Gradual adaptation of animal influenza A viruses to human-type sialic acid receptors.

Influenza A viruses (IAVs) originating from animal reservoirs pose continuous threats to human health as demonstrated by the Spanish flu pandemic. Infection starts by attachment to host receptors, a crucial step that is targeted by immunological, prophylactic, and therapeutic intervention. Fine-tuning of virus hemagglutinin binding to host-specific receptor repertoires needs to remain balanced to receptor-destroying neuraminidase (NA) activity and is a key step in host adaptation. It determines NA-dependent virus motility, enabling IAVs to traverse the mucus layer and to bind to, and migrate over, the epithelial cell surface for reaching a location supporting endocytic uptake. Canonical adaptations in enzootic/zoonotic IAVs enhancing human-type receptor binding are well-known, but the context and timespan required for their selection pose many questions. We discuss recent developments, focusing on the dynamic nature of interactions of IAV with the heterogeneous receptor repertoires present in humans and potential intermediate hosts. Potential pre-adaption toward human-type receptor binding in intermediate hosts will be discussed.

Move and countermove: the integrated stress response in picorna- and coronavirus-infected cells.

Viruses, when entering their host cells, are met by a fierce intracellular immune defense. One prominent antiviral pathway is the integrated stress response (ISR). Upon activation of the ISR - typically though not exclusively upon detection of dsRNA - translation-initiation factor eukaryotic initiation factor 2 (eIF2) becomes phosphorylated to act as an inhibitor of guanine nucleotide-exchange factor eIF2B. Thus, with the production of ternary complex blocked, a global translational arrest ensues. Successful virus replication hinges on effective countermeasures. Here, we review ISR antagonists and antagonistic mechanisms employed by picorna- and coronaviruses. Special attention will be given to a recently discovered class of viral antagonists that inhibit the ISR by targeting eIF2B, thereby allowing unabated translation initiation even at exceedingly high levels of phosphorylated eIF2.

Direct-acting antivirals and host-targeting strategies to combat enterovirus infections.

Enteroviruses (e.g., poliovirus, enterovirus-A71, coxsackievirus, enterovirus-D68, rhinovirus) include many human pathogens causative of various mild and more severe diseases, especially in young children. Unfortunately, antiviral drugs to treat enterovirus infections have not been approved yet. Over the past decades, several direct-acting inhibitors have been developed, including capsid binders, which block virus entry, and inhibitors of viral enzymes required for genome replication. Capsid binders and protease inhibitors have been clinically evaluated, but failed due to limited efficacy or toxicity issues. As an alternative approach, host-targeting inhibitors with potential broad-spectrum activity have been identified. Furthermore, drug repurposing screens have recently uncovered promising new inhibitors with disparate viral and host targets. Together, these findings raise hope for the development of (broad-range) anti-enteroviral drugs.

Viral rewiring of cellular lipid metabolism to create membranous replication compartments.

Positive-strand RNA (+RNA) viruses (e.g. poliovirus, hepatitis C virus, dengue virus, SARS-coronavirus) remodel cellular membranes to form so-called viral replication compartments (VRCs), which are the sites where viral RNA genome replication takes place. To induce VRC formation, these viruses extensively rewire lipid metabolism. Disparate viruses have many commonalities as well as disparities in their interactions with the host lipidome and accumulate specific sets of lipids (sterols, glycerophospholipids, sphingolipids) at their VRCs. Recent years have seen an upsurge in studies investigating the role of lipids in +RNA virus replication, in particular of sterols, and uncovered that membrane contact sites and lipid transfer proteins are hijacked by viruses and play pivotal roles in VRC formation.