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Exact budget equations for the second-order structure function tensor $\\langle \\unicode[STIX]{x1D6FF}u_{i}\\unicode[STIX]{x1D6FF}u_{j}\\rangle$, where $\\unicode[STIX]{x1D6FF}u_{i}$ is the difference of the $i$th fluctuating velocity component between two points, are used to study the two-point statistics of velocity fluctuations in inhomogeneous turbulence. The anisotropic generalised Kolmogorov equations (AGKE) describe the production, transport, redistribution and dissipation of every Reynolds stress component occurring simultaneously among different scales and in space, i.e. along directions of statistical inhomogeneity. The AGKE are effective to study the inter-component and multi-scale processes of turbulence. In contrast to more classic approaches, such as those based on the spectral decomposition of the velocity field, the AGKE provide a natural definition of scales in the inhomogeneous directions, and describe fluxes across such scales too. Compared to the generalised Kolmogorov equation, which is recovered as their half-trace, the AGKE can describe inter-component energy transfers occurring via the pressure–strain term and contain also budget equations for the off-diagonal components of $\\langle \\unicode[STIX]{x1D6FF}u_{i}\\unicode[STIX]{x1D6FF}u_{j}\\rangle$. The non-trivial physical interpretation of the AGKE terms is demonstrated with three examples. First, the near-wall cycle of a turbulent channel flow at a friction Reynolds number of $Re_{\\unicode[STIX]{x1D70F}}=200$ is considered. The off-diagonal component $\\langle -\\unicode[STIX]{x1D6FF}u\\unicode[STIX]{x1D6FF}v\\rangle$, which cannot be interpreted in terms of scale energy, is discussed in detail. Wall-normal scales in the outer turbulence cycle are then discussed by applying the AGKE to channel flows at $Re_{\\unicode[STIX]{x1D70F}}=500$ and $1000$. In a third example, the AGKE are computed for a separating and reattaching flow. The process of spanwise-vortex formation in the reverse boundary layer within the separation bubble is discussed for the first time.

Interferon‐stimulated gene 20 kDa protein (ISG20) is a relatively understudied antiviral protein capable of inhibiting a broad spectrum of viruses. ISG20 exhibits strong RNase properties, and it belongs to the large family of DEDD exonucleases, present in both prokaryotes and eukaryotes. ISG20 was initially characterized as having strong RNase activity in vitro, suggesting that its inhibitory effects are mediated via direct degradation of viral RNAs. This mechanism of action has since been further elucidated and additional antiviral activities of ISG20 highlighted, including direct degradation of deaminated viral DNA and translational inhibition of viral RNA and nonself RNAs. This review focuses on the current understanding of the main molecular mechanisms of viral inhibition by ISG20 and discusses the latest developments on the features that govern specificity or resistance to its action. ISG20 is a broad antiviral inhibitor and a potent RNase in vitro. However, a precise understanding of its mechanism of action is lacking. In this review, we discuss the latest developments on this fascinating innate defense factor.

TRIM proteins are a family of innate immune factors that play diverse roles in innate immunity and protect the cell against viral and bacterial aggression. As part of this special issue on TRIM proteins, we will take advantage of our findings on TRIM69, which acts by reorganizing the microtubules (MTs) in a manner that is fundamentally antiviral, to more generally discuss how host–pathogen interactions that take place for the control of the MT network represent a crucial facet of the struggle that opposes viruses to their cell environment. In this context, we will present several other TRIM proteins that are known to interact with microtubules in situations other than viral infection, and we will discuss evidence that may suggest a possible contribution to viral control. Overall, the present review will highlight the importance that the control of the microtubule network bears in host–pathogen interactions.

HIV-1 is a complex retrovirus that is adapted to replicate in cells of the immune system. To do so, HIV-1, like other viruses, developed strategies to use several cellular processes to its advantage, but had also to come to terms with an arsenal of cellular innate defense proteins, or antiviral factors, that target more or less efficiently, virtually every step of the virus replicative cycle. Among antiviral restriction factors, the family of interferon-induced transmembrane proteins (IFITMs) has emerged as a crucial component of cellular innate defenses for their ability to interfere with both early and late phases of viral replication by inhibiting cellular and viral membranes fusion. Here, we review the enormous advances made since the discovery of IFITMs as interferon-regulated genes more than thirty years ago, with a particular focus on HIV-1 and on the elements that modulate its susceptibility or resistance towards members of this family. Given the recent advances of the field in the elucidation of the mechanism of IFITM inhibition and on the mechanism(s) of viral resistance, we expect that future years will bring novel insights into the definition of the multiple facets of IFITMs and on their possible use for novel therapeutical approaches.

Never before such a vast amount of data, including genome sequencing, has been collected for any viral pandemic than for the current case of COVID-19. This offers the possibility to trace the virus evolution and to assess the role mutations play in its spread within the population, in real time. To this end, we focused on the Spike protein for its central role in mediating viral outbreak and replication in host cells. Employing the Levenshtein distance on the Spike protein sequences, we designed a machine learning algorithm yielding a temporal clustering of the available dataset. From this, we were able to identify and define emerging persistent variants that are in agreement with known evidences. Our novel algorithm allowed us to define persistent variants as chains that remain stable over time and to highlight emerging variants of epidemiological interest as branching events that occur over time. Hence, we determined the relationship and temporal connection between variants of interest and the ensuing passage to dominance of the current variants of concern. Remarkably, the analysis and the relevant tools introduced in our work serve as an early warning for the emergence of new persistent variants once the associated cluster reaches 1% of the time-binned sequence data. We validated our approach and its effectiveness on the onset of the Alpha variant of concern. We further predict that the recently identified lineage AY.4.2 (‘Delta plus’) is causing a new emerging variant. Comparing our findings with the epidemiological data we demonstrated that each new wave is dominated by a new emerging variant, thus confirming the hypothesis of the existence of a strong correlation between the birth of variants and the pandemic multi-wave temporal pattern. The above allows us to introduce the epidemiology of variants that we described via the Mutation epidemiological Renormalisation Group framework.

ISG20 is a broad spectrum antiviral protein thought to directly degrade viral RNA. However, this mechanism of inhibition remains controversial. Using the Vesicular Stomatitis Virus (VSV) as a model RNA virus, we show here that ISG20 interferes with viral replication by decreasing protein synthesis in the absence of RNA degradation. Importantly, we demonstrate that ISG20 exerts a translational control over a large panel of non-self RNA substrates including those originating from transfected DNA, while sparing endogenous transcripts. This activity correlates with the protein's ability to localize in cytoplasmic processing bodies. Finally, these functions are conserved in the ISG20 murine ortholog, whose genetic ablation results in mice with increased susceptibility to viral infection. Overall, our results posit ISG20 as an important defense factor able to discriminate the self/non-self origins of the RNA through translation modulation.

Bats are asymptomatic reservoirs of several zoonotic viruses. This may result from long-term co-evolution between viruses and bats, that have led to host adaptations contributing to an effective balance between strong antiviral responses with innate immune tolerance. To better understand these virus-host interactions, we combined comparative transcriptomics, phylogenomics and functional assays to characterize the evolution of bat innate immune antiviral factors. First, we stimulated the type I interferon immune pathway in Myotis yumanensis primary cells and identified guanylate-binding protein 5 (GBP5) as the most differentially expressed interferon-stimulated gene (ISG). Phylogenomic analyses showed that bat GBP5 has been under strong episodic positive selection, with numerous rapidly evolving sites and species-specific gene duplications, suggesting past evolutionary arms races. Functional tests on GBP5 orthologs from 10 bat species covering the >60 million years of Chiroptera evolution revealed species- and virus-specific restrictions against RNA viruses (retrovirus HIV, and rhabdoviruses European bat lyssavirus and VSV), which are typical signatures of adaptations to past viral epidemics. Interestingly, we also observed a lineage-specific loss of the GBP5 prenylation motif in the common ancestor of Pipistrellus and Eptesicus bats. Importantly, resurrection of the prenylation motif in Eptesicus fuscus GBP5 in corresponding bat cells was associated with different GBP5 subcellular localization and loss of anti-rhabdoviral functions, suggesting specific adaptation to ancient viral epidemics ~22 million years ago. Altogether, our results highlight adaptations that contribute to bat specific immunity and provide insights into the functional evolution of antiviral effector GBP5.

Sterile alpha motif domain-containing proteins 9 and 9-like (SAMD9/9L) are associated with life-threatening genetic diseases in humans and are restriction factors of poxviruses. Yet, their cellular function and the extent of their antiviral role are poorly known. Here, we found that interferon-stimulated human SAMD9L restricts HIV-1 in the late phases of replication, at the posttranscriptional and prematuration steps, impacting viral translation and, possibly, endosomal trafficking. Surprisingly, the paralog SAMD9 exerted an opposite effect, enhancing HIV-1. More broadly, we showed that SAMD9L restricts primate lentiviruses, but not a gammaretrovirus (MLV), nor 2 RNA viruses (arenavirus MOPV and rhabdovirus VSV). Using structural modeling and mutagenesis of SAMD9L, we identified a conserved Schlafen-like active site necessary for HIV-1 restriction by human and a rodent SAMD9L. By testing a gain-of-function constitutively active variant from patients with SAMD9L-associated autoinflammatory disease, we determined that SAMD9L pathogenic functions also depend on the Schlafen-like active site. Finally, we found that the constitutively active SAMD9L strongly inhibited HIV, MLV, and, to a lesser extent, MOPV. This suggests that the virus-specific effect of SAMD9L may involve its differential activation/sensing and the virus ability to evade from SAMD9L restriction. Overall, our study identifies SAMD9L as an HIV-1 antiviral factor from the cell autonomous immunity and deciphers host determinants underlying the translational repression. This provides novel links and therapeutic avenues against viral infections and genetic diseases.

To better characterize the behavior of HIV-1 capsids we developed EURT, for Entry/Uncoating assay based on core-packaged RNA availability and Translation. EURT is an alternative to Blam-Vpr, but as reporter RNA translation relies on core opening, it can be used to study viral capsids behavior. Our study reveals the existence of two major capsid species, a dead end one in which the viral genome is readily exposed to the cytoplasm and a functional one in which such exposure requires artificial core destabilization. Although reverse transcription drives a faster loss of susceptibility of viral cores to high doses of PF74, it does not lead to higher exposure of the viral genome, implying that viral cores protect the genome irrespectively of reverse transcription. Lastly, IFNα drifts cores from functional to non-functional species, revealing a novel core-destabilizing activity. This assay sheds new light on the behavior of viral cores inside target cells.

The current outbreak of Ebola virus (EBOV) in West Africa has claimed the lives of more than 15,000 people and highlights an urgent need for therapeutics capable of preventing virus replication. In this study we screened known nucleoside analogues for their ability to interfere with EBOV replication. Among them, the cytidine analogue β-d-N4-hydroxycytidine (NHC) demonstrated potent inhibitory activities against EBOV replication and spread at non-cytotoxic concentrations. Thus, NHC constitutes an interesting candidate for the development of a suitable drug treatment against EBOV.