Effects of 2,2'-O-cyclocytidine and acyclovir on latent herpes simplex virus in trigeminal ganglia of mice

Abstract

The effects of 2,2'-O-cyclocytidine (CC) and acyclovir (ACV) on latent herpes simplex virus (HSV) in trigeminal ganglia were studied in an in vitro model using reactivation of HSV type 1 (HSV-1) as a model. It was shown that both CC (10 ,ug/ml) and ACV (2.5 ,ug/ml) significantly inhibited the reactivation of the latent HSV-1 in infected ganglia. The effect of CC (25 jLg/ml), which was as good as that of ACV (10 ,ug/ml), did not last as long as that of ACV after removal of the drugs. The latent state of HSV-1 in vitro was dependent on the continuous presence of either drug. Even though the latent HSV-1 could not be eliminated completely from the trigeminal ganglia by discontinuous administration of either drug, its titers were markedly reduced. The combination of CC and ACV had a synergistic effect on preventing the reactivation of the latent HSV-1 in vitro.Latently infected ganglia have been thought to be the source of virus for recurrent herpetic diseases in humans (8). At present, antiviral chemotherapy is generally recognized as the most promising way to eliminate or control latent herpes simplex virus (HSV) infection of ganglia. Unfortunately, although the prophylactic administration of the available drugs can prevent the establishment of latent HSV infection, there is no drug that has any effect on already established latent HSV infection (2,7,10,11,13). The efficacy of acyclovir (ACV) in preventing the in vitro reactivation of latent HSV has already been confirmed (6, 7, 9), but so far nothing has been reported about the effectiveness of 2,2'-O-cyclocytidine (CC), which has been used in the People's Republic of China for the treatment of HSV ocular diseases for more than 10 years and which has an antiviral effect that has been confirmed in different types of HSV keratitis (3). In this study we investigated the effects of CC and ACV on latent HSV infection in trigeminal ganglia (TG) in combination or singly, and made a preliminary exploration of the possibility of eliminating or controlling latent HSV infection by discontinuous treatment with CC and ACV.MATERIALS AND METHODS Virus. HSV type 1 (HSV-1) strain SM44 was obtained from the Institute of Virology, China National Centre for Preventive Medicine, and was propagated on African green monkey kidney cells (Vero cells) to yield a titer of 106.5 50% tissue culture infective doses (TCID50) per milliliter. Eagle's minimal essential medium was used.Mice. Inbred strain 615 mice (age, 5 weeks; weight, 15 to 18 g) were maintained for at least 1 week before the experiment.Drugs. CC and 9-(2-hydroxyethoxymethyl)guanine (ACV) used in this study were supplied by the Shanghai No. 12 Pharmaceutical Factory and the Hubei Institute of Medicine Industry, respectively. One percent of CC solution and ACV suspension were prepared and stored at -10°C until used.Inoculation of HSV-1. The scarified eyes of mice were inoculated with a 10-,ul suspension of HSV-1 (103 5 TCID50/ml, i.e., 10 times the 50% lethal dose), as described previously (10).Determination of virus titer in TG...

Inhibition of herpes simplex virus-1 infection by MBZM-N-IBT: in silico and in vitro studies

“…The cytotoxic effect of MBZM-N-IBT (50 to 800 µM) on Vero cells was tested previously and the CC50 value was considered to be > 800 µM [13]. To assess the antiviral property of MBZM-N-IBT against HSV-1, both infected and uninfected Vero cells were treated with 100 µM, 150 µM and 200 µM concentrations of MBZM-N-IBT for 24 h. Acyclovir (44.4 µM) was used as a positive control [20]. No morphological change was observed in the uninfected Vero cells with or without treatment of drugs (Fig.…”