Effect of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (brovavir) on experimental infections in mice with herpes simplex virus type 1 strains of different degrees of virulence

Abstract

In vivo antiherpesvirus effects of 1-,-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil (brovavir) were tested in two mouse model infections with herpes simplex virus type 1 (HSV-1) strains which showed different degrees of virulence in mice. Successful efficacies of oral and intraperitoneal (i.p.) treatments with brovavir were demonstrated in both intracerebral and i.p. infections with the HSV-1 WT-51 strain of moderate virulence. However, only weak or modest effects of brovavir were observed against the two model infections with a highly virulent strain, HSV-1 VR-3. Brovavir was not effective in reducing mortality of mice infected i.p. with HSV-1 KOS, which exhibited the highest virulence in mice among HSV-1 strains used when inoculated i.p. However, the drug had a significant effect on intracerebral infection with the KOS strain. Efficacies of oral treatment with brovavir were almost equal to those of i.p. administration in the model infections. After intracerebral inoculation, the VR-3 strain grew in brains of mice at a higher rate than the WT-51 strain. By oral treatment with 50 mg of brovavir per kg twice daily, replication of the WT-51 strain in the brains was markedly suppressed and was eliminated after transient elevation of the titer. Growth of the VR-3 strain in the brains was simply delayed by the drug treatment. Thus, the antiviral efficacy of brovavir in mice was affected by the degree of virulence of the challenge virus strain used for infection.1-,-D-Arabinofuranosyl-E-5-(2-bromovinyl)uraciI (brovavir) is one of the most promising antiherpesviral agents under investigation (7). Previously, we showed in vivo antiviral activity of brovavir in mice infected with herpes simplex virus type 1 (HSV-1) (6). The in vivo effect was almost equivalent to that of E-5-(2-bromovinyl)-2'-deoxyuridine. However, therapeutic efficacies of the antiherpesviral bromovinyl nucleosides we observed were not as marked as those shown by Reefschlager et al.

Effect of 1-beta-D-arabinofuranosyl-E-5-(2-bromovinyl)uracil against herpes simplex virus type 1 infection in immunosuppressed mice

“…Thus, the efficacy of BV-araU against infection with strain KOS(S) was more marked than that against infection with strain WT-51, despite the use of a larger viral inoculum. Differences in the minimum effective doses required for reduction of significant mortality for infections with strains WT-51 and KOS(S) may be-related to the degree of virulence of the challenge virus used, as we reported for normal mice (8). Treatment with 20 mg of BV-araU per kg twice daily led to reduction of the mortality of 7-week-old CYP mice infected with strain WT-51 (Table 2).…”

“…Treatment with 20 and 50 mg/kg, doses at which it reduced the mortality of normal mice (8), prolonged the mean survival time but did not reduce mortality. Effects of BV-araU against infection with strain KOS(S) were more marked; BV-araU at a dose as low as 5 mg/kg reduced the mortality of infected mice.…”

“…with 200 mg of cyclophosphamide (Aldrich Chemical Co., Inc.) per kg of body weight 1 day before virus inoculation by the method of Ikeda et al (2). Two strains of HSV-1 were used; strain WT-51 was moderately virulent (8), and strain KOS(S), a substrain of strain KOS (supplied by Y. Ozaki, Shiga University of Medical Science, Shiga-ken, Japan), was avirulent for non-CYP (normal) mice. There was no significant difference between these two strains in susceptibility to BV-araU [50o plaque reduction doses of BV-araU for strains WT-51 and KOS(S) were 0.020 and 0.082 ,uLg/ml, respectively, when assayed on human embryonic lung cells].…”

“…Four-week-old, random-bred, albino male Swiss ICR mice were obtained as previously described (8). To induce immunosuppression, mice were treated i.p.…”

“…The mortality and mean survival time of CYP mice infected with strain KOS(S) depended upon the age of the mice used. BV-araU was administered orally to infected mice twice daily for 7 days, beginning at 4 h postinfection, as described previously (8). The mice were observed twice daily for 21 days for death.…”