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Effects of interferon-?/? on HBV replication determined by viral load.

ABSTRACT: Interferons ? and ? (IFN-?/?) are type I interferons produced by the host to control microbial infections. However, the use of IFN-? to treat hepatitis B virus (HBV) patients generated sustained response to only a minority of patients. By using HBV transgenic mice as a model and by using hydrodynamic injection to introduce HBV DNA into the mouse liver, we studied the effect of IFN-?/? on HBV in vivo. Interestingly, our results indicated that IFN-?/? could have opposite effects on HBV: they suppressed HBV replication when viral load was high and enhanced HBV replication when viral load was low. IFN-?/? apparently suppressed HBV replication via transcriptional and post-transcriptional regulations. In contrast, IFN-?/? enhanced viral replication by inducing the transcription factor HNF3? and activating STAT3, which together stimulated HBV gene expression and replication. Further studies revealed an important role of IFN-?/? in stimulating viral growth and prolonging viremia when viral load is low. This use of an innate immune response to enhance its replication and persistence may represent a novel strategy that HBV uses to enhance its growth and spread in the early stage of viral infection when the viral level is low.

SUBMITTER: Tian Y

PROVIDER: S-EPMC3145790 | biostudies-literature | 2011 Jul

REPOSITORIES: biostudies-literature

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Effects of interferon-α/β on HBV replication determined by viral load.

Tian Yongjun Y Chen Wen-ling WL Ou Jing-hsiung James JH

PLoS pathogens 20110728 7

Interferons α and β (IFN-α/β) are type I interferons produced by the host to control microbial infections. However, the use of IFN-α to treat hepatitis B virus (HBV) patients generated sustained response to only a minority of patients. By using HBV transgenic mice as a model and by using hydrodynamic injection to introduce HBV DNA into the mouse liver, we studied the effect of IFN-α/β on HBV in vivo. Interestingly, our results indicated that IFN-α/β could have opposite effects on HBV: they suppr ...[more]

PMID: 21829354

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Project description:Type I interferons (IFNs) are key mediators of the innate immune response. Although members of this family of cytokines signal through a single shared receptor, biochemical and functional variation exists in response to different IFN subtypes. While previous work has demonstrated that type I IFNs are essential to control infection by chikungunya virus (CHIKV), a globally emerging alphavirus, the contributions of individual IFN subtypes remain undefined. To address this question, we evaluated CHIKV pathogenesis in mice lacking IFN-? (IFN-? knockout [IFN-?-KO] mice or mice treated with an IFN-?-blocking antibody) or IFN-? (IFN regulatory factor 7 knockout [IRF7-KO] mice or mice treated with a pan-IFN-?-blocking antibody). Mice lacking either IFN-? or IFN-? developed severe clinical disease following infection with CHIKV, with a marked increase in foot swelling compared to wild-type mice. Virological analysis revealed that mice lacking IFN-? sustained elevated infection in the infected ankle and in distant tissues. In contrast, IFN-?-KO mice displayed minimal differences in viral burdens within the ankle or at distal sites and instead had an altered cellular immune response. Mice lacking IFN-? had increased neutrophil infiltration into musculoskeletal tissues, and depletion of neutrophils in IFN-?-KO but not IRF7-KO mice mitigated musculoskeletal disease caused by CHIKV. Our findings suggest disparate roles for the IFN subtypes during CHIKV infection, with IFN-? limiting early viral replication and dissemination and IFN-? modulating neutrophil-mediated inflammation.IMPORTANCE Type I interferons (IFNs) possess a range of biological activity and protect against a number of viruses, including alphaviruses. Despite signaling through a shared receptor, there are established biochemical and functional differences among the IFN subtypes. The significance of our research is in demonstrating that IFN-? and IFN-? both have protective roles during acute chikungunya virus (CHIKV) infection but do so by distinct mechanisms. IFN-? limits CHIKV replication and dissemination, whereas IFN-? protects from CHIKV pathogenesis by limiting inflammation mediated by neutrophils. Our findings support the premise that the IFN subtypes have distinct biological activities in the antiviral response.

Dataset Information

Effects of interferon-?/? on HBV replication determined by viral load.

Publications

Effects of interferon-α/β on HBV replication determined by viral load.

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