Significance Here we report that all three types of IFNs, the primary mediators of host innate and adaptive antiviral responses, promote infection by human coronavirus HCoV-OC43. They do so through the IFN-induced transmembrane proteins that normally restrict a broad spectrum of viruses but serve as entry factors for HCoV-OC43 to infect its host cells. Our finding reveals a unique mechanism by which HCoV-OC43 evades host antiviral immune responses and suggests that the cytokine response to infection or noninfectious stimuli can be co-opted to promote the infection and spreading of opportunistic pathogens that have evolved adaptations similar to that of HCoV-OC43.

Chronic hepatitis B virus (HBV) infection

Covalently closed circular DNA (cccDNA) of hepadnaviruses exists as an episomal minichromosome in the nucleus of infected hepatocyte and serves as the transcriptional template for viral mRNA synthesis. Elimination of cccDNA is the prerequisite for either a therapeutic cure or immunological resolution of HBV infection. Although accumulating evidence suggests that inflammatory cytokines-mediated cure of virally infected hepatocytes does occur and plays an essential role in the resolution of an acute HBV infection, the molecular mechanism by which the cytokines eliminate cccDNA and/or suppress its transcription remains elusive. This is largely due to the lack of convenient cell culture systems supporting efficient HBV infection and cccDNA formation to allow detailed molecular analyses. In this study, we took the advantage of a chicken hepatoma cell line that supports tetracycline-inducible duck hepatitis B virus (DHBV) replication and established an experimental condition mimicking the virally infected hepatocytes in which DHBV pregenomic (pg) RNA transcription and DNA replication are solely dependent on cccDNA. This cell culture system allowed us to demonstrate that cccDNA transcription required histone deacetylase activity and IFN-α induced a profound and long-lasting suppression of cccDNA transcription, which required protein synthesis and was associated with the reduction of acetylated histone H3 lysine 9 (H3K9) and 27 (H3K27) in cccDNA minichromosomes. Moreover, IFN-α treatment also induced a delayed response that appeared to accelerate the decay of cccDNA. Our studies have thus shed light on the molecular mechanism by which IFN-α noncytolytically controls hepadnavirus infection.

Host cellular endoplasmic reticulum α-glucosidases I and II are essential for the maturation of viral glycosylated envelope proteins that use the calnexin mediated folding pathway. Inhibition of these glycan processing enzymes leads to the misfolding and degradation of these viral glycoproteins and subsequent reduction in virion secretion. We previously reported that, CM-10-18, an imino sugar α-glucosidase inhibitor, efficiently protected the lethality of dengue virus infection of mice. In the current study, through an extensive structure-activity relationship study, we have identified three CM-10-18 derivatives that demonstrated superior in vitro antiviral activity against representative viruses from four viral families causing hemorrhagic fever. Moreover, the three novel imino sugars significantly reduced the mortality of two of the most pathogenic hemorrhagic fever viruses, Marburg virus and Ebola virus, in mice. Our study thus proves the concept that imino sugars are promising drug candidates for the management of viral hemorrhagic fever caused by variety of viruses.

e Chronicity of hepatitis B virus (HBV) infection is due to the failure of a host to mount a sufficient immune response to clear the virus. The aim of this study was to identify small-molecular agonists of the pattern recognition receptor (PRR)-mediated innate immune response to control HBV infection. To achieve this goal, a coupled mouse macrophage and hepatocyte culture system mimicking the intrahepatic environment was established and used to screen small-molecular compounds that activate macrophages to produce cytokines, which in turn suppress HBV replication in a hepatocyte-derived stable cell line supporting HBV replication in a tetracycline-inducible manner. An agonist of the mouse stimulator of interferon ( Hepatitis B virus (HBV) is a noncytopathic hepadnavirus that chronically infects more than 350 million people worldwide. The outcomes and pathogenesis of HBV infections are largely determined by the nature and magnitude of the host antiviral immune response (1), which is generally related to the person's age at the time of infection. While over 95% of adult-acquired infections are spontaneously cleared within 6 months by a vigorous and polyclonal HBV-specific T cell response, more than 90% of exposed neonates and approximately 30% of children 1 to 5 years old develop a chronic infection (2, 3), which is associated with a weaker and often barely detectable virus-specific T cell response.Sustained suppression of viral replication by long-term nucleos(t)ide analogue therapy or through a finite duration of pegylated alpha interferon (IFN-␣) therapy has been associated with improvement of liver diseases, prevention of liver decompensation, and reduction of hepatocellular carcinoma morbidity and mortality (4, 5). However, a "functional cure," characterized by normalization of liver function, HBV surface antigen (HBsAg) seroconversion, and durable immune control of HBV replication, is rarely achieved with the current therapies (6, 7). Hence, the restoration of host innate and HBV-specific adaptive immune responses is essential for a functional cure of chronic HBV infection (8).Although hepatocytes are the primary host cells of HBV, hepatic nonparenchymal cells (NPCs) have been shown to play a critical role in the priming of effective HBV-specific antiviral immunity (9, 10). For instance, it was demonstrated recently that activation of hepatic macrophages induces the expression of a distinct profile of cytokines/chemokines that regulate the priming of a successful immune response against HBV in the livers of mice (10). It is therefore conceivable that pharmacological activation of Kupffer cells and/or intrahepatic dendritic cells with agonists of Toll-like receptors (TLRs) or other pattern recognition receptors (PRRs) may facilitate the intrahepatic priming of an anti-HBV immune response. In support of this hypothesis, it has been demonstrated recently in woodchucks and chimpanzees that administration of TLR7 agonists not only induced an innate cytokine response that suppresses HBV replication but also shaped...