The mammalian APOBEC3 (A3) proteins comprise a multigene family of cytidine deaminases that act as potent inhibitors of retroviruses and retrotransposons. The A3 locus on the chromosome 28 of the horse genome contains multiple A3 genes: two copies of A3Z1, five copies of A3Z2, and a single copy of A3Z3, indicating a complex evolution of multiple gene duplications. We have cloned and analyzed for expression the different equine A3 genes and examined as well the subcellular distribution of the corresponding proteins. Additionally, we have tested the functional antiretroviral activity of the equine and of several of the human and nonprimate A3 proteins against the Equine infectious anemia virus (EIAV), the Simian immunodeficiency virus (SIV), and the Adeno-associated virus type 2 (AAV-2). Hematopoietic cells of horses express at least five different A3s: A3Z1b, A3Z2a-Z2b, A3Z2c-Z2d, A3Z2e, and A3Z3, whereas circulating macrophages, the natural target of EIAV, express only part of the A3 repertoire. The five A3Z2 tandem copies arose after three consecutive, recent duplication events in the horse lineage, after the split between Equidae and Carnivora. The duplicated genes show different antiviral activities against different viruses: equine A3Z3 and A3Z2c-Z2d are potent inhibitors of EIAV while equine A3Z1b, A3Z2a-Z2b, A3Z2e showed only weak anti-EIAV activity. Equine A3Z1b and A3Z3 restricted AAV and all equine A3s, except A3Z1b, inhibited SIV. We hypothesize that the horse A3 genes are undergoing a process of subfunctionalization in their respective viral specificities, which might provide the evolutionary advantage for keeping five copies of the original gene.The Equine infectious anemia virus (EIAV) (family Retroviridae, genus Lentivirus) infects equids almost worldwide, causing a persistent infection characterized by recurring viremia, fever, thrombocytopenia, and wasting symptoms (40). EIAV infections are used as a model for natural immunologic control of lentivirus replication and virus persistence and as a test system to improve vaccines against lentiviruses (10,40,41,82). In vivo EIAV replicates predominantly in macrophages (77). Interaction with the equine lentiviral receptor 1 (ELR1) has been demonstrated to be responsible for EIAV internalization (96). There have been no reported cases of EIAV infections in humans, suggesting that it is an intrinsically safe virus and of interest for use in a clinical setting. Therefore, EIAV-based lentiviral vectors for human gene therapy were recently developed (1, 67, 68).In the last few years, two cellular proteins that inhibit many different retroviruses have been characterized: tripartite motif protein 5 alpha (TRIM5␣) and apolipoprotein B mRNAediting enzyme-catalytic polypeptide 3 (APOBEC3 [A3]) (for a review, see reference 92). With respect to TRIM5␣ proteins, both human and nonhuman primate TRIM5␣ orthologues can restrict infection by EIAV (26,72). The activity of equine TRIM5␣ on EIAV infection, however, has not been described so far. With respect to A3 proteins...
Cell types and mechanisms involved in type I interferon (IFN)‐mediated anti‐inflammatory effects are poorly understood. Upon injection of artificial double‐stranded RNA (poly(I:C)), we observed severe liver damage in type I IFN‐receptor (IFNAR) chain 1‐deficient mice, but not in wild‐type (WT) controls. Studying mice with conditional IFNAR ablations revealed that IFNAR triggering of myeloid cells is essential to protect mice from poly(I:C)‐induced liver damage. Accordingly, in poly(I:C)‐treated WT, but not IFNAR‐deficient mice, monocytic myeloid‐derived suppressor cells (MDSCs) were recruited to the liver. Comparing WT and IFNAR‐deficient mice with animals deficient for the IFNAR on myeloid cells only revealed a direct IFNAR‐dependent production of the anti‐inflammatory cytokine interleukin‐1 receptor antagonist (IL‐1RA) that could be assigned to liver‐infiltrating cells. Upon poly(I:C) treatment, IFNAR‐deficient mice displayed both a severe lack of IL‐1RA production and an increased production of proinflammatory IL‐1β, indicating a severely imbalanced cytokine milieu in the liver in absence of a functional type I IFN system. Depletion of IL‐1β or treatment with recombinant IL‐1RA both rescued IFNAR‐deficient mice from poly(I:C)‐induced liver damage, directly linking the deregulated IL‐1β and IL‐1RA production to liver pathology. Conclusion: Type I IFN signaling protects from severe liver damage by recruitment of monocytic MDSCs and maintaining a balance between IL‐1β and IL‐1RA production. (Hepatology 2014;59:1555‐1563)
Interfering with interferon: A low‐molecular‐weight inhibitor has been discovered that blocks the interaction between interferon‐α (IFN‐α) and its receptor (see picture for a model of the interfaces). The resulting lead compound significantly reduces IFN‐α production in vitro. NMR and SPR experiments confirm the direct interaction of the inhibitor with IFN‐α.
Interferone der Klasse I (nachfolgend als IFN-a und IFN-b bezeichnet) sind proinflammatorische Zytokine, die eine wichtige Rolle bei der Bekämpfung viraler Infektionen spielen.[1] Sie ermçglichen eine erste Abwehr gegen Pathogene und tragen zum Überleben des Wirts bei, bis die adaptive Immunantwort einsetzt.[2] IFN Typ I wird hauptsächlich von plasmazytoiden dendritischen Zellen (pDCs) produziert. [3] Alle IFN vom Typ I binden an einen gemeinsamen Rezeptor (IFNAR). Durch die Bindung wird ein positiver Rückkopp-lungskreislauf in Gang gesetzt, der zu einem weiteren Anstieg der IFN-Ausschüttung führt.[4] Es gibt Indizien dafür, dass chronisch aktivierte pDC IFN-a als Reaktion auf die Stimulation von Toll-like-Rezeptoren (TLRs) produzieren. Dies trägt mçglicherweise zur Pathogenese von systemischem Lupus erythematosus, einer schweren Autoimmunkrankheit, bei.[5] ¾hnliche immuntoxische Symptome kçnnen während der IFN-Behandlung von chronischer Hepatitis und autoimmuninduzierter Diabetes Typ I auftreten. [6,7] Hier beschreiben wir die Identifizierung eines nicht- NMR-Strukturen des humanen IFN-a als Apostruktur (PDB-ID:1itf, [9] Modell 16) und im Komplex mit der Ektodomäne des Rezeptors (IFNAR2-EC) (PDB-ID: 2hym, [10] Modell 6) wurden der Proteindatenbank (PDB) [11] entnommen (Abbildung 1 A). Wir selektierten repräsentative niedrigenergetische Konformationen mit der kleinsten durchschnittlichen Abweichung (gemessen als Wurzel der mittleren quadratischen Abweichung aller Nicht-Wasserstoffatome, rmsd) zu allen weiteren NMR-Modellen, die im Datenbankeintrag gespeichert waren (rmsd = 2.6 AE 0.4 für IFN-a, rmsd = 1.0 AE 0.1 für IFNAR2-EC). Die Kontaktfläche des IFN-a zu IFNAR2-EC umfasst dabei 801 2 . Da die Kontaktflächen von Protein-Protein-und Protein-WirkstoffKomplexen häufig überlappen, [12] und um durch die IFN-IFNAR-Wechselwirkung induzierte lokale Konformationsänderungen [13] mçglichst zu vermeiden, entschieden wir uns dazu, eine vielversprechende Ligandenbindestelle auf der ungebundenen Apostruktur des humanen IFN-a zu ermitteln. Der durchschnittliche rmsd-Wert zwischen der Struktur des gebundenen und ungebundenem IFN-a beträgt 1.14 .
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