NF-κB-Dependent IFIT3 Induction by HBx Promotes Hepatitis B Virus Replication

Abstract

Therapeutic administration of type I IFN (IFN-I) is a common treatment option for individuals suffering from hepatitis B virus (HBV) infection. IFN-I therapy, however, has a relatively low response rate in HBV-infected patients and can induce serious side-effects, limiting its clinical efficacy. There is, thus, a clear need to understand the molecular mechanisms governing the influence of IFN-I therapy in HBV treatment in order to improve patient outcomes. In this study, we explored the interactions between HBV and IFITs (IFN-induced proteins with tetratricopeptide repeats), which are classical IFN-inducible genes. Specifically, we found that HBV patients undergoing IFN-I therapy exhibited elevated expression of IFITs in their peripheral blood mononuclear cells (PBMCs). We further observed upregulation in the expressions of IFIT1, IFIT2, and IFIT3 in cells transfected with the pHBV1.3 plasmid, which yields infectious virions in hepatic cells. We additionally found that HBx, which is the only regulatory protein encoded within the HBV genome, activates NF-κB, which in turn directly drives IFIT3 transcription. When IFIT3 was overexpressed in HepG2 cells, HBV replication was enhanced. Together, these results suggest that IFIT genes may unexpectedly enhance viral replication, thus making these genes potential therapeutic targets in patients with HBV.

Identification of significant alteration genes, pathways and TFs induced by LPS in ARDS via bioinformatical analysis

“…Recent studies showed that IFIT3 could modulate IFIT1 RNA Binding specificity and protein stability [ 28 , 29 ]. Xu et al reported that IFIT3 transcription was dependent on NF-κB activation [ 30 ], while NF-κB played a vital role in ARDS [ 31 , 32 ]. Exome-wide analysis showed that IFIT3 mutation was associated with COPD and airflow limitation [ 33 ].…”

Murine Ifit3 restricts the replication of Rabies virus both in vitro and in vivo

“…Previous studies have shown that several virus could subvert the functions of IFITs by utilizing their own proteins and evading capture by the innate immune system. For instance, the herpes simplex virus 1 (HSV-1) tegument protein UL41 abrogates the antiviral activity of human IFIT3 by diminishing the accumulation of its mRNA [64]; the vaccinia virus (VACA) C9 protein binds and degrades human IFIT1, IFIT2 and IFIT3 in a proteasomal manner [65]; and the hepatitis B virus (HBV) HBx protein induces human IFIT3 transcription and enhances its replication [66]. Human IFIT1 can inhibit human papillomavirus (HPV) DNA propagation by binding to the viral protein E1 [67].…”

Blood Transcriptomes of Anti-SARS-CoV-2 Antibody-Positive Healthy Individuals Who Experienced Asymptomatic Versus Clinical Infection

“…However, on the basis of these findings some assumptions can be made, since, indeed, the first 6 genes with higher expression in individuals with clinical infection compared to asymptomatic individuals, namely IFIT3, IFI44L, FOLR3, RSAD3, PI3, and ALOX15 , share some common characteristics that can be relevant. For example, IFIT3, IFI44L and RSAD3 expression can be induced by viruses which in turn enhances the progress of the viral infection ( 62 – 64 ), whereas higher intrinsic expression of IFIT3, FOLR3, PI3 and ALOX-15 have all been associated with immune-mediated chronic diseases ( 65 – 68 ) In contrast, a protective effect of GZMH, CLEC1B, CLEC12A , that have a higher expression in asymptomatic individuals, may be associated with the effectiveness of GZMH in viral eradication ( 69 ) and the ability of CLEC1B and CLEC12A to enhance neutrophil extracellular trap formation, thus presenting an antiviral effect that helps to control systemic virus levels ( 70 ). Despite the fact that our findings have to be validated in a larger independent cohort of prior SARS-CoV-2 infected individuals, taken together with those of the literature support the hypothesis that there are differences in the innate immune responses between clinical and asymptomatic individuals during SARS-CoV-2 infections ( 15 , 16 ).…”