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Mechanisms of Hepatitis C Virus Clearance by Interferon and Ribavirin Combination
Published in Satya Prakash Gupta, Cancer-Causing Viruses and Their Inhibitors, 2014
Srikanta Dash, Partha K. Chandra, Kurt Ramazan, Robert F. Garry, Luis A. Balart
Over the past several years, many studies have been performed to understand how the mechanisms of IFN-α antiviral action against HCV are impaired by cellular and viral proteins (Blindenbacher et al. 2003; Bode et al. 2003; Duong et al. 2004, 2006, 2010; Lin et al. 2006; Randal et al. 2006; Christen et al. 2007; Kim et al. 2009; Sarasin-Filipowicz et al. 2009; Bellecave et al. 2010). These reports indicate that IFN-α signaling is controlled by a number of negative regulators such as suppressor of cytokine signaling (SOCS), ubiquitin-specific peptidase 18 (USP18), protein inhibitor of STAT1 (PIAS), and protein phosphatases. The SOCS family members, SOCS1 and SOCS3, prevent Stat phosphorylation by inhibiting the IFN-α receptor-associated Jak kinases (Kim et al. 2009). PIAS1 inhibits binding of STAT1 dimers to the response elements in the promoter region of the IFN-target genes. The upregulation of protein phosphatase 2A (PP2A) in HCV-infected cells inhibits IFN-α signaling. USP18 is a classical ISG that provides a strong negative feedback loop at the level of the receptor kinase complex. The mechanisms by which many patients develop resistance to RBV are not well understood. One group reported that reduced RBV uptake by HCV-infected cells contributed to an impaired antiviral response (Ibarra and Pfeiffer 2009; Ibarra et al. 2011). These investigators demonstrated that RBV uptake was reduced in the infected cells. No additional systematic study has been performed to understand how the IFN-α and RBV synergistic antiviral mechanism is impaired in HCV infection.
Host and Pathogen-Specific Drug Targets in COVID-19
Published in Debmalya Barh, Kenneth Lundstrom, COVID-19, 2022
Bruce D. Uhal, David Connolly, Farzaneh Darbeheshti, Yong-Hui Zheng, Ifeanyichukwu E. Eke, Yutein Chung, Lobelia Samavati
Besides being a viral protease, PLpro has been shown to exert its effects on the host antiviral immunity. It was discovered that PLpro functions as a deubiquitinating agent (DUB). This was further validated since both GRL0617 and Z93, another potential inhibitor for PLpro, were used as inhibitors for human ubiquitin carboxyl-terminal hydrolase 2 (USP)-2 [57]. However, PLpro shows more homology to the USP18 and its primary target is the host Ubiquitin-Like Protein interferon stimulated gene ISG15. ISG15 is induced by type I interferon (IFN-I) signaling via interferon-response factor (IRF) and functions like ubiquitination processing K48 [58], a process known as ISGlylation [59]. ISGlylation has two major antiviral functions. It can be directed to viral transcriptases/replicases to inhibit viral protein synthesis. Examples of that are seen for the influenza virus, where ISGylation of the replication complex protein NS1 shuts down virion production [59]. ISGlylation of host viral RNA sensors RIG-1 and MDA5 provides positive feedback of IFN-I responses as well as directly inhibits viral replication [60]. PLpro has been demonstrated to be a de-ISGlylation agent which directly cleaves ISG15 [61] (Figure 10.1). The role of PLpro and how it downregulates ISG15 was starting to merge, as a protease beside cleaving viral polyprotein, alternatively it antagonizes IFN-1-induced antiviral activities [58, 62, 63]. This implies that targeted drugs that inhibit PLpro are very important, as they are not only controlling viral replication but also restoring host responses to viral infections. Currently, it is not clear whether ISGlylation occurs directly at the SARS-CoV-2 RTC complex. Nevertheless, the role of PLpro and its antagonism on ISGlylation needs to be further studied.
Augmented interferon regulatory factor 7 axis in whole tumor cell vaccines prevents tumor recurrence by inducing interferon gamma-secreting B cells
Published in OncoImmunology, 2023
Nabeel Kajihara, Yoshino Tanaka, Riko Takeuchi, Takuto Kobayashi, Masafumi Tanji, Tsukasa Ataka, Shiho Nakano, Taisho Yamada, Akinori Takaoka, Yoshinori Hasegawa, Ken-Ichiro Seino, Haruka Wada
Moreover, Usp18, the third most highly expressed gene in cancer cells with vaccine effectiveness, was transfected into Irf7 and Ifi44 transgenic 4T1A (Figure S1f). To determine whether vaccination with Irf7/Ifi44/Usp18 transgenic 4T1A protects mice against the growth of recurrent tumors, they were administered to BALB/c mice. Two weeks following the vaccination, when mice were challenged with naive tumors, mice vaccinated with transgenic tumors presented drastic suppression effects of tumor onset; some mice remained tumor-free for 100 days after the tumor challenge (Figure 2d). Most notably, the WTCV by CT26 transfected with three genes Irf7/Ifi44/Usp18 completely suppressed tumor development and led to 100% survival (Figure S1g, 2e). Similarly, the transfection of the three genes into 3LL cells without vaccine effectiveness resulted in a significant improvement in tumor-suppression efficacy (Figure S1h, i). Incidentally, Irf7/Ifi44/Usp18 transgenic 4T1A showed no beneficial therapeutic effect as a therapeutic vaccine (Figure S1j).
Type I interferon detection in autoimmune diseases: challenges and clinical applications
Published in Expert Review of Clinical Immunology, 2021
Vassilis E. Papadopoulos, Charalampos Skarlis, Maria-Eleftheria Evangelopoulos, Clio P. Mavragani
A number of studies have traced the footprints of type I IFNs in CNS autoimmune pathogenesis. Other types of CNS cells could also be involved in a type I IFN-driven pathogenetic mechanism. IFNAR1 and IFNAR2 mRNA transcripts can be found in astrocytes, microglia, neurons, oligodendrocytes, and cerebrovascular endothelial cells [113]. Interestingly, AGS and pseudo- TORCH (Toxoplasmosis, Other Agents, Rubella, Cytomegalovirus, and Herpes Simplex) syndrome patients carrying mutations in TREX1 or Ubiquitin-specific peptidase 18 (USP18) among others, have elevated type I IFN levels and develop severe neurodevelopmental phenotypes. This finding paves the way to hypothesize that deregulated activation of IFNAR on microglial cells, as a result of defective USP18-mediated control, could be involved in CNS autoimmune pathology [114]. Whether type I IFN also enters the CNS originating from the periphery or contributes to disease by the locally produced amounts from CNS microglia is not completely clear [115].
Genetic and epigenetic regulation of natural resistance to HIV-1 infection: new approaches to unveil the HESN secret
Published in Expert Review of Clinical Immunology, 2020
Claudio Fenizia, Irma Saulle, Mario Clerici, Mara Biasin
The biological reason for the loss of a potent antiviral protein should result in protection from viral infections is puzzling. Several studies suggest that INFL4 acts as a potent antagonist or a desensitizing factor of IFNA in vivo [82,90–92]. In particular, Obajemu et al. reported that, following viral stimulation, IFN-λ4 induces a particularly prompt and potent production of antiviral ISGs, but stimulates the generation of negative regulators of the IFN response, including USP18 and SOCS1, as well [90]. Therefore, they speculate that the earlier antiviral response endorsed by Type III IFNs can be harmful if it is unproductive and weakens the activity of other IFNs [93], or if it inhibits the acquired immune response [94]. Prompt antiviral release of IFN-λ4 might thus be useful for infections needing an extremely fast, although transitory, immune response, but it is a hazard in infections requiring a more protracted defense such as HCV or HIV. Notably, these studies showed a recessive model of inheritance for the minor alleles in the case of parenteral transmission [87], but a dominant model in the case of sexual transmission and HCV infection [80,88,95,96]. These discrepancies further underline the need to replicate such researches on larger cohorts with different exposure route as different HIV-1 infection risk could correlate with the need of different IFNL4 levels.