The Tiers and Dimensions of Evasion of the Type I Interferon Response by Human Cytomegalovirus

Human cytomegalovirus (HCMV) is a member of the β-herpesvirus family that invariably occupies hosts for life despite a consistent multi-pronged antiviral immune response that targets the infection. This persistence is enabled by the large viral genome that encodes factors conferring a wide assortment of sophisticated, often redundant phenotypes that disable or otherwise manipulate impactful immune effector processes. The type I interferon system represents a first line of host defense against infecting viruses. The physiological reactions induced by secreted interferon act to effectively block replication of a broad spectrum of virus types, including HCMV. As such, the virus must exhibit counteractive mechanisms to these responses that involve their inhibition, tolerance, or re-purposing. The goal of this review is to describe the impact of the type I interferon system on HCMV replication and to showcase the number and diversity of strategies employed by the virus that allow infection of hosts in the presence of interferon-dependent activity.     

The role of type I interferons in TLR responses

Recent advances in unravelling the complexities of the signalling pathways that constitute innate immunity have highlighted type I interferon as a key component in the response to infection. Here we focus on the emerging field of pattern-recognition receptor signalling, specifically Toll-like receptors and retinoic acid inducible gene-like helicases, from the perspective of this 50-year-old cytokine. The type I interferon gene family encompasses more than 20 subtypes, whose nature and properties have been extensively studied during its relatively long history. In this review we update and integrate available data on the mechanics of activation of the interferon genes and the role of this cytokine family in the innate immune response.     

Regulation of the production of immune interferon and cytotoxic T lymphocytes by interleukin 2

The activation of alloantigen-specific cytotoxic T lymphocyte precursors is dependent upon the presence of both macrophages and helper T cells or regulatory molecules derived from these facilitative cells. Three biochemically distinct helper factors have been identified: interleukin 1 (macrophage-derived), Interleukin 2 (T cell derived), and immune interferon. All 3 factors are found in supernatants of mixed lymphocyte cultures (MLC), however, the removal of macrophages from these cultures completely ablates the production of these factors as well as the induction of cytotoxic T lymphocytes (CTL). The addition of IL 2 to these macrophage-depleted MLC restores the ability of responder T cells to: 1) bypass the requirement for macrophage soluble function, 2) produce immune interferon, and 3) generate CTL. The kinetics and dose response of immune interferon production in response to IL 2 correlates with the generation of CTL. The production of immune interferon as well as the generation of CTL requires T cells, alloantigen, and IL2. Furthermore, the induction of CTL by IL2 was neutralized by the addition of anti-immune interferon. These data suggest that: 1) the regulation of immune interferon production is based on a T to T cell interaction mediated by IL 2, and 2) immune interferon production may be required for IL 2 induction of CTL. These findings are consistent with the hypothesis that the induction of CTL involves a linear cell-factor interaction in which IL 1 (macrophage-derived) stimulates T cells to produce IL 2, which in turn stimulates other T cells to produce immune interferon and become cytotoxic.     

Identification and initial characterization of concanavalin A- and interferon-induced human suppressor factors: evidence for a human equivalent of murine soluble immune response suppressor (SIRS)

Human suppressor T cells activated by leukocyte interferon have properties similar to murine suppressor cells activated by interferon or by concanavalin A. Murine suppressor cells release a soluble mediator, soluble immune response suppressor (SIRS), which accounts, at least in part, for suppressive activity in murine systems. To compare and contrast murine and human suppressor pathways, we evaluated the suppression of human polyclonal plaque-forming cell responses by concanavalin A, by leukocyte interferon, and by immune interferon, or by suppressor cells activated by these agents. In each instance, suppressive activity was prevented by levamisole, ascorbic acid, catalase, or 2-mercaptoethanol, agents known to interfere with murine SIRS activity. Furthermore, concanavalin A, immune interferon, and leukocyte interferon induced T lymphocytes to release 110,000 to 150,000 m.w. proteins which suppressed responses only when added early in the culture period. As with murine SIRS, suppression by each of these human factors was inhibited by 2-mercaptoethanol, ascorbic acid, catalase, or levamisole. The reaction of human suppressor factors with H2O2 (10(-6) M) activated suppressor factors so that they suppress responses when added late in the culture period. Human suppressor factors were protease- and acid (pH 2)-sensitive. The similarities between these human suppressor factors and murine SIRS show the existence of a human SIRS pathway.     

Inhibition of type I interferon induction and signalling by mosquito‐borne flaviviruses

The Flavivirus genus (Flaviviridae family) contains a number of important human pathogens, including dengue and Zika viruses, which have the potential to cause severe disease. In order to efficiently establish a productive infection in mammalian cells, flaviviruses have developed key strategies to counteract host immune defences, including the type I interferon response. They employ different mechanisms to control interferon signal transduction and effector pathways, and key research generated over the past couple of decades has uncovered new insights into their abilities to actively decrease interferon antiviral activity. Given the lack of antivirals or prophylactic treatments for many flaviviral infections, it is important to fully understand how these viruses affect cellular processes to influence pathogenesis and disease outcome. This review will discuss the strategies mosquito‐borne flaviviruses have evolved to antagonise type I interferon mediated immune responses.     

The implication of SUMO in intrinsic and innate immunity

Since its discovery, SUMOylation has emerged as a key post-translational modification involved in the regulation of host-virus interactions. SUMOylation has been associated with the replication of a large number of viruses, either through the direct modification of viral proteins or through the modulation of cellular proteins implicated in antiviral defense. SUMO can affect protein function via covalent or non-covalent binding. There is growing evidence that SUMO regulates several host proteins involved in intrinsic and innate immunity, thereby contributing to the process governing interferon production during viral infection; as well as the interferon-activated Jak/STAT pathway. Unlike the interferon-mediated innate immune response, intrinsic antiviral resistance is mediated by constitutively expressed antiviral proteins (defined as restriction factors), which confer direct viral resistance through a variety of mechanisms. The aim of this review is to evaluate the role of SUMO in intrinsic and innate immunity; highlighting the involvement of the TRIM family proteins, with a specific focus on the mechanism through which SUMO affects i- interferon production upon viral infection, ii-interferon Jak/STAT signaling and biological responses, iii-the relationship between restriction factors and RNA viruses.     

Alveolar macrophage lipoxygenase products of arachidonic acid: isolation and recognition as the predominant constituents of the neutrophil chemotactic activity elaborated by alveolar macrophages

Human immune interferon preparations have anticellular activity on human cell lines (WISH and HEp-2). This anticellular activity copurified with the human immune interferon and appears to be a function of the immune interferon molecule. On the basis of a unit of antiviral activity, purified human immune interferon had about 20 and 100 times more anticellular activity than purified fibroblast or leukocyte interferon, respectively. The possible implications of this finding in the treatment of human neoplasia are discussed.     

RLRs介导的抗鲤春病毒血症病毒作用研究进展

鲤春病毒血症病毒(SVCV)是水生动物病毒中重要的病原体,常引起鲤科鱼类疾病暴发。近些年研究发现,维甲酸诱导基因I样受体家族(RLRs)信号通路在SVCV免疫过程中起到重要的作用。主要功能是在识别病原体相关模式,激活下游信号分子,诱导天然免疫的产生,以及控制病毒的早期复制。当病毒进入机体时会形成病毒-RLRs-IFN互联反馈回路,RLRs相关基因识别SVCV的RNA,最终引起Ⅰ型干扰素(IFN-I)表达量升高,并且RLRs族内成员相互作用增强抗病毒作用。RLRs不仅可以活化天然免疫信号通路,还可增强适应性免疫效应,在控制病毒感染过程中发挥重要作用。介绍RLRs家族,RLRs抗病毒信号调控因子,干扰素诱导的鱼类Mx (myxovirus resistant)蛋白对鲤春病毒血症病毒的抑制作用。     

Biochemical relationship between murine immune interferon and a killer cell helper factor.

Concanavalin A and alloantigen-stimulated mouse spleen cells release into the supernatant at least two distinct antigen-nonspecific factors that enhance the generation of cytotoxic cells in vitro. As previously reported, analysis of the supernatant by ammonium sulfate fractionation, gel filtration, hydroxylapatite chromatography, and hydrophobic chromatographic showed one of the two killer cell helper factors (KHF) to be associated with thymocyte mitogenic factor. This report demonstrates the second KHF to be separable from thymocyte mitogenic factor but inseparable from type II (immune) interferon. In addition, this KHF exhibits the same sensitivity to exposure to pH-2 buffer as does immune interferon. The KHF activity of an unfractionated supernatant, which is greater than of either the TMF-associated or interferon-associated KHF alone, is the result of the additive activities of the two independently acting helper factors.     

Viral and Cellular FLICE-Inhibitory Proteins: a Comparison of Their Roles in Regulating Intrinsic Immune Responses

FLICE-inhibitory proteins (FLIPs) are a family of viral (poxvirus and herpesvirus) and cellular proteins. The hallmark of this family is the presence of tandem death-effector domains (DEDs). Despite this shared motif, each protein possesses different abilities to modulate apoptosis, NF-κB, and interferon regulatory factor 3 (IRF3). These similarities and differences are discussed and highlighted here. The comparative study of FLIPs provides a unique basis to understand virus-host interactions, viral pathogenesis, and cellular regulation of immune system signal transduction pathways.     

Arterivirus and nairovirus ovarian tumor domain-containing Deubiquitinases target activated RIG-I to control innate immune signaling

The innate immune response constitutes the first line of defense against viral infection and is extensively regulated through ubiquitination. The removal of ubiquitin from innate immunity signaling factors by deubiquitinating enzymes (DUBs) therefore provides a potential opportunity for viruses to evade this host defense system. It was previously found that specific proteases encoded by the unrelated arteri- and nairoviruses resemble the ovarian tumor domain-containing (OTU) family of DUBs. In arteriviruses, this domain has been characterized before as a papain-like protease (PLP2) that is also involved in replicase polyprotein processing. In nairoviruses, the DUB resides in the polymerase protein but is not essential for RNA replication. Using both in vitro and cell-based assays, we now show that PLP2 DUB activity is conserved in all members of the arterivirus family and that both arteri- and nairovirus DUBs inhibit RIG-I-mediated innate immune signaling when overexpressed. The potential relevance of RIG-I-like receptor (RLR) signaling for the innate immune response against arterivirus infection is supported by our finding that in mouse embryonic fibroblasts, the production of beta interferon primarily depends on the recognition of arterivirus RNA by the pattern-recognition receptor MDA5. Interestingly, we also found that both arteri- and nairovirus DUBs inhibit RIG-I ubiquitination upon overexpression, suggesting that both MDA5 and RIG-I have a role in countering infection by arteriviruses. Taken together, our results support the hypothesis that arteri- and nairoviruses employ their deubiquitinating potential to inactivate cellular proteins involved in RLR-mediated innate immune signaling, as exemplified by the deubiquitination of RIG-I.     

干扰素调节因子家族

干扰素调节因子（IRFs）是调节干扰素（IFN）、干扰素刺激性应答基因（ISG）及其它相关基因表达的重要转录因子,通过调节IFN、ISG和其它密切相关基因表达而发挥多种生物学效应.