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As viruses continue to pose risks to global health, having a better understanding of virus–host protein–protein interactions aids in the development of treatments and vaccines. Here, we introduce Viruses.STRING, a protein–protein interaction database specifically catering to virus–virus and virus–host interactions. This database combines evidence from experimental and text-mining channels to provide combined probabilities for interactions between viral and host proteins. The database contains 177,425 interactions between 239 viruses and 319 hosts. The database is publicly available at viruses.string-db.org, and the interaction data can also be accessed through the latest version of the Cytoscape STRING app.

Viruses are one of the major causes of acute and chronic infectious diseases and thus a major contributor to the global burden of disease. Several studies have shown how viruses have evolved to hijack basic cellular pathways and evade innate immune response by modulating key host factors and signaling pathways. A collective view of these multiple studies could advance our understanding of virus-host interactions and provide new therapeutic perspectives for the treatment of viral diseases. Here, we performed an integrative meta-analysis to elucidate the 17 different host-virus interactomes. Network and bioinformatics analyses showed how viruses with small genomes efficiently achieve the maximal effect by targeting multifunctional and highly connected host proteins with a high occurrence of disordered regions. We also identified the core cellular process subnetworks that are targeted by all the viruses. Integration with functional RNA interference (RNAi) datasets showed that a large proportion of the targets are required for viral replication. Furthermore, we performed an interactome-informed drug re-purposing screen and identified novel activities for broad-spectrum antiviral agents against hepatitis C virus and human metapneumovirus. Altogether, these orthogonal datasets could serve as a platform for hypothesis generation and follow-up studies to broaden our understanding of the viral evasion landscape.

The COVID-19 disease has plagued over 200 countries with over three million cases and has resulted in over 200,000 deaths within 3 months. To gain insight into the high infection rate of the SARS-CoV-2 virus, we compare the interaction between the human ACE2 receptor and the SARS-CoV-2 spike protein with that of other pathogenic coronaviruses using molecular dynamics simulations. SARS-CoV, SARS-CoV-2, and HCoV-NL63 recognize ACE2 as the natural receptor but present a distinct binding interface to ACE2 and a different network of residue–residue contacts. SARS-CoV and SARS-CoV-2 have comparable binding affinities achieved by balancing energetics and dynamics. The SARS-CoV-2–ACE2 complex contains a higher number of contacts, a larger interface area, and decreased interface residue fluctuations relative to the SARS-CoV–ACE2 complex. These findings expose an exceptional evolutionary exploration exerted by coronaviruses toward host recognition. We postulate that the versatility of cell receptor binding strategies has immediate implications for therapeutic strategies.

Half a century of research on membrane-containing phages has had a major impact on virology, providing new insights into virus diversity, evolution and ecological importance. The recent revolutionary technical advances in imaging, sequencing and lipid analysis have significantly boosted the depth and volume of knowledge on these viruses. This has resulted in new concepts of virus assembly, understanding of virion stability and dynamics, and the description of novel processes for viral genome packaging and membrane-driven genome delivery to the host. The detailed analyses of such processes have given novel insights into DNA transport across the protein-rich lipid bilayer and the transformation of spherical membrane structures into tubular nanotubes, resulting in the description of unexpectedly dynamic functions of the membrane structures. Membrane-containing phages have provided a framework for understanding virus evolution. The original observation on membrane-containing bacteriophage PRD1 and human pathogenic adenovirus has been fundamental in delineating the concept of “viral lineages”, postulating that the fold of the major capsid protein can be used as an evolutionary fingerprint to trace long-distance evolutionary relationships that are unrecognizable from the primary sequences. This has brought the early evolutionary paths of certain eukaryotic, bacterial, and archaeal viruses together, and potentially enables the reorganization of the nearly immeasurable virus population (~1 × 1031) on Earth into a reasonably low number of groups representing different architectural principles. In addition, the research on membrane-containing phages can support the development of novel tools and strategies for human therapy and crop protection.

As a canonical lymphocyte antigen-6/urokinase-type plasminogen activator receptor Ly6/uPAR family protein, lymphocyte antigen 6 complex, locus E (LY6E), plays important roles in immunological regulation, T cell physiology, and oncogenesis. Emerging evidence indicates that LY6E is also involved in the modulation of viral infection. Consequently, viral infection and associated pathogenesis have been associated with altered LY6E gene expression. The interaction between viruses and the host immune system has offered insights into the biology of LY6E. In this review, we summarize the current knowledge of LY6E in the context of viral infection, particularly viral entry.

Herpes simplex virus type 1 (HSV-1) is widespread double-stranded DNA (dsDNA) virus that establishes life-long latency and causes diverse severe symptoms. The mechanisms of HSV-1 infection and HSV-1’s interactions with various host cells have been studied and reviewed extensively. Type I interferons were secreted by host cells upon HSV infection and play a vital role in controlling virus proliferation. A few studies, however, have focused on HSV-1 infection without the presence of interferon (IFN) signaling. In this study, HEK 293T cells with low toll-like receptor (TLR) and stimulator of interferon genes protein (STING) expression were infected with HSV-1 and subjected to a quantitative proteomic analysis. By using a subcellular fractionation strategy and high-performance mass spectrometry, a total of 6607 host proteins were quantified, of which 498 proteins were differentially regulated. A bioinformatics analysis indicated that multiple signaling pathways might be involved in HSV-1 infection. A further functional study indicated the role of Interferon-induced transmembrane protein 3 (IFITM3), Coiled-coil-helix-coiled-coil-helix domain-containing protein 2 (CHCHD2), and Tripartite motif-containing protein 27 (TRIM27) in inhibiting viral DNA replication and proliferation. Our data provide a global view of host responses to HSV-1 infection in HEK 293T cells and identify the proteins involved in the HSV-1 infection process.

Since their discovery in the early 1980s, viruses that infect the third domain of life, the Archaea, have captivated our attention because of their virions' unusual morphologies and proteins, which lack homologues in extant databases. Moreover, the life cycles of these viruses have unusual features, as revealed by the recent discovery of a novel virus egress mechanism that involves the formation of specific pyramidal structures on the host cell surface. The available data elucidate the particular nature of the archaeal virosphere and shed light on questions concerning the origin and evolution of viruses and cells. In this review, we summarize the current knowledge of archeoviruses, their interaction with hosts and plasmids and their role in the evolution of life.

Background and Aims The human Rhinovirus, a positive‐sense, single‐stranded RNA virus within the Enterovirus genus of the Picornaviridae family, is the most prevalent viral pathogen in humans and the primary cause of the common cold (Verywell Health 2024). Virus‐host interactions, particularly receptor‐mediated adhesion, are pivotal in viral pathogenesis. Competitive inhibition and the use of anti‐adhesive agents have emerged as potential strategies to prevent viral docking. This study aims to explore the structural biology of rhinovirus receptors, specifically the canyon‐like depressions involved in host cell recognition, and investigate molecular approaches to minimize infection and reduce recovery time. Methods A comprehensive structural analysis of human Rhinovirus 14 was conducted, focusing on its unique surface depressions (canyons) surrounding the five‐fold axes. Literature was reviewed for monoclonal antibody interactions via hybridoma technology, as well as anti‐adhesive agents like alginic acid, gelatin, chitosan, and carboxymethyl cellulose. Molecular docking simulations were referenced to evaluate the potential of organic compounds to disrupt viral adhesion. Results The canyon regions on the viral capsid were confirmed as receptor‐binding sites that are structurally shielded from antibody access, allowing the virus to evade immune detection. Anti‐adhesive agents demonstrated theoretical efficacy in competitively inhibiting receptor‐ligand interactions at these sites. Monoclonal antibodies, while effective in certain contexts, showed limited access to conserved binding residues due to spatial constraints. Organic compounds with flexible conformational geometry showed potential in blocking receptor sites by steric hindrance. Conclusion The structural characteristics of human Rhinovirus 14 play a crucial role in immune evasion and receptor binding. While current treatments are limited by the virus's high mutation rate, anti‐adhesive strategies offer a promising avenue to inhibit early‐stage infection and reduce recovery time. Further experimental validation of these agents is necessary to develop effective antiviral therapeutics.

The population diversity and structure of CRISPR-Cas immunity provides key insights into virus–host interactions. Here, we examined two geographically and genetically distinct natural populations of the thermophilic crenarchaeon Sulfolobus islandicus and their interactions with Sulfolobus spindle-shaped viruses (SSVs) and S. islandicus rod-shaped viruses (SIRVs). We found that both virus families can be targeted with high population distributed immunity, whereby most immune strains target a virus using unique unshared CRISPR spacers. In Kamchatka, Russia, we observed high immunity to chronic SSVs that increases over time. In this context, we found that some SSVs had shortened genomes lacking genes that are highly targeted by the S. islandicus population, indicating a potential mechanism of immune evasion. By contrast, in Yellowstone National Park, we found high inter- and intra-strain immune diversity targeting lytic SIRVs and low immunity to chronic SSVs. In this population, we observed evidence of SIRVs evolving immunity through mutations concentrated in the first five bases of protospacers. These results indicate that diversity and structure of antiviral CRISPR-Cas immunity for a single microbial species can differ by both the population and virus type, and suggest that different virus families use different mechanisms to evade CRISPR-Cas immunity. This article is part of a discussion meeting issue ‘The ecology and evolution of prokaryotic CRISPR-Cas adaptive immune systems’.

Background Viruses are traditionally viewed as intracellular parasites that exploit host resources to propagate, often at the host’s expense. However, emerging evidence suggests more nuanced interactions, including potential mutualism. The L-A double-stranded RNA (dsRNA) virus, a non-lytic, cytoplasmic virus commonly found in Saccharomyces cerevisiae , presents an intriguing case, as it lacks clear pathogenic effects in the absence of its M1 satellite. Results To address how and why L-A persistently resides in its yeast host, we conducted a genome-wide screen using yeast deletion and temperature-sensitive (ts) mutant collections, covering approximately 93% of annotated genes, to identify host factors required for efficient L-A maintenance. This screen revealed 96 genes spanning diverse biological processes. Transcriptomic profiling indicated that L-A presence alters the host stress-response gene expression. Furthermore, competitive fitness assays under stress conditions demonstrated that L-A can enhance host resilience, suggesting a mutualistic relationship. Conclusion Our findings uncover a previously unrecognized virus-host mutualism, wherein L-A benefits its host under environmental stress. These results not only expand our understanding of persistent viral infections in eukaryotes but also challenge the canonical view of viruses as purely parasitic, offering new insights into virus-host co-evolution and endogenous viral persistence. Graphical Abstract