Reversible methylation of histone tails serve as either positive signals recognized by transcriptional assemblies or negative signals that result in repression 1–4. Invading viral pathogens that depend upon the host cell’s transcriptional apparatus are also subject to the regulatory impact of chromatin assembly and modifications5–8. Here we show that infection by the α-herpesviruses HSV and VZV results in the rapid accumulation of chromatin bearing repressive histone H3-lysine 9 methylation. To enable expression of viral immediate early (IE) genes, both viruses use the cellular transcriptional coactivator HCF-1 to recruit the demethylase LSD1 to the viral immediate early promoters. Depletion of LSD1 or inhibition of its activity with MAO inhibitors results in the accumulation of repressive chromatin and a block to viral gene expression. As HCF-1 is a component of the Set1 and MLL1 histone H3 lysine 4 methyl-transferase complexes 9,10, it thus coordinates modulation of repressive H3-lysine 9 methylation levels with addition of activating H3-lysine 4 trimethylation marks. Strikingly, MAO inhibitors also block the reactivation of HSV from latency in sensory neurons, indicating that the HCF-1 complex is a critical component of the reactivation mechanism. The results support pharmaceutical control of histone modifying enzymes as a strategy for controlling herpesvirus infections.

Background: Exosomes are extracellular vesicles that have been implicated in intercellular communication.Results: Exosomes that originate from human cells infected with HIV-1 contain virus-derived small noncoding RNA. Conclusion: Virus-derived small RNA present in exosomes exert functional consequences in naive recipient cells. Significance: Viral RNA molecules present in exosomes may be critical mediators of intercellular viral spread in infected hosts.

Background: Extracellular exosomes contain various functional elements. Results: Exosomal Tax protein causes phenotypic changes in uninfected cells. Conclusion: Exosomes may play critical roles in extracellular delivery of oncogenic material derived from HTLV-1-infected cells. Significance: Exosomal delivery of Tax and other putative oncogenic components produced during HTLV-1 infection potentially contributes to pathogenesis of adult T-cell leukemia, myelopathy, or tropical spastic paraparesis.

Successful in vivo infection following pathogen entry requires the evasion and subversion of multiple immunological barriers. Antimicrobial peptides (AMPs) are one of the first immune pathways upregulated during infection by multiple pathogens, in multiple organs in vivo. In humans, there are many classes of AMPs exhibiting broad antimicrobial activities, with defensins and the human cathelicidin LL-37 being the best studied examples. Whereas historically the efficacy and therapeutic potential of AMPs against bacterial infection has been the primary focus of research, recent studies have begun to elucidate the antiviral properties of AMPs as well as their role in regulation of inflammation and chemoattraction. AMPs as therapeutic tools seem especially promising against emerging infectious viral pathogens for which no approved vaccines or treatments are currently available, such as dengue virus (DENV) and Zika virus (ZIKV). In this review, we summarize recent studies elucidating the efficacy and diverse mechanisms of action of various classes of AMPs against multiple viral pathogens, as well as the potential use of human AMPs in novel antiviral therapeutic strategies.

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Human T-cell lymphotropic virus type 1 (HTLV-1) has been identified as the causative agent of adult T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The virus infects between 15 and 20 million people worldwide of which approximately 2–5% develop ATL. The past 35 years of research have yielded significant insight into the pathogenesis of HTLV-1, including the molecular characterization of Tax, the viral transactivator, and oncoprotein. In spite of these efforts, the mechanisms of oncogenesis of this pleiotropic protein remain to be fully elucidated. In this review, we illustrate the multiple oncogenic roles of Tax by summarizing a recent body of literature that refines our understanding of cellular transformation. A focused range of topics are discussed in this review including Tax-mediated regulation of the viral promoter and other cellular pathways, particularly the connection of the NF-κB pathway to both post-translational modifications (PTMs) of Tax and subcellular localization. Specifically, recent research on polyubiquitination of Tax as it relates to the activation of the IkappaB kinase (IKK) complex is highlighted. Regulation of the cell cycle and DNA damage responses due to Tax are also discussed, including Tax interaction with minichromosome maintenance proteins and the role of Tax in chromatin remodeling. The recent identification of HTLV-3 has amplified the importance of the characterization of emerging viral pathogens. The challenge of the molecular determination of pathogenicity and malignant disease of this virus lies in the comparison of the viral transactivators of HTLV-1, -2, and -3 in terms of transformation and immortalization. Consequently, differences between the three proteins are currently being studied to determine what factors are required for the differences in tumorogenesis.

The 2019 novel coronavirus, SARS-CoV-2, is an emerging pathogen of critical significance to international public health. Knowledge of the interplay between molecular-scale virus-receptor interactions, single-cell viral replication, intracellular-scale viral transport, and emergent tissue-scale viral propagation is limited. Moreover, little is known about immune system-virus-tissue interactions and how these can result in low-level (asymptomatic) infections in some cases and acute respiratory distress syndrome (ARDS) in others, particularly with respect to presentation in different age groups or pre-existing inflammatory risk factors like diabetes. A critical question for treatment and protection is why it appears that the severity of infection may correlate with the initial level of virus exposure. Given the nonlinear interactions within and among each of these processes, multiscale simulation models can shed light on the emergent dynamics that lead to divergent outcomes, identify actionable "choke points" for pharmacologic interactions, screen potential therapies, and identify potential biomarkers that differentiate response dynamics. Given the complexity of the problem and the acute need for an actionable model to guide therapy discovery and optimization, we introduce a prototype of a multiscale model of SARS-CoV-2 dynamics in lung and intestinal tissue that will be iteratively refined. The first prototype model was built and shared internationally as open source code and interactive, cloud-hosted executables in under 12 hours. In a sustained community effort, this model will integrate data and expertise across virology, immunology, mathematical biology, quantitative systems physiology, cloud and high performance computing, and other domains to accelerate our response to this critical threat to international health.

As the Ebola outbreak in West Africa wanes, it is time for the international scientific community to reflect on how to improve the detection of and coordinated response to future epidemics. Our interdisciplinary team identified key lessons learned from the Ebola outbreak that can be clustered into three areas: environmental conditions related to early warning systems, host characteristics related to public health, and agent issues that can be addressed through the laboratory sciences. In particular, we need to increase zoonotic surveillance activities, implement more effective ecological health interventions, expand prediction modeling, support medical and public health systems in order to improve local and international responses to epidemics, improve risk communication, better understand the role of social media in outbreak awareness and response, produce better diagnostic tools, create better therapeutic medications, and design better vaccines. This list highlights research priorities and policy actions the global community can take now to be better prepared for future emerging infectious disease outbreaks that threaten global public health and security.