The effect of HSV multiplication rate on antiviral drug efficacy in vitro

HSV-1 multiplication rates have been shown to vary in different tissues and the rate of multiplication may correlate with susceptibility to antiviral chemotherapy. Herpetic stromal keratitis is a necrotizing condition refractive to antiviral therapy and this lack of antiviral efficacy in stromal disease may be the result of very low rates of viral replication in the corneal stromal keratocytes. In this study, we investigated the efficacy of antiviral drugs in an in vitro system in which the virus multiplication rate is slow. In this system, the reduced rate of virus multiplication is achieved by a reduction in the incubation temperature. Vero cells were infected at one of several multiplicities of infection with McKrae strain HSV-1 and incubated for 24, 48, or 72 h at 26 or 36.5 degrees C in the presence or absence of trifluridine (50 micrograms/ml) or acyclovir (20 micrograms/ml). Both drugs suppressed viral replication at 36.5 degrees C. However, under some specific sets of conditions, trifluridine was not effective in suppressing viral replication in cells incubated at 26 degrees C. At this temperature, viral replication and cell metabolism are slowed to a pace which may be similar to that which occurs in corneal stromal keratocytes in vivo. Acyclovir significantly reduced HSV-1 replication under all conditions at 26 degrees C, indicating that the antiviral activity of this compound is effective in cells whose metabolic rate is slow and in which viral replication is taking place slowly.