title: Effects of postchallenge administration of ST-246 on dissemination of IHD-J-Luc vaccinia virus in normal mice and in immune-deficient mice reconstituted with T cells.
abstract: Whole-body bioimaging was used to study dissemination of vaccinia virus (VACV) in normal and in immune deficient (nu(-)/nu(-)) mice protected from lethality by postchallenge administration of ST-246. Total fluxes were recorded in the liver, spleen, lungs, and nasal cavities of live mice after intranasal infection with a recombinant IHD-J-Luc VACV expressing luciferase. Areas under the flux curve were calculated for individual mice to assess viral loads. Treatment for 2 to 5 days of normal BALB/c mice with ST-246 at 100 mg/kg starting 24 h postchallenge conferred 100% protection and reduced viral loads in four organs compared to control mice. Mice also survived after 5 days of treatment with ST-246 at 30 mg/kg, and yet the viral loads and poxes were higher in these mice compared to 100-mg/kg treatment group. Nude mice were not protected by ST-246 alone or by 10 million adoptively transferred T cells. In contrast, nude mice that received T cells and 7-day treatment with ST-246 survived infection and exhibited reduced viral loads compared to nonreconstituted and ST-246-treated mice after ST-246 was stopped. Similar protection of nude mice was achieved using adoptively transferred 1.0 and 0.1 million, but not 0.01 million, purified T cells or CD4(+) or CD8(+) T cells in conjunction with ST-246 treatment. These data suggest that ST-246 protects immunocompetent mice from lethality and reduces viral dissemination in internal organs and poxvirus lesions. Furthermore, immune-deficient animals with partial T cell reconstitution can control virus replication after a course of ST-246 and survive lethal vaccinia virus challenge.
authors.affiliation: Division of Viral Products, Food and Drug Administration, Bethesda, Maryland, USA. marina.zaitseva@fda.hhs.gov
authors.forename: Marina
authors.initials: M
authors.lastname: Zaitseva
authors.forename: Elisabeth
authors.initials: E
authors.lastname: Shotwell
authors.forename: John
authors.initials: J
authors.lastname: Scott
authors.forename: Stephanie
authors.initials: S
authors.lastname: Cruz
authors.forename: Lisa R
authors.initials: LR
authors.lastname: King
authors.forename: Jody
authors.initials: J
authors.lastname: Manischewitz
authors.forename: Claudia G
authors.initials: CG
authors.lastname: Diaz
authors.forename: Robert A
authors.initials: RA
authors.lastname: Jordan
authors.forename: Douglas W
authors.initials: DW
authors.lastname: Grosenbach
authors.forename: Hana
authors.initials: H
authors.lastname: Golding
mesh_terms: D019264:Adoptive Transfer; D000825:Animal Structures / Q000821:virology; D000818:Animals; D000998:Antiviral Agents / Q000008:administration & dosage*; D001549:Benzamides / Q000008:administration & dosage*; D004195:Disease Models, Animal; D005260:Female; D017930:Genes, Reporter; D016867:Immunocompromised Host; D054833:Isoindoles / Q000008:administration & dosage*; D008156:Luciferases / Q000032:analysis / Q000235:genetics; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D013194:Staining and Labeling; D016019:Survival Analysis; D013601:T-Lymphocytes / Q000276:immunology*; D016896:Treatment Outcome; D014615:Vaccinia / Q000473:pathology* / Q000628:therapy*; D014616:Vaccinia virus / Q000472:pathogenicity*; D019562:Viral Load; D051598:Whole Body Imaging; D010797:Phthalimides
chemical_list: D000998:Antiviral Agents; D001549:Benzamides; D054833:Isoindoles; D008156:Luciferases; C505045:tecovirimat; D010797:Phthalimides