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We propose a framework to analyse partisan debates that involves extracting, classifying and exploring the latent argumentation structure and dynamics of online societal controversies. In this paper, the focus is placed on causal arguments, and the proposed framework is applied to the Twitter debate on the consequences of a hard Brexit scenario. Regular expressions based on causative verbs, structural topic modelling, and dynamic time warping techniques were used to identify partisan faction arguments, as well as their relations, and to infer agenda-setting dynamics. The results highlight that the arguments employed by partisan factions are mostly constructed around constellations of effect-classes based on polarised verb groups. These constellations show that the no-deal debate hinges on structurally balanced building blocks. Brexiteers focus more on arguments related to greenfield trading opportunities and increased autonomy, whereas Remainers argue more about what a no-deal Brexit could destroy, focusing on hard border issues, social tensions in Ireland and Scotland and other economy- and healthcare-related problems. More notably, inferred debate leadership dynamics show that, despite their different usage of terms and arguments, the two factions’ argumentation dynamics are strongly intertwined. Moreover, the identified periods in which agenda-setting roles change are linked to major events, such as extensions, elections and the Yellowhammer plan leak, and to new issues that emerged in relation to these events.

Despite efficient combination of the antiretroviral therapy (cART), which significantly decreased mortality and morbidity of HIV-1 infection, a definitive HIV cure has not been achieved. Hidden HIV-1 in cellular and anatomic reservoirs is the major hurdle toward a functional cure. Microglial cells, the Central Nervous system (CNS) resident macrophages, are one of the major cellular reservoirs of latent HIV-1. These cells are believed to be involved in the emergence of drugs resistance and reseeding peripheral tissues. Moreover, these long-life reservoirs are also involved in the development of HIV-1-associated neurocognitive diseases (HAND). Clearing these infected cells from the brain is therefore crucial to achieve a cure. However, many characteristics of microglial cells and the CNS hinder the eradication of these brain reservoirs. Better understandings of the specific molecular mechanisms of HIV-1 latency in microglial cells should help to design new molecules and new strategies preventing HAND and achieving HIV cure. Moreover, new strategies are needed to circumvent the limitations associated to anatomical sanctuaries with barriers such as the blood brain barrier (BBB) that reduce the access of drugs.

The innate response to a pathogen is critical in determining the outcome of the infection. However, the interplay of different cellular responses that are activated following viral infection and their contribution to innate antiviral signalling has not been clearly established. This work shows that flaviviruses, including Dengue, Zika, West Nile and Tick-borne encephalitis viruses, activate the unfolded protein response before transcription of interferon regulatory factor 3 induced genes. Infection in conditions of unfolded protein response priming leads to early activation of innate antiviral responses and cell intrinsic inhibition of viral replication, which is interferon regulatory factor 3 dependent. These results demonstrate that the unfolded protein response is not only a physiological reaction of the cell to viral infection, but also synergizes with pattern recognition sensing to mount a potent antiviral response. Innate immune responses are essential in the control of flavivirus infection. Here, the authors provide evidence that the unfolded protein response and the pattern recognition receptor pathways synergize to orchestrate innate antiviral responses and cell intrinsic inhibition of viral replication, a process mediated by IRF3.

Classical antiviral therapy targets viral functions, mostly viral enzymes or receptors. Successful examples include precursor herpesvirus drugs, antiretroviral drugs that target reverse transcriptase and protease, influenza virus directed compounds as well as more recent direct antiviral agents (DAA) applied in the treatment of hepatitis C virus (HCV). However, from early times, the possibility of targeting the host cell to contain the infection has frequently re-emerged as an alternative and complementary antiviral strategy. Advantages of this approach include an increased threshold to the emergence of resistance and the possibility to target multiple viruses. Major pitfalls are related to important cellular side effects and cytotoxicity. In this mini-review, the concept of host directed antiviral therapy will be discussed with a focus on the most recent advances in the field of Flaviviruses, a family of important human pathogens for which we do not have antivirals available in the clinics.

Latency allows HIV-1 to persist in long-lived cellular reservoirs, preventing virus eradication. We have previously shown that the heat shock protein 90 (Hsp90) is required for HIV-1 gene expression and mediates greater HIV-1 replication in conditions of hyperthermia. Here we report that specific inhibitors of Hsp90 such as 17-(N-allylamino)-17-demethoxygeldanamycin and AUY922 prevent HIV-1 reactivation in CD4+ T cells. A single modification at position 19 in the Hsp90 inhibitors abolished this activity, supporting the specificity of the target. We tested the impact of Hsp90 on known pathways involved in HIV-1 reactivation from latency; they include protein kinase Cs(PKCs), mitogen activated protein kinase/extracellular signal regulated kinase/positive transcriptional elongation factor-b and NF-κB. We found that Hsp90 was required downstream of PKCs and was not required for mitogen activated protein kinase activation. Inhibition of Hsp90 reduced degradation of IkBα and blocked nuclear translocation of transcription factor p65/p50, suppressing the NF-κB pathway. Coimmunoprecipitation experiments showed that Hsp90 interacts with inhibitor of nuclear factor kappa-B kinase (IKK) together with cochaperone Cdc37, which is critical for the activity of several kinases. Targeting of Hsp90 by AUY922 dissociated Cdc37 from the complex. Therefore, Hsp90 controls HIV-1 reactivation from latency by keeping the IKK complex functional and thus connects T-cell activation with HIV-1 replication. AUY922 is in phase II clinical trial and, in combination with a PKC-ϑ inhibitor in phase II clinical trial, almost completely suppressed HIV-1 reactivation at 15 nM with no cytotoxicity. Selective targeting of the Hsp90/Cdc37 interaction may provide a powerful approach to suppress HIV-1 reactivation from latency.

Repurposing clinically available drugs to treat the new coronavirus disease 2019 (COVID-19) is an urgent need in the course of the Severe Acute Respiratory Syndrome coronavirus (SARS-CoV-2) pandemic, as very few treatment options are available. The iminosugar Miglustat is a well-characterized drug for the treatment of rare genetic lysosome storage diseases, such as Gaucher and Niemann-Pick type C, and has also been described to be active against a variety of enveloped viruses. The activity of Miglustat is here demonstrated in the micromolar range for SARS-CoV-2 in vitro. The drug acts at the post-entry level and leads to a marked decrease of viral proteins and release of infectious viruses. The mechanism resides in the inhibitory activity toward α-glucosidases that are involved in the early stages of glycoprotein N-linked oligosaccharide processing in the endoplasmic reticulum, leading to a marked decrease of the viral Spike protein. Indeed, the antiviral potential of protein glycosylation inhibitors against SARS-CoV-2 is further highlighted by the low-micromolar activity of the investigational drug Celgosivir. These data point to a relevant role of this approach for the treatment of COVID-19.

HIV-1 latency is mainly characterized at transcriptional level, and little is known about post-transcriptional mechanisms and their contribution to reactivation. The viral protein Rev controls the nucleocytoplasmic export of unspliced and singly-spliced RNA that is central to proviral replication-competence and is therefore a prerequisite for efficient viral reactivation during the “shock-and-kill” cure therapy. Here we show that during infection and reactivation, unspliced HIV-1 RNA is a subject to complex and dynamic regulation by the Rev cofactor MATR3 and the MTR4 cofactor of the nuclear exosome. MATR3 and MTR4 coexist in the same ribonucleoprotein complex functioning to either maintain or degrade the RNA, respectively, with Rev orchestrating this regulatory switch. Moreover, we provide evidence of nuclear retention of unspliced HIV-1 RNA in ex vivo cultures from 22 ART-treated people with HIV, highlighting a reversible post-transcriptional block to viral RNA nucleocytoplasmic export that is relevant to the design of curative interventions. In their study, Dorman and Bendoumou et al., reveal a post-transcriptional regulation of unspliced HIV-1 RNA by host factors MATR3, MTR4, and the viral protein Rev, identifying a previously uncharacterized post-transcriptional block in nucleocytoplasmic export, which plays a crucial role in HIV-1 latency and reactivation.

Flaviviruses are relevant animal and human pathogens of increasing importance worldwide. The similarities of the initial clinical symptoms and the serological cross-reactivity of viral structural antigens make a laboratory diagnosis of flavivirus infection problematic. The main aim of the present study was the comparative specificity and sensitivity analysis of the non-structural protein NS1 as an antigen to detect flavivirus antibodies in sera from exposed individuals. A strategy for the purification of native recombinant non-structural protein 1 of representative flaviviruses including tick-borne encephalitis, West Nile, Zika and dengue virus was developed. The immunological properties of the purified antigens were analyzed using sera of immunized mice and of infected individuals in comparison with standard commercial assays. Recombinant NS1 protein was confirmed as a valuable option for the detection of flavivirus antibodies with reduced cross-reactivity and high sensitivity offering additional advantages for the detection of vaccine breakthrough cases.

Dengue virus (DENV) causes the most prevalent and rapidly spreading arboviral disease of humans. It enters human cells by receptor-mediated endocytosis. Numerous cell-surface proteins were proposed as DENV entry factors. Among these, the phosphatidylserine receptor TIM-1 is the only one known to mediate virus internalization. However, several cellular models lacking TIM-1 are permissive to DENV infection, suggesting that other receptors exist. Here, we show that the low-density lipoprotein receptor-related protein-1 (LRP1) binds DENV virions by interacting with the DIII of the viral envelope glycoprotein. DENV infection is effectively inhibited by the purified receptor at 5 × 10−8 mol/L, and the interaction of the envelope protein with LRP1 is also blocked by a natural ligand of LRP1. The depletion of LRP1 causes 100-fold lower production of infectious virus than controls. Our results indicate that LRP1 is another DENV receptor, thus becoming an attractive target to evaluate for the development of effective antiviral drugs against DENV.

Surveillance of Usutu virus is crucial to prevent future outbreaks both in Europe and in other countries currently naïve to the infection, such as the Americas. This goal remains difficult to achieve, notably because of the lack of large-scale cohort studies and the absence of commercially available diagnostic reagents for USUV. This work started with the first identification of USUV in a blood donor in the Friuli Venezia Giulia (FVG) Region in Northern-Eastern Italy, which is endemic for West Nile virus. Considering that only one IgG ELISA is commercially available, but none for IgM, a novel NS1 antigen based IgG/M ELISA has been developed. This assay tested successfully for the detection of Usutu virus in blood donors with the identification of a second case of transmission and high levels of exposure. Furthermore, two pan-flavivirus antiviral drugs, that we previously characterized to be inhibitors of other flavivirus infectivity, were successfully tested for inhibition of Usutu virus with inhibitory concentrations in the low micromolar range. To conclude, this work identifies North-Eastern Italy as endemic for Usutu virus with implications for the screening of transfusion blood. A novel NS1-based ELISA test has been implemented for the detection of IgM/G that will be of importance as a tool for the diagnosis and surveillance of Usutu virus infection. Finally, Usutu virus is shown to be sensitive to a class of promising pan-flavivirus drugs.