Hepatitis B Virus-Induced Calreticulin Protein Is Involved in IFN Resistance

Abstract

IFN-α is a widely used treatment for hepatitis B virus (HBV) infection, and IFN resistance caused by viral and/or host factors is currently a challenging clinical problem. A better understanding of the molecular mechanisms underlying IFN immunotherapy in the treatment of viral infection would be very beneficial clinically and is of immense clinical importance. Calreticulin (CRT) is an endoplasmic reticulum luminal calcium-binding chaperone that is involved in the regulation of calcium homoeostasis, the folding of newly synthesized proteins, and many other cellular functions. However, little is known about the role of CRT in HBV infection. In this study, we observed high levels of CRT expression in the sera and PBMCs of patients with HBV relative to those of healthy individuals. HBV upregulated the expression of CRT at the transcriptional level. Further investigation showed that HBV-induced CRT enhanced HBV replication by antagonizing the IFN pathway. CRT suppressed the production of endogenous IFN-α by reducing the nuclear translocation of IFN regulatory factor-7 but not IFN regulatory factor-3. Furthermore, CRT also suppressed the antiviral activity of IFN-α by inhibiting the phosphorylation of STAT1 and decreasing the expression of two IFN-α downstream effectors, protein kinase R and 2',5′-oligoadenylate synthetase. Our results offer new insights into the pathogenesis of HBV infection and may provide potential targets for anti-HBV therapy.

Clinical and molecular response to interferon-α therapy in essential thrombocythemia patients with CALR mutations

“…This is an important observation because wild-type CALR protein has been involved in resistance to IFNa therapy in viral hepatitis patients. 30 Adverse events reported in this cohort were not different from those observed in JAK2V617F-mutated ET or PV patients, and only 19% of patients discontinued therapy because of toxicity while the exact same proportion stopped for efficacy and sustained HR.…”

Human hepatitis B virus surface and e antigens inhibit major vault protein signaling in interferon induction pathways

“…1D). To make sure that this was not a cell-specific event, an additional pair of human hepatoma cells, HuH7 and HuH7.37 (HuH7.37 cells contain an integrated HBV genotype B and stably express HBV) [22] were also tested for MVP expression. Consistent with HepG2.2.15 cells, HuH7.37 cells expressed higher levels of MVP mRNA and protein (Fig.…”

MicroRNA-26b Inhibits Hepatitis B Virus Transcription and Replication by Targeting the Host Factor CHORDC1 Protein

“…The PCR products were digested with EcoRI/XhoI and cloned directly into the pCMV-Tag2B expression vector. CHORDC1 3ЈUTR-luc, CCND2-3ЈUTR-luc, and STK39-3ЈUTR-luc reporter plasmids were constructed by insertion of the 3ЈUTRs containing the predicted miR-26b target sequences downstream of the firefly luciferase ORF as described previously (28). The following primer pairs for the cloning of luciferase reporters are used: CHORDC1, 3ЈUTR-luc, 5Ј-TTAAAGC-TTGAAGGAAGGCTATTACATTA-3Ј (sense) and 5Ј-TAACT-CGAGTAAAGTACAATATATAGTCA-3Ј (antisense); CCND2, 3ЈUTR-luc, 5Ј-TTAAAGCTTTGACATTCCCATCACAA-CAT-3Ј (sense) and 5Ј-TAACTCGAGACTGCTTCTGTATTC-CTCAT-3Ј (antisense); and STK39, 3ЈUTR-luc, 5Ј-CCCAAGCT-TTACTTATAAAATTAAG-3Ј (sense) and 5Ј-CCGCTCGAGT-CTTGAACCTTAACAGC-3Ј (antisense).…”