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

Zaitseva, Marina; Shotwell, Elisabeth; Scott, John; Cruz, Stephanie Oliveira Diaz da; King, Lisa R.; Manischewitz, Jody; Diaz, Claudia G.; Jordan, Robert; Grosenbach, Douglas W.; Golding, Hana

doi:10.1128/jvi.03426-12

Cited by 19 publications

(21 citation statements)

References 29 publications

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“…The data showed that a three-dose or nine-dose regimen of BCV extended survival of nude mice. These data are in agreement with previous reports on another VACV inhibitor, ST-246, including our own studies, demonstrating that the virostatic drug protected immune-deficient mice from lethality while they were on treatment (29,37). As expected, nude mice succumbed after BCV was stopped.…”

Section: Discussionsupporting

confidence: 83%

“…In agreement with our previous studies, 10 6 T cells adoptively transferred into nude mice failed to protect them from infection or to reduce viral loads (29). In contrast, BCV treatment in combination with an adoptive transfer of 10 5 or 10 4 T cells conferred survival to 100% or 60% of mice, respectively.…”

Section: Discussionsupporting

confidence: 78%

“…Since the majority of immunocompromised individuals retain some functional T cells and since in some individuals immune deficiency status may be a result of temporary treatment with immune-modulating therapies, we modeled less severe immunocompromised conditions by partially reconstituting nu/nu mice with T cells from normal mice as previously described (29). BALB/c nu/nu mice received an adoptive transfer with 10 4 , 10 5 , or 10 6 T cells (10 4 Tc, 10 5 Tc, or 10 6 Tc, respectively) isolated from the spleens of normal BALB/c mice, or mice were sham reconstituted with PBS (Fig.…”

Section: Effectmentioning

confidence: 99%

“…To gain further insight into the effect of BCV on viral loads in surviving mice, we subjected acquired photon fluxes to biostatistical analysis; a direct correlation between the acquired photon fluxes per area per second and viral loads (PFU per gram of tissue) was previously described (27,29). Fluxes acquired between days 1 and 21 were used to calculate AUCs for the individual mice in the groups where BCV conferred 100% protection from lethal challenge (Fig.…”

Section: Effectmentioning

confidence: 99%

“…Previous publications including data from our laboratory have shown that whole-body bioluminescence imaging (BLI) provides an advantage over more traditional methods for assessing the effectiveness of vaccines and immunoglobulin-based treatments in mouse models of respiratory challenge with VACV (25)(26)(27)(28)(29). In the current study, we explored the effects of brincidofovir on protection of normal and immune-deficient mice from lethality following intranasal challenge with IHD-J-Luc VACV.…”

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confidence: 99%

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Postchallenge Administration of Brincidofovir Protects Healthy and Immune-Deficient Mice Reconstituted with Limited Numbers of T Cells from Lethal Challenge with IHD-J-Luc Vaccinia Virus

Zaitseva

McCullough

Cruz

et al. 2015

J Virol

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Protection from lethality by postchallenge administration of brincidofovir (BCV, CMX001) was studied in normal and immune-deficient (nude, nu/nu) BALB/c mice infected with vaccinia virus (VACV). Whole-body bioluminescence imaging was used to record total fluxes in the nasal cavity, lungs, spleen, and liver and to enumerate pox lesions on tails of mice infected via the intranasal route with 10 5 PFU of recombinant IHD-J-Luc VACV expressing luciferase. Areas under the flux curve (AUCs) were calculated for individual mice to assess viral loads. A three-dose regimen of 20 mg/kg BCV administered every 48 h starting either on day 1 or day 2 postchallenge protected 100% of mice. Initiating BCV treatment earlier was more efficient in reducing viral loads and in providing protection from pox lesion development. All BCV-treated mice that survived challenge were also protected from rechallenge with IHD-J-Luc or WRvFire VACV without additional treatment. In immune-deficient mice, BCV protected animals from lethality and reduced viral loads while animals were on the drug. Viral recrudescence occurred within 4 to 9 days, and mice succumbed ϳ10 to 20 days after treatment termination. Nude mice reconstituted with 10 5 T cells prior to challenge with 10 4 PFU of IHD-J-Luc and treated with BCV postchallenge survived the infection, cleared the virus from all organs, and survived rechallenge with 10 5 PFU of IHD-J-Luc VACV without additional BCV treatment. Together, these data suggest that BCV protects immunocompetent and partially T cell-reconstituted immune-deficient mice from lethality, reduces viral dissemination in organs, prevents pox lesion development, and permits generation of VACV-specific memory. IMPORTANCEMass vaccination is the primary element of the public health response to a smallpox outbreak. In addition to vaccination, however, antiviral drugs are required for individuals with uncertain exposure status to smallpox or for whom vaccination is contraindicated. Whole-body bioluminescence imaging was used to study the effect of brincidofovir (BCV) in normal and immunedeficient (nu/nu) mice infected with vaccinia virus, a model of smallpox. Postchallenge administration of 20 mg/kg BCV rescued normal and immune-deficient mice partially reconstituted with T cells from lethality and significantly reduced viral loads in organs. All BCV-treated mice that survived infection were protected from rechallenge without additional treatment. In immunedeficient mice, BCV extended survival. The data show that BCV controls viral replication at the site of challenge and reduces viral dissemination to internal organs, thus providing a shield for the developing adaptive immunity that clears the host of virus and builds virus-specific immunological memory. Smallpox was eradicated following a global immunization program using live vaccinia virus (VACV) vaccine implemented by the World Health Organization (WHO). Routine smallpox vaccination was subsequently discontinued due to a low but significant risk of severe adverse reactions. A...

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Section: Discussionsupporting

confidence: 83%

Section: Discussionsupporting

confidence: 78%

Section: Effectmentioning

confidence: 99%

Section: Effectmentioning

confidence: 99%

mentioning

confidence: 99%

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