Inhibition of Hepatitis B Virus Replication during <i>Schistosoma mansoni</i> Infection in Transgenic Mice

McClary, Heike; Koch, Rick J.; Chisari, Francis V.; Guidotti, Luca G.

doi:10.1084/jem.192.2.289

Cited by 39 publications

(31 citation statements)

References 25 publications

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“…When transgenic mice supporting HBV replication were infected with Schistosoma mansoni, a Th1-type response was followed by both Th1 and Th2 responses. HBV replication levels remained suppressed during both the Th1 response and the subsequent Th1 and Th2 responses (179). In gamma interferon (IFN-␥) knockout mice coinfected with Schistosoma mansoni, the suppression of HBV replication was minimal, suggesting that IFN-␥ is the major antiviral cytokine in Schistosoma mansoni infection.…”

Section: Coinfection With Other Microbesmentioning

confidence: 88%

Molecular Mechanisms Underlying Occult Hepatitis B Virus Infection

2012

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SUMMARY Chronic hepatitis B virus (HBV) infection is a complex clinical entity frequently associated with cirrhosis and hepatocellular carcinoma (HCC). The persistence of HBV genomes in the absence of detectable surface antigenemia is termed occult HBV infection. Mutations in the surface gene rendering HBsAg undetectable by commercial assays and inhibition of HBV by suppression of viral replication and viral proteins represent two fundamentally different mechanisms that lead to occult HBV infections. The molecular mechanisms underlying occult HBV infections, including recently identified mechanisms associated with the suppression of HBV replication and inhibition of HBV proteins, are reviewed in detail. The availability of highly sensitive molecular methods has led to increased detection of occult HBV infections in various clinical settings. The clinical relevance of occult HBV infection and the utility of appropriate diagnostic methods to detect occult HBV infection are discussed. The need for specific guidelines on the diagnosis and management of occult HBV infection is being increasingly recognized; the aspects of mechanistic studies that warrant further investigation are discussed in the final section.

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Section: Coinfection With Other Microbesmentioning

confidence: 88%

Molecular Mechanisms Underlying Occult Hepatitis B Virus Infection

2012

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“…Woodchuck hepatitis B infection was apparently not affected by S. mansoni infection (Andrade et al 2001). Surprisingly hepatitis B replication in HBV transgenic mice was inhibited by S. mansoni infection (McClary et al 2000).…”

Section: Interaction Of Schistosomiasis With Other Diseasesmentioning

confidence: 88%

Experimental models of Schistosoma mansoni infection

Cheever

Lenzi²,

Lenzi³

et al. 2002

Mem. Inst. Oswaldo Cruz

123

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“…Within 4 hours of vector administration there was a more then 8-fold induction of OAS, a downstream product of IFN␣␤ signaling, and a specific marker of IFN␣ and IFN␤ expression 12 in the liver and spleen of both groups of mice (Figures 2, S1 [found on the Blood website; see the Supplemental Materials link at the top of the online article). Induction of IFN␣ was also found by direct measurement within the serum of treated mice ( Figure 2C).…”

Section: In Vivo Administration Of LV Activates An Ifn␣␤ Responsementioning

confidence: 99%

“…11 The mouse interleukin-1␣ (mIL-1␣), mIL-1␤, mIL-2, mIL-3, mIL-4, mIL-5, mIFN-␥, mTNF-␣, mTNF-␤, 2Ј5Ј oligoadenylate synthetase (OAS), and mL32 subclones in pGEM-4 transcription vector were described in a previous report. 12 Mouse serum or cell supernatants were analyzed at indicated time points and tested by enzymelinked immunosorbent assay (ELISA) for the presence of murine IFN␣ (PBL Biomedical, Piscataway, NJ) and by cytokine bead array for TNF-␣. …”

mentioning

confidence: 99%

In vivo administration of lentiviral vectors triggers a type I interferon response that restricts hepatocyte gene transfer and promotes vector clearance

Brown

Sitia

Annoni

et al. 2006

Blood

Self Cite

155

149

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Liver gene transfer is a highly sought goal for the treatment of inherited and infectious diseases. Lentiviral vectors (LVs) have many desirable properties for hepatocyte-directed gene delivery, including the ability to integrate into nondividing cells. Unfortunately, upon systemic administration, LV transduces hepatocytes relatively inefficiently compared with nonparenchymal cells, and the duration of transgene expression is often limited by immune responses. Here, we investigated the role of innate antiviral responses in these events. We show that administration of LVs to mice triggers a rapid and transient IFN␣␤ response. This effect was dependent on functional vector particles, and in vitro challenge of antigen-presenting cells suggested that plasmacytoid dendritic cells initiated the response. Remarkably, when LVs were administered to animals that lack the capacity to respond to IFN␣␤, there was a dramatic increase in hepatocyte transduction, and stable transgene expression was achieved. These findings indicate that, even in the setting of acute delivery of replication-defective vectors, IFNs effectively interfere with transduction in a celltype-specific manner. Moreover, because disabling a single component of the innate/immune network was sufficient to establish persistent xenoantigen expression, our results raise the hope that the immunologic barriers to gene therapy are less insurmountable than expected. IntroductionLentiviral vectors (LVs) are a promising candidate system for therapeutic gene transfer. Because of their capacity to transduce nondividing cells and stably integrate a gene expression cassette of relatively large size and complexity, LVs have significant potential for achieving long-term expression of a therapeutic molecule. Several groups, including our own, have carried out studies using LV for in vivo gene delivery in rodents. [1][2][3][4][5] Efficient gene transfer to the liver could be achieved; however, hepatocytes, which were the main target of the therapy, were transduced at a relatively low efficiency compared with nonparenchymal cells. At a low vector dose, this effect was particularly pronounced. While a high frequency of Kupffer cells (KCs) were found to be vector positive, only a small fraction of hepatocytes were transduced.Interestingly, by increasing the concentration of injected vector a threshold is reached in which hepatocyte transduction becomes dose responsive, and improved hepatocyte gene transfer is achieved. This may be due to the requirement for saturating the particleclearance systems of the sinusoid-lining cells in blood-filtering organs. 6 Nonetheless, a better understanding of the rate-limiting factors in transduction would help to improve both the dose-effect relationship and risk-benefit ratio of systemic LV administration.A high incidence of transgene-specific immunity has also been observed in studies using LVs for in vivo gene delivery. [1][2][3][4][5] This response resulted in elimination of transduced cells and/or neutralization of the transgene product,...

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Inhibition of Hepatitis B Virus Replication during Schistosoma mansoni Infection in Transgenic Mice

Cited by 39 publications

References 25 publications

Molecular Mechanisms Underlying Occult Hepatitis B Virus Infection

Molecular Mechanisms Underlying Occult Hepatitis B Virus Infection

Experimental models of Schistosoma mansoni infection

In vivo administration of lentiviral vectors triggers a type I interferon response that restricts hepatocyte gene transfer and promotes vector clearance

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