Infection of Mouse Liver by Human Adenovirus Type 5

Duncan, Sylvia Jean; Gordon, F. C. A.; Gregory, D. W.; McPhie, J. L.; Postlethwaite, R.; White, Ruth; Willcox, H. N. A.

doi:10.1099/0022-1317-40-1-45

Cited by 112 publications

(88 citation statements)

References 2 publications

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“…in the liver, a result in accord with previous studies directly or indirectly noting that HAd5 can indeed replicate its DNA to a limited degree upon infection of the murine liver. [32][33][34][35] In contrast, although each of the other Ad serotype genomes were detected in the murine liver at 6 h.p.i., none showed evidence of significant genomic increases (replication) by 24 h.p.i. In fact, there was a significant decrease in the liver content of HAd3, HAd37 and HAd41 genomes by 24 h.p.i.…”

Section: Alternative Serotype Ads Exhibit Significantly Different Biomentioning

confidence: 93%

Wild-type adenoviruses from groups A–F evoke unique innate immune responses, of which HAd3 and SAd23 are partially complement dependent

et al. 2008

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Section: Alternative Serotype Ads Exhibit Significantly Different Biomentioning

confidence: 93%

Wild-type adenoviruses from groups A–F evoke unique innate immune responses, of which HAd3 and SAd23 are partially complement dependent

et al. 2008

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“…Transaminase elevation is an indicator of liver injury after systemic administration of adenoviruses, 21 and it has been reported after a high-dose injection of oncolytic adenovirus in clinical trials. 22,23 A dose of 5 Â 10 10 viral particles of AdwtRGD caused up to an 80-fold elevation of both AST and ALT compared with non-treated animals ( Figure 2a).…”

Section: Icovir-7 Replication Is Restricted In Normal Cellsmentioning

confidence: 99%

A modified E2F-1 promoter improves the efficacy to toxicity ratio of oncolytic adenoviruses

et al. 2009

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The E2F-1 promoter has been used to confer tumorselective E1A expression in oncolytic adenoviruses. Tumor specificity is mainly conferred by a unique structure of E2F-responsive sites organized in palindromes. Binding of the E2F-pRb complex to these palindromes results in repression of transcription in normal cells. Owing to deregulation of the Rb/p16 pathway in tumor cells, binding of free E2F activates transcription and initiates an autoactivation loop involving E1A and E4-6/7. ICOVIR-7 is a new oncolytic adenovirus designed to increase the E2F dependency of E1A gene expression. It incorporates additional palindromes of E2F-responsive sites in an insulated E2F-1 promoter controlling E1A-D24. The E2F palindromes inhibited replication in normal cells, resulting in a low systemic toxicity at high doses in immunocompetent mice. The D24 deletion avoids a loop of E2F-mediated selfactivation in nontumor cells. Importantly, the additional E2F-binding hairpins boost the positive feedback loop on the basis of E1A-mediated transcriptional regulation of E4-6/7 turned on in cancer cells and increased antitumoral potency as shown in murine subcutaneous xenograft models treated by intravenous injection. These results suggest that the unique genetic combination featured in ICOVIR-7 may be promising for treating disseminated neoplasias.

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“…Although mice are not the natural host for human Ads, past investigators have found that wild-type human Ads can efficiently infect and replicate in the liver, causing morbidity in these animals at high doses (11). In this same vein, we have previously shown that fully replication-incompetent [E1-,E2b-,E3-] Ad vectors persist for longer periods of time in vivo (beyond 3 weeks postinfection) and induce less inflammation and toxicity at 72 h postinfection (hpi) than do [E1-E3-] Ad vectors (13,20).…”

Section: Systemic Ad Vector Injection Causes a Massive Intracellular mentioning

confidence: 99%

Adenovirus Infection Triggers a Rapid, MyD88-Regulated Transcriptome Response Critical to Acute-Phase and Adaptive Immune Responses In Vivo

Hartman¹,

Kiang²,

Everett³

et al. 2007

J Virol

132

156

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Nearly 50 years ago, the discovery of interferon prompted the notion that host cells innately respond to viral invasion. Since that time, technological advances have allowed this response to be extensively characterized and dissected in vitro. However, these advances have only recently been applied to highly complex, in vivo biological systems. To this end, we exploited high-titer adenovirus (Ad) vectors to globally investigate the innate immune response to nonenveloped viral infection in vivo. Our results indicated a potent cellular transcriptome response shortly after infection, with global assessments revealing significant dysregulation in ϳ15% of the measured transcripts derived from Ad vector-transduced tissue. Bioinformatics-based transcriptome analysis revealed a complex innate response to Ad infection, with induction of proinflammatory responses (and suppression of metabolism and mitochondrial genes) akin to those observed when mice are challenged with lipopolysaccharide. Despite this commonality, there were many unique aspects of the Ad-dependent transcriptome response, including the upregulation of several RNA regulatory mechanisms and apoptosisrelated pathways, accompanied by the suppression of lysosomal and endocytic genes. Our results also implicated the Toll-like receptors (TLRs) in these responses, prompting specific investigations into this pathway. By using MyD88KO mice, our results confirmed that Ad-induced dysregulation of five functionally related gene clusters are significantly dependent on this TLR adaptor gene. MyD88 deficiency also resulted in significantly diminished, although not abolished, adaptive and acute-phase immune responses to Ad, confirming the transcriptome data, as well as specifically identifying MyD88 as a significant Ad immunity amplifier and regulator in vivo.For the past 100 years, a significant body of research has sought to understand the mammalian innate immune system, with recent efforts focusing on understanding its molecular workings (5). The discovery of a new family of "pathogen-sensing" genes, the Toll-like receptors (TLRs) and the deciphering of their role in mammalian innate immunity has been an especially robust area of recent investigation (2, 28). However, critical issues remain unanswered, chief among which is the intracellular innate response to viral infections in vivo. While recent studies have sought to investigate intracellular viral immunity and TLR involvement, almost all have relied on tissue culture systems, with little or no attention paid to in vivo models.

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Infection of Mouse Liver by Human Adenovirus Type 5

Cited by 112 publications

References 2 publications

Wild-type adenoviruses from groups A–F evoke unique innate immune responses, of which HAd3 and SAd23 are partially complement dependent

Wild-type adenoviruses from groups A–F evoke unique innate immune responses, of which HAd3 and SAd23 are partially complement dependent

A modified E2F-1 promoter improves the efficacy to toxicity ratio of oncolytic adenoviruses

Adenovirus Infection Triggers a Rapid, MyD88-Regulated Transcriptome Response Critical to Acute-Phase and Adaptive Immune Responses In Vivo

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