Latent reservoirs of HIV-1-infected cells are refractory to antiretroviral therapies (ART) and remain the major barrier to curing HIV-1. Because latently infected cells are long-lived, ...immunologically invisible, and may undergo homeostatic proliferation, a “shock and kill” approach has been proposed to eradicate this reservoir by combining ART with inducers of viral transcription. However, all attempts to alter the HIV-1 reservoir in vivo have failed to date. Using humanized mice, we show that broadly neutralizing antibodies (bNAbs) can interfere with establishment of a silent reservoir by Fc-FcR-mediated mechanisms. In established infection, bNAbs or bNAbs plus single inducers are ineffective in preventing viral rebound. However, bNAbs plus a combination of inducers that act by independent mechanisms synergize to decrease the reservoir as measured by viral rebound. Thus, combinations of inducers and bNAbs constitute a therapeutic strategy that impacts the establishment and maintenance of the HIV-1 reservoir in humanized mice.
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•bNAbs can be used for postexposure prophylaxis (PEP) in humanized mice•bNAb PEP efficacy requires Fc-receptor binding•bNAbs plus a single inducer of HIV-1 transcription do not reduce viral rebound•bNAbs plus a combination of inducers significantly reduce viral rebound
A combination of broadly neutralizing antibodies and viral inducers reduce the frequency of viral rebound in the humanized mouse model of HIV-1 infection.
Viral infection is commonly associated with virus-driven hijacking of host proteins. Here we describe a novel mechanism by which influenza virus affects host cells through the interaction of ...influenza non-structural protein 1 (NS1) with the infected cell epigenome. We show that the NS1 protein of influenza A H3N2 subtype possesses a histone-like sequence (histone mimic) that is used by the virus to target the human PAF1 transcription elongation complex (hPAF1C). We demonstrate that binding of NS1 to hPAF1C depends on the NS1 histone mimic and results in suppression of hPAF1C-mediated transcriptional elongation. Furthermore, human PAF1 has a crucial role in the antiviral response. Loss of hPAF1C binding by NS1 attenuates influenza infection, whereas hPAF1C deficiency reduces antiviral gene expression and renders cells more susceptible to viruses. We propose that the histone mimic in NS1 enables the influenza virus to affect inducible gene expression selectively, thus contributing to suppression of the antiviral response.
Studies investigating the causes of autism spectrum disorder (ASD) point to genetic, as well as epigenetic, mechanisms of the disease. Identification of epigenetic processes that contribute to ASD ...development and progression is of major importance and may lead to the development of novel therapeutic strategies. Here, we identify the bromodomain and extraterminal domain-containing proteins (BETs) as epigenetic regulators of genes involved in ASD-like behaviors in mice. We found that the pharmacological suppression of BET proteins in the brain of young mice, by the novel, highly specific, brain-permeable inhibitor I-BET858 leads to selective suppression of neuronal gene expression followed by the development of an autism-like syndrome. Many of the I-BET858-affected genes have been linked to ASD in humans, thus suggesting the key role of the BET-controlled gene network in the disorder. Our studies suggest that environmental factors controlling BET proteins or their target genes may contribute to the epigenetic mechanism of ASD.
Effective antiviral immunity depends on the ability of infected cells or cells triggered with virus-derived nucleic acids to produce type I interferon (IFN), which activates transcription of numerous ...antiviral genes. However, disproportionately strong or chronic IFN expression is a common cause of inflammatory and autoimmune diseases. We describe an epigenetic mechanism that determines cell type-specific differences in IFN and IFN-stimulated gene (ISG) expression in response to exogenous signals. We identify di-methylation of histone H3 at lysine 9 (H3K9me2) as a suppressor of IFN and IFN-inducible antiviral gene expression. We show that levels of H3K9me2 at IFN and ISG correlate inversely with the scope and amplitude of IFN and ISG expression in fibroblasts and dendritic cells. Accordingly, genetic ablation or pharmacological inactivation of lysine methyltransferase G9a, which is essential for the generation of H3K9me2, resulted in phenotypic conversion of fibroblasts into highly potent IFN-producing cells and rendered these cells resistant to pathogenic RNA viruses. In summary, our studies implicate H3K9me2 and enzymes controlling its abundance as key regulators of innate antiviral immunity.
Induction of vast transcriptional programs is a central event of innate host responses to viral infections. Here we report a transcriptional program with potent antiviral activity, driven by E74-like ...ETS transcription factor 1 (ELF1). Using microscopy to quantify viral infection over time, we found that ELF1 inhibits eight diverse RNA and DNA viruses after multi-cycle replication. Elf1 deficiency results in enhanced susceptibility to influenza A virus infections in mice. ELF1 does not feed-forward to induce interferons, and ELF1's antiviral effect is not abolished by the absence of STAT1 or by inhibition of JAK phosphorylation. Accordingly, comparative expression analyses by RNA-seq revealed that the ELF1 transcriptional program is distinct from interferon signatures. Thus, ELF1 provides an additional layer of the innate host response, independent from the action of type I interferons.
Aire controls immunologic tolerance by inducing a battery of thymic transcripts encoding proteins characteristic of peripheral tissues. Its unusually broad effect is achieved by releasing RNA ...polymerase II paused just downstream of transcriptional start sites. We explored Aire’s collaboration with the bromodomain-containing protein, Brd4, uncovering an astonishing correspondence between those genes induced by Aire and those inhibited by a small-molecule bromodomain blocker. Aire:Brd4 binding depended on an orchestrated series of posttranslational modifications within Aire’s caspase activation and recruitment domain. This interaction attracted P-TEFb, thereby mobilizing downstream transcriptional elongation and splicing machineries. Aire:Brd4 association was critical for tolerance induction, and its disruption could account for certain point mutations that provoke human autoimmune disease. Our findings evoke the possibility of unanticipated immunologic mechanisms subtending the potent antitumor effects of bromodomain blockers.
The basic concepts and advantages of more/all electric aircraft (M/AEA) are briefly addressed. The combined starter/generator (CS/G) system is introduced as a key technology to enable M/AEA. Some ...important performance requirements for CS/G system are obtained. Based on these requirements, a high speed switched reluctance machine (SRM) is designed to operate as a starter/generator. The entire design process is mainly divided into two stages: electromagnetic design and thermal design. In electromagnetic design stage, the electromagnetic structure and dimensions of the machine and the number of phase winding turns per pole are obtained; the topology and main technical details of the converter are briefly introduced as well. In thermal design stage, a liquid-cooling system is designed based on the thermal analysis of the machine. In the end, the performances of the designed SRM are basically verified by simulation. To get high performances, the exciting angles are optimized in two different operating modes respectively, and the optimized performances in the motoring mode are given as well.
Inflammation is associated with the activation of genes that contribute to immune defense and tissue repair. The bromodomain-containing proteins of the BET family, which recognize histone lysine ...acetylation, play a key role in the transcriptional control of inflammatory genes. Inhibition of BET proteins by the small-molecule inhibitor I-BET affects the expression of a particular subset of inflammatory genes-namely, ones that follow an "analog-like," but not "digital-like" activation pattern. This ability of I-BET to target genes based on the dynamic pattern of their activation may facilitate the further development of anti-inflammatory treatment protocols that are tuned to the individual or to disease-specific patterns of gene expression.
A variable magnetic permeability is introduced to the skin effect coefficient to reflect the influence of flux density variation on eddy current losses. The evaluation results show that the new iron ...loss model can cover a wide range of frequencies without using piecewise functions. Two types of punched edges are defined and the additional iron losses are tested, separated, and modeled, so that the punching and burrs' connection effects on iron losses can be considered more accurately. The iron loss model proposed in this article is very useful for a more accurate design of high-speed motors including the punching effects.
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