Cidofovir and brincidofovir reduce the pathology caused by systemic infection with human type 5 adenovirus in immunosuppressed Syrian hamsters, while ribavirin is largely ineffective in this model

Tollefson, Ann E.; Spencer, Jacqueline F.; Bai, Ying; Buller, R. Mark; Wold, William S.M.; Tóth, Károly

doi:10.1016/j.antiviral.2014.10.005

Cited by 43 publications

(39 citation statements)

References 29 publications

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“…This HAdV type was previously associated with ARDS in young military (and presumably healthy) trainees [12]. Antiviral agents with reported potential efficacy against adenovirus are cidofovir and brincidofovir, especially in children or hematopoietic cell transplant recipients [17,18]. To date, no randomized controlled trials have been conducted to assess the efficacy of cidofovir in severe adenoviral infections [1,8,9].…”

Section: Discussionmentioning

confidence: 98%

Acute respiratory distress syndrome in adenovirus type 4 pneumonia: A case report

Narra

Bono

Zoccoli

et al. 2016

Journal of Clinical Virology

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Section: Discussionmentioning

confidence: 98%

Acute respiratory distress syndrome in adenovirus type 4 pneumonia: A case report

Narra

Bono

Zoccoli

et al. 2016

Journal of Clinical Virology

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“…With Syrian hamsters, the situation is reversed; the liver pathology is the result of the replication of Ads in permissive hepatocytes (Fig. 11), and it can be alleviated with drugs inhibiting virus replication (32)(33)(34)(35). In this model, the uptake of virus by Kupffer cells reduces infection of the hepatocytes and, thus, mitigates pathogenesis.…”

Section: Ad6 Ad5mentioning

confidence: 92%

“…Using immunosuppressed Syrian hamsters, we have successfully evaluated compounds that may inhibit Ad5 replication and pathogenicity. We found that brincidofovir (previously named CMX-001) (32,33), cidofovir (33), ganciclovir (34), and valganciclovir (35) are very effective.…”

mentioning

confidence: 96%

Pathology in Permissive Syrian Hamsters after Infection with Species C Human Adenovirus (HAdV-C) Is the Result of Virus Replication: HAdV-C6 Replicates More and Causes More Pathology than HAdV-C5

Tollefson

Bai

Spencer

et al. 2017

J Virol

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Syrian hamsters are permissive for the replication of species C human adenoviruses (HAdV-C). The virus replicates to high titers in the liver of these animals after intravenous infection, while respiratory infection results in virus replication in the lung. Here we show that two types belonging to species C, HAdV-C5 and HAdV-C6, replicate to significantly different extents and cause pathology with significantly different severities, with HAdV-C6 replicating better and inducing more severe and more widespread lesions. The virus burdens in the livers of HAdV-C6-infected hamsters are higher than the virus burdens in HAdV-C5-infected ones because more of the permissive hepatocytes get infected. Furthermore, when hamsters are infected intravenously with HAdV-C6, live, infectious virus can be isolated from the lung and the kidney, which is not seen with HAdV-C5. Similarly to mouse models, in hamsters, HAdV-C6 is sequestered by macrophages to a lesser degree than HAdV-C5. Depletion of Kupffer cells from the liver greatly increases the replication of HAdV-C5 in the liver, while it has only a modest effect on the replication of HAdV-C6. Elimination of Kupffer cells also dramatically increases the pathology induced by HAdV-C5. These findings indicate that in hamsters, pathology resulting from intravenous infection with adenoviruses is caused mostly by replication in hepatocytes and not by the abortive infection of Kupffer cells and the following cytokine storm. Immunocompromised human patients can develop severe, often lethal adenovirus infections. Respiratory adenovirus infection among military recruits is a serious problem, in some cases requiring hospitalization of the patient. Furthermore, adenovirus-based vectors are frequently used as experimental viral therapeutic agents. Thus, it is imperative that we investigate the pathogenesis of adenoviruses in a permissive animal model. Syrian hamsters are susceptible to infection with certain human adenoviruses, and the pathology accompanying these infections is similar to what is observed with adenovirus-infected human patients. We demonstrate that replication in permissive cells in a susceptible host animal is a major part of the mechanism by which systemic adenovirus infection induces pathology, as opposed to the chiefly immune-mediated pathology observed in nonsusceptible hosts. These findings support the use of compounds inhibiting adenovirus replication as a means to block adenovirus-induced pathology.

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“…In contrast to other species studied, the Syrian hamster is permissive for species C HAdV replication. HAdV5 causes severe systemic disease in the immunosuppressed Syrian hamster that is similar to that observed in immunocompromised patients, with high replication rates in organs, blood, and tissue, and organ damage [19,60,61]. Several other experimental models (Table 1) have been used to study antiviral therapies against HAdV infection, including mice [62], pigs [63], dogs [64], New Zealand rabbit [65], or cotton rat, a semi-permissive model for HAdV infection that has been used as a model for oncolytic vectors and pneumonia [30,66,67].…”

Section: In Vivo Modelsmentioning

confidence: 91%

Antiadenovirus drug discovery: potential targets and evaluation methodologies

Martínez-Aguado

Serna-Gallego

Marrugal-Lorenzo

et al. 2015

Drug Discovery Today

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Cidofovir and brincidofovir reduce the pathology caused by systemic infection with human type 5 adenovirus in immunosuppressed Syrian hamsters, while ribavirin is largely ineffective in this model

Cited by 43 publications

References 29 publications

Acute respiratory distress syndrome in adenovirus type 4 pneumonia: A case report

Acute respiratory distress syndrome in adenovirus type 4 pneumonia: A case report

Pathology in Permissive Syrian Hamsters after Infection with Species C Human Adenovirus (HAdV-C) Is the Result of Virus Replication: HAdV-C6 Replicates More and Causes More Pathology than HAdV-C5

Antiadenovirus drug discovery: potential targets and evaluation methodologies

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