title: Limited efficacy of inhibitors of herpes simplex virus DNA synthesis in murine models of recrudescent disease.
abstract: The herpesvirus DNA polymerase inhibitor foscarnet, applied topically, and the anti-herpesvirus guanosine analogue buciclovir, given orally, decreased virus replication and disease development in primary skin infections of mice caused by herpes simplex virus type 1 (HSV-1). If the same tissues were infected via sensory nerves, following zosteriform spread of the virus the same treatments showed strongly decreased efficacy, or were inefficacious, when started before development of clinical signs in the infected tissues. These results were obtained in murine models of zosteriform spread of HSV-1 to the ear (following inoculation of the ventral side of the neck) or to the lower flank (following inoculation of the upper flank). In these models the immune system played a dominant role in virus clearance. The topically applied foscarnet could not prevent disease development in these models of recrudescent disease even when applied before the virus was detected in the skin, but a decrease in virus titre was obtained. Orally administered buciclovir lost efficacy when administered at the time of virus entry into the skin, i.e. 1 or 2 days before development of clinical signs. In the flank model, measuring lesion development, orally administered acyclovir also had a strongly decreased efficacy, when compared with its effect during infections in which lesion development did not involve translocation of virus through nerves. In the presence of developing immunity the inhibitors could not accelerate the clearance of virus from infected tissues. Furthermore, all treatments (topical foscarnet and oral buciclovir or acyclovir) were without effect on disease development when treatment was initiated on appearance of the first clinical signs of disease. As disease development following zosteriform spread of HSV resembles that in recurrent herpes in humans, and as the limited efficacy of the inhibitors observed resembles the poor results obtained with inhibitors of herpesvirus DNA synthesis in clinical studies on the treatment of symptomatic recurrent herpes, we suggest the use of animal models of zosteriform spread for pre-clinical evaluation of new antiherpes drugs.
authors.affiliation: Department of Antiviral Therapy, Astra Alab AB, Södertälje, Sweden.
authors.forename: A
authors.initials: A
authors.lastname: Kristofferson
authors.forename: A C
authors.initials: AC
authors.lastname: Ericson
authors.forename: A
authors.initials: A
authors.lastname: Sohl-Akerlund
authors.forename: R
authors.initials: R
authors.lastname: Datema
mesh_terms: D000212:Acyclovir / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000494:pharmacology / Q000627:therapeutic use*; D000284:Administration, Oral; D000287:Administration, Topical; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use*; D004261:DNA Replication / Q000187:drug effects; D004279:DNA, Viral / Q000096:biosynthesis / Q000187:drug effects; D004195:Disease Models, Animal; D017245:Foscarnet; D006561:Herpes Simplex / Q000188:drug therapy* / Q000382:microbiology; D008297:Male; D051379:Mice; D009422:Nervous System Diseases / Q000188:drug therapy; D009943:Organophosphorus Compounds / Q000627:therapeutic use*; D010746:Phosphonoacetic Acid / Q000008:administration & dosage / Q000031:analogs & derivatives / Q000494:pharmacology / Q000627:therapeutic use*; D012008:Recurrence; D018139:Simplexvirus / Q000187:drug effects / Q000235:genetics / Q000502:physiology; D012867:Skin / Q000382:microbiology; D012874:Skin Diseases, Infectious / Q000188:drug therapy; D014779:Virus Replication / Q000187:drug effects
chemical_list: D000998:Antiviral Agents; D004279:DNA, Viral; D009943:Organophosphorus Compounds; D017245:Foscarnet; C037591:buciclovir; D010746:Phosphonoacetic Acid; D000212:Acyclovir