Abstract
As concerns increase about adenovirus type 5 (Ad5) being a safe gene transfer vector, it is important to evaluate its distribution, residence time, and possible toxicity in immunodeficient populations. To characterize the potential risk associated with different Ad5 vector delivery modes, we used immunocompetent and immunodeficient Rag2−/− animals to establish mouse and rat models that could be monitored with bioluminescent imaging following intramuscular or intravascular infection with an engineered replication-incompetent Ad5 virus carrying the firefly luciferase gene (Ad5-Fluc). The Ad5 vector was less well-tolerated by Rag2−/− animals than by wildtype ones, with delayed residence time, wider virus dissemination, less weight gain, and relatively severe pathological changes. In intravascularly Ad5-Fluc-infected Rag2−/− mice, systemic virus dissemination extended from the abdomen to the limbs and head on day 9 post-infection. Additionally, significant increases in plasma TNF-α and IFN-γ, which may be important factors in the heightened immunopathology in the liver and brain, were detected in the Rag2−/− mice 30 days after intravascular delivery. The Ad5 vector was better tolerated after intramuscular delivery than after intravascular delivery. Ad5-Fluc/Rag2−/− mice and rats can be used as reliable models of an immunodeficient population in which to evaluate the safety of Ad5-vectored vaccines or gene therapy products.
Highlights
Adenovirus type 5 (Ad5) is widely used experimentally and clinically for gene delivery in oncology, cardioangiology, and regenerative medicine and is used as a vaccine vector[1,2,3]
A tumour necrosis factor α (TNF-α)- and interferon γ (IFN-γ)-related cytokine storm occurred in the Rag2−/− mice that were infected intravascularly with Adv[5], and the level of the cytokine storm correlated with the pathological changes in the liver and brain
We observed that the number of CD3−NK1.1+ natural killer (NK) cells increased in the Rag2−/− mice (77.3%) compared with the wildtype mice (11.1%) (Supplementary Fig. S1)
Summary
Adenovirus type 5 (Ad5) is widely used experimentally and clinically for gene delivery in oncology, cardioangiology, and regenerative medicine and is used as a vaccine vector[1,2,3]. Immunosuppression occurs in various types of patients, including those infected with human immunodeficiency virus (HIV), the recipients of organ transplantation, and those with hypogammaglobulinaemia[6, 7]. All of these patients are generally characterized by an increased and distinctive susceptibility to various types of pathogens, depending on the nature of the immune defect[8]. The immunodeficient Rag2−/− rats were generated previously to resemble immunodeficient human populations[9]. Both Rag2−/− mice and Rag2−/− rats were used for Ad5 vector safety evaluation. A tumour necrosis factor α (TNF-α)- and interferon γ (IFN-γ)-related cytokine storm occurred in the Rag2−/− mice that were infected intravascularly with Adv[5], and the level of the cytokine storm correlated with the pathological changes in the liver and brain
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