Scientific Publications by FDA Staff

J Virol 2013 May;87(10):5564-76

Effects of post-challenge administration of ST-246 on dissemination of IHD-J-Luc vaccinia virus in normal and in immune deficient mice reconstituted with T cells.

Zaitseva M, Shotwell E, Scott J, Cruz S, King LR, Manischewitz J, Diaz CG, Jordan R, Grosenbach D, Golding H

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 post challenge administration of ST-246. Total fluxes were recorded in the liver, spleen, lungs, and nasal cavity in live mice following intranasal infection with a recombinant IHD-J-Luc VACV expressing luciferase. Areas Under the flux Curve (AUC) were calculated for individual mice to assess viral loads. Two to five days treatment of normal BALB/c mice with ST-246 at 100 mg/kg starting 24 hr post challenge conferred 100% protection and reduced viral loads in 4 organs compared with control mice. Mice also survived after 5-day treatment with 30 mg/kg of ST-246, yet viral loads and poxes were higher in these mice compared with 100 mg/kg 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 with non-reconstituted and ST-246-treated mice after ST-246 was stopped. Similar protection of nude mice was achieved using adoptively transferred 1.0, 0.1, but not 0.01 million of purified T cells or CD4+ or CD8+ T cells in conjunction with ST-246 treatment. These data suggest that ST-246 protects immune competent 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 challenge.