm-CCX during the HSV replication cycle reduced the infectious virus yield to less than 0.01%: CCX is the more potent anti-herpes agent. The contribution made by cytotoxicity to the overall antiviral effect (measured by 24 h yield) was negligible in Flow 2002 cells, and was relatively unimportant in BHK cells. The amount of HSV-1 or HSV-2 adsorbing to pretreated BHK cells was reduced by 20% and 40% respectively at the highest drug concentrations. Neither 500 µm-CBX nor 300 µm-CCX treatment for 24 h completely inhibited HSV-1 replication, but HSV-2 replication was abolished. The drugs appear to be continuously active throughout the infectious cycle. Infectious HSV particles appeared to become inactivated during or soon after egress from the cell. The two triterpenoid drugs lowered the number of virus particles made, and to a much greater extent reduced the infectious virus yield; thus, the progeny virus quality is greatly diminished. HSV-2 infections were more readily inhibited by either CCX or CBX than were HSV-1 infections.