Promyelocytic leukemia nuclear bodies (PML-NBs) are nuclear structures that accumulate intrinsic host factors to restrict viral infections. To ensure viral replication, these must be limited by expression of viral early regulatory proteins that functionally inhibit PML-NB-associated antiviral effects. To benefit from the activating capabilities of Sp100A and simultaneously limit repression by Sp100B, -C, and -HMG, adenoviruses (Ads) employ several features to selectively and individually target these isoforms. Ads induce relocalization of Sp100B, -C, and -HMG from PML-NBs prior to association with viral replication centers. In contrast, Sp100A is kept at the PML tracks that surround the newly formed viral replication centers as designated sites of active transcription. We concluded that the host restriction factors Sp100B, -C, and -HMG are potentially inactivated by active displacement from these sites, whereas Sp100A is retained to amplify Ad gene expression. Ad-dependent loss of Sp100 SUMOylation is another crucial part of the virus repertoire to counteract intrinsic immunity by circumventing Sp100 association with HP1, therefore limiting chromatin condensation. We provide evidence that Ad selectively counteracts antiviral responses and, at the same time, benefits from PML-NB-associated components which support viral gene expression by actively recruiting them to PML track-like structures. Our findings provide insights into novel strategies for manipulating transcriptional regulation to either inactivate or amplify viral gene expression. IMPORTANCEWe describe an adenoviral evasion strategy that involves isoform-specific and active manipulation of the PML-associated restriction factor Sp100. Recently, we reported that the adenoviral transactivator E1A targets PML-II to efficiently activate viral transcription. In contrast, the PML-associated proteins Daxx and ATRX are inhibited by early viral factors. We show that this concept is more intricate and significant than originally believed, since adenoviruses apparently take advantage of specific PML-NBassociated proteins and simultaneously inhibit antiviral measures to maintain the viral infectious program. Specifically, we observed Ad-induced relocalization of the Sp100 isoforms B, C, and HMG from PML-NBs juxtaposed with viral replication centers. In contrast, Sp100A is retained at Ad-induced PML tracks that surround the newly formed viral replication centers, acting as designated sites of active transcription. The host restriction factors Sp100B, -C, and -HMG are potentially inactivated by active displacement from these sites, whereas Sp100A is retained to amplify Ad gene expression.

The development of treatments for Ebola virus disease (EVD) has been hampered by the lack of small-animal models that mimick human disease. Here we show that mice with transplanted human hematopoetic stem cells reproduce features typical of EVD. Infection with Ebola virus was associated with viremia, cell damage, liver steatosis, signs of hemorrhage, and high lethality. Our study provides a small-animal model with human components for the development of EVD therapies.

The adenovirus E1B 55K (E1B) protein plays major roles in productive adenoviral infection and cellular transformation. Interest in E1B increased because of the potential of adenoviruses as therapeutic vectors, and the E1B gene is commonly deleted from adenovirus vectors for anticancer therapy. E1B activities are spatiotemporally regulated through SUMOylation and phosphorylation, and through interactions with multiple partners that occur presumably at different intracellular sites and times postinfection. E1B is implicated in the formation of viral replication compartments and regulates viral genome replication and transcription, transcriptional repression, degradation of cellular proteins, and several intranuclear steps of viral late mRNA biogenesis. Here, we review advances in our understanding of E1B during productive adenovirus replication and discuss fundamental aspects that remain unresolved.The adenovirus E1B 55K protein (called E1B throughout this review) plays key roles during productive viral replication and contributes to oncogenic transformation. The E1B gene is usually deleted or modified in oncolytic adenoviruses because such viruses preferentially replicate in and kill cancer cells (reviewed in [1,2]). Although structural data for the 496 amino acid (aa) polypeptide are scarce, some structural or functional motifs are known or have been proposed, and the E1B protein may contain intrinsically disordered regions (IDR). E1B activities are regulated by posttranslational modifications (PTMs) that impact on both intracellular localization and the interactions that E1B establishes with viral and cellular proteins. E1B acts as a small ubiquitin-like modifier (SUMO)-1 ligase for p53 and participates in the polyubiquitylation-induced degradation of cellular targets that would otherwise interfere with viral replication. E1B also promotes viral replication through repression of interferon (IFN)-stimulated genes (ISG) and p53 regulation. Of note, efficient viral DNA replication depends on the formation of adenoviral replication compartments (RCs), another process in which E1B is involved. Furthermore, E1B interacts with viral RNA and this interaction optimizes production and splicing of viral late mRNAs. Yet, many aspects of the biology of E1B remain to be elucidated, including the protein's threedimensional structure and the molecular mechanisms whereby E1B regulates viral genome replication and gene expression. Most of the knowledge of E1B comes from the study of the human serotypes 2 and 5 from species C; however, sequences and functional features from other adenovirus species have also been described. A very complete review of the E1B protein Abbreviations CRM1, chromosome region maintenance 1 protein homolog; CDK, cyclin-dependent kinase; E1B-AP5, E1B-associated protein 5; eIF4E, eukaryotic translation initiation factor 4E; hnRNP, heteronuclear ribonucleoprotein; LH3, hexon-interlacing protein LH3; I-TASSER, iterative threading ASSEmbly refinement; Mre11, meiotic recombination 11; Nxf1/Tap, nuclear RNA expo...

Severe human adenovirus (HAdV) infections are an increasing threat for immunosuppressed individuals, particularly those who have received stem cell transplants. It has been previously hypothesized that severe infections might be due to reactivation of a persistent infection, but this hypothesis has been difficult to test owing to the lack of a permissive in vivo model of HAdV infection. Here we established a humanized mouse model that reproduces features of acute and persistent HAdV infection. In this model, acute infection correlated with high mortality, weight loss, liver pathology, and expression of viral proteins in several organs. In contrast, persistent infection was asymptomatic and led to establishment of HAdV-specific adaptive immunity and expression of early viral genes exclusively in the bone marrow. These findings validate the use of humanized mice to study acute and persistent HAdV infection and strongly suggest the presence of cellular reservoirs in the bone marrow.