Summary. In the trigeminal ganglia of cats latently infected with feline herpesvirus 1, transcripts of opposite strand to the immediate-early mRNA were detected by in situ hybridization and Northern blot analysis.Feline herpesvirus 1 (FHV-1) is a member of family Herpesviridae, subfamily Alphaherpesvirinae. FHV-1 causes a severe upper respiratory disease such as rhinotracheitis and abortion in cats. In kittens, the infection results in 50% mortality. Like other herpesviruses, FHV-1 causes latent infection, and the site of latency appears to be the tfigeminal ganglia [2]. Recovered animals remain latently infected with the virus, although periodic episodes of virus shedding may occur either spontaneously or be induced by corticosteroid or by the stress of re-housing [3].Recent molecular biological studies on herpes simplex virus 1 (HSV-1), bovine herpesvirus 1 (BHV-1), and swine herpesvirus 1 (SHV-1), demonstrated that only a limited region of the viral genome is transcribed in the ganglionic neurons during latent infection [1,9,12]. To obtain information on the latent infection with FHV-1, we analyzed expression of the genome in the trigeminal ganglia of latently infected cats in the present study.FHV-1 strain C7301, kindly provided by Dr. T. Mikami, University of Tokyo, of 107 TCIDs0/0.2 ml was inoculated by dropping into nasal and ocular routes of six cats (nos. 1-6, 12-18 months old) serologically negative for the homologous virus. One of them (no. 6) was sacrificed on day 3 post inoculation (p.i.) to collect samples of acute phase of infection.FHV-1 DNA was isolated from purified virions grown in CRFK cells as
Antiherpetic activity of (1′S,2′R)-9-{[1′,2′-bis(hydroxymethyl)cycloprop-1′-yl]methyl}guanine (A-5021) was compared with those of acyclovir (ACV) and penciclovir (PCV) in cell cultures. In a plaque reduction assay using a selection of human cells, A-5021 showed the most potent activity in all cells. Against clinical isolates of herpes simplex virus type 1 (HSV-1,n = 5) and type 2 (HSV-2, n = 6), mean 50% inhibitory concentrations (IC50s) for A-5021 were 0.013 and 0.15 μg/ml, respectively, in MRC-5 cells. Corresponding IC50s for ACV were 0.22 and 0.30 μg/ml, and those for PCV were 0.84 and 1.5 μg/ml, respectively. Against clinical isolates of varicella-zoster virus (VZV, n = 5), mean IC50s for A-5021, ACV, and PCV were 0.77, 5.2, and 14 μg/ml, respectively, in human embryonic lung (HEL) cells. A-5021 showed considerably more prolonged antiviral activity than ACV when infected cells were treated for a short time. The selectivity index, the ratio of 50% cytotoxic concentration to IC50, of A-5021 was superior to those of ACV and PCV for HSV-1 and almost comparable for HSV-2 and VZV. In a growth inhibition assay of murine granulocyte-macrophage progenitor cells, A-5021 showed the least inhibitory effect of the three compounds. These results show that A-5021 is a potent and selective antiviral agent against HSV-1, HSV-2, and VZV.
A series of 5-substituted uracil nucleoside derivatives with a 1(1'S, 2'R)-[1',2'-bis(hydroxymethyl)cyclopropyl]methyl group as an acyclosugar moiety were synthesized and evaluated for their anti-herpetic activities. Among the compounds synthesized, (E)-5-halovinyluracil derivatives showed superior anti-varicella zoster virus (VZV) activity over acyclovir (ACV) but were less potent than ACV against herpes symplex virus type-1 (HSV-1). IC(50) values for the VZV Kawaguchi strain were 0.027 for Br, 0.070 for Cl, and 0.054 microg/mL for I derivatives and 3.4 microg/mL for ACV. The most potent compound, (1'S,2'R)-5-[(E)-2-bromoethenyl]-1-[[1', 2'-bis(hydroxymethyl)cycloprop-1'-yl]methyl]-2,4-(1H, 3H)-pyrimidinedione (3a), was 40-60-fold more potent than ACV against clinical isolates of VZV. It showed good oral bioavailability in rats (68.5%) and, unlike (E)-5-(2-bromovinyl)-1-beta-D-arabinofuranosyluracil (BVaraU), did not result in the release of (E)-5-(2-bromovinyl)uracil (BVU), a potent dihydropyrimidine dehydrogenase inhibitor, in plasma after oral administration.
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