Temporal Analysis of Early Immune Responses in Patients With Acute Hepatitis B Virus Infection

Dunn, Claire; Peppa, Dimitra; Khanna, Pooja; Nebbia, Gaia; Jones, Meleri; Brendish, Nathan J; Lascar, RM; Brown, David J.; Gilson, Richard; Tedder, Richard S.; Gm, Dusheiko; Jacobs, Michael; Klenerman, Paul; Maini, Mala K.

doi:10.1053/j.gastro.2009.06.054

Cited by 331 publications

(334 citation statements)

References 48 publications

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“…Nonetheless, the lack of early intrahepatic antiviral genes induction may be peculiar to chimpanzee models, because NK and NKT cells are activated within 72 h after infection of woodchuck with WHV (woodchuck hepatitis virus), and results in transient suppression of viral replication (Guy et al, 2008). Moreover, IL-15 level and activation of NK and NKT cells are elevated during incubation phase of natural HBV infection, but tend to decline at the peak of viraemia, implying that HBV could counteract innate immune response (Dunn et al, 2009;Fisicaro et al, 2009). We have now provided evidence that production of type I IFN in response to SeV infection is dampened by HBV replication in HepG2.2.15 cells, when compared to that in HepG2 cells.…”

Section: Discussionmentioning

confidence: 99%

“…The lack of detection of immune-related genes in the liver of infected chimpanzees has led to the consideration that HBV is a stealth virus (Wieland et al, 2004). However, this view seems to be contradicted by the observation that NK and NKT cells are promptly activated before the peak of virus expansion in natural human infection (Webster et al, 2000;Dunn et al, 2009;Fisicaro et al, 2009). Therefore, strategies may have been adapted by HBV to suppress the initial defenses of innate immunity, including type I IFN response.…”

Section: Introductionmentioning

confidence: 93%

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Mechanism of inhibiting type I interferon induction by hepatitis B virus X protein

Jiang

Tang

2010

Protein Cell

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 93%

Mechanism of inhibiting type I interferon induction by hepatitis B virus X protein

Jiang

Tang

2010

Protein Cell

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“…22 HBV is claimed to be a 'stealth virus' in the early phase of infection because it does not induce IFNs and IFN-stimulated genes (ISGs) in acute HBV-infected chimpanzees 23 or patients. 24 This fact could be explained by two possibilities: inability of HBV to activate PPRs or viral inhibition of PPR signaling pathways. Accumulating evidence supports the latter hypothesis that HBV is able to interfere with PPR signaling pathways.…”

Section: Interaction Between Tlrs and Hbvmentioning

confidence: 99%

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

Zhang

Yang

et al. 2014

Cell Mol Immunol

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It is well accepted that adaptive immunity plays a key role in the control of hepatitis B virus (HBV) infection. In contrast, the contribution of innate immunity has only received attention in recent years. Toll-like receptors (TLRs) sense pathogen-associated molecule patterns and activate antiviral mechanisms, including intracellular antiviral pathways and the production of antiviral effector interferons (IFNs) and pro-inflammatory cytokines. Experimental results from in vitro and in vivo models have demonstrated that TLRs mediate the activation of cellular signaling pathways and the production of antiviral cytokines, resulting in a suppression of HBV replication. However, HBV infection is associated with downregulation of TLR expression on host cells and blockade of the activation of downstream signaling pathways. In primary HBV infection, TLRs may slow down HBV infection, but contribute only indirectly to viral clearance. Importantly, TLRs may modulate HBV-specific T-and B-cell responses in vivo, which are essential for the termination of HBV infection. Thus, TLR agonists are promising candidates to act as immunomodulators for the treatment of chronic HBV infection. Antiviral treatment may recover TLR expression and function in chronic HBV infection and may increase the efficacy of therapeutic approaches based on TLR activation. A combined therapeutic strategy with antiviral treatment and TLR activation could facilitate the restoration of HBV-specific immune responses and thereby, achieve viral clearance in chronically infected HBV patients.

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“…Although the activation of the innate immune response has a key role in initiating the adaptive immune response, experimental results of HBV infection in both chimpanzees and woodchucks demonstrated non-or limited activation of innate immunity in acute HBV infection. 5,6 A number of recent studies [7][8][9][10] have investigated and suggested the involvement of innate cells, such as nature killer and nature killer T cells, in chronic HBV infection and suggested that these cells could play a role in liver damage during reactivation. Nevertheless, the role of innate immunity in viral clearance during HBV infection is still not clear.…”

Section: Introductionmentioning

confidence: 99%

Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

Chyuan

Tsai²,

Tzeng

et al. 2015

Cell Mol Immunol

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Hepatitis B virus (HBV) reactivation and recurrence are common in patients undergoing immunosuppression therapy. Tumor necrosis factor (TNF) blockage therapy is effective for the treatment of many autoimmune inflammatory diseases. However, the role of TNF-a blockage therapy in the innate and adaptive immune responses against HBV is still not clear. A detailed analysis of HBV infection under TNF-a blockage therapy is essential for the prophylaxis and therapy for HBV reactivation and recurrence. In this study, HBV clearance and T-cell responses were analyzed in a HBV-transfected mouse model under anti-TNF blockage therapy. Our results demonstrated that under TNF-a blockage therapy, HBV viral clearance was impaired with persistent elevated HBV viral load in a dose-and temporal-dependent manner. The impairment of HBV clearance under anti-TNF-a blockage therapy occurred at early time points after HBV infection. In addition, TNF-a blockade maintained a higher serum HBV viral load and increased the number of intrahepatic programmed cell death (PD)-1 high CD127 low exhausted T cells. Furthermore, TNF-a blockade abolished Toll-like receptor 9 (TLR9) ligand-induced facilitation of HBV viral clearance. Taken together, TNF-a blockade impairs HBV clearance and enhances viral load, and these effects depend on early administration after HBV infection. Our results here demonstrate that early TNF-a blockade reduces viral clearance and persistently maintains elevated HBV viral load in a mouse model, suggesting that HBV may reactivate during therapy with TNF-a-blocking agents.

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Temporal Analysis of Early Immune Responses in Patients With Acute Hepatitis B Virus Infection

Cited by 331 publications

References 48 publications

Mechanism of inhibiting type I interferon induction by hepatitis B virus X protein

Mechanism of inhibiting type I interferon induction by hepatitis B virus X protein

Contribution of Toll-like receptors to the control of hepatitis B virus infection by initiating antiviral innate responses and promoting specific adaptive immune responses

Tumor necrosis factor-alpha blockage therapy impairs hepatitis B viral clearance and enhances T-cell exhaustion in a mouse model

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