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PubMed2026

The organization and dynamics of viral factories.

Viral factories (VFs) are dynamic, virus-induced microcompartments that serve as centralized hubs in the host cell for viral genome replication, transcription, and virion assembly. These structures employ unique viral mechanisms for remodeling cellular architecture to create specialized replication organelles and improve the efficiency of viral propagation. VFs exhibit striking structural and functional diversity among RNA and DNA viruses, from reoviruses and poxviruses to the Nucleocytoviricota phylum. Some are enclosed by host-derived membranes, while others exist as biomolecular condensates from liquid-liquid phase separation. VFs recruit host lipids, cytoskeletal elements, and metabolic enzymes, effectively reprogramming the intracellular environment to favor viral replication. This review provides a comprehensive examination of the molecular composition, ultrastructure, and biogenesis of viral factories across a wide range of viral lineages and host systems. We describe membrane-bound and phase-separated VFs and the mechanisms by which they hijack host machinery to create these replication organelles and explore viral strategies to shield replication intermediates from host immune responses. Additional emphasis is placed on the complex VFs formed by giant viruses in the Nucleocytoviricota, whose ability to spatially compartmentalize replication and transcription, exclude ribosomes, and recruit host mitochondria and membranes blurs the line between viral and cellular organization. By integrating findings from cell biology and evolutionary virology, this review proposes that viral factories offer a conceptual framework for understanding virus-host coevolution and provides new insights into how their organization may have shaped the emergence of eukaryotic complexity.

Nucleocytoviricota↗
PubMed1979

Reovirus serotypes 1 and 3 differ in their in vitro association with microtubules.

Utilizing negative-stain electron microscopy in which similar concentrations of reovirus types 1 and 3 are incubated with a carbon support film containing chick brain, rabbit brain, or HeLa cell microtubules, 81% of the type 1 and 56% of type 3 exhibited an association with the apparent "edge" of the microtubule. This implies that there is a high level of specific affinity for type 1 but not for type 3 to microtubules, since it has previously been determined that only 50% of randomly associated particles would be associated with the edge. The high edge binding of reovirus type 1 is virtually independent of the origin of microtubule, or of whether microtubules or virus has been initially adhered to the support film. On the other hand, reovirus type 1-specific antiserum reduced the edge binding or reovirus type 1 to 45%, whereas type 3 specific antiserum caused no less (within the variability of the assay) of the edge binding of reovirus type 1 to microtubules (76% edge bound). High edge binding of reovirus type 1 to microtubules is correlated with the presence of type 1 or sigma 1 polypeptide. This minor outer capsid polypeptide is encoded in the S1 double-stranded RNA segment and is the viral hemagglutinin and neutralization antigen. Recombinant reovirus clones containing the S1 double-stranded RNA segment of type 1 (80 and 802) show about 85% edge binding, as compared to a value of 42% for clones and the S1 gene of type 3 (204. Electron microscopy of purified reovirus types 1 and 3 by negative staining reveals that type 1 and 802 capsomers are distinctly visualized, whereas those of type 3 and 204 appear diffuse. Thus, the greater in vitro binding of type 1 to microtubules may reflect an increased accessibility of certain of its outer capsomers, and thereby, sigma 1 polypeptides to microtubules. Examination of its outer sections of reovirus type 1- and 3-infected cells at 24 to 48 h postinfection at 31 degrees C showed that about eight times as many viral factoris in type 1-infected cells exhibited an extensive association of virus particles with microtubules, as compared to viral factories of type 3-infected cells. Thus, both in vivo and in vitro there appears to be a greater specificity for the association of reovirus type 1 particles with microtubules, as compared to reovirus type 3 particles.

Animals↗
PubMed2026

Direct interaction between RSV polymerase L and active Rab11a mediates viral ribonucleoprotein transport to assembly sites.

Respiratory syncytial virus (RSV) is an enveloped, negative-sense, single-stranded RNA virus whose ribonucleoproteins (vRNPs) must be transported from cytoplasmic viral factories to the plasma membrane for efficient virion assembly. Viral vRNPs comprise genomic RNA encapsidated by nucleoprotein N and associated with the polymerase complex (L, P, and M2-1). It was previously demonstrated that newly synthesized vRNPs are transported along microtubules by hijacking Rab11a, a small GTPase involved in the regulation of recycling endosomes. In our previous study, we showed an interaction between Rab11a and vRNPs in infected cells by immunoprecipitation assays, nevertheless the molecular mechanisms underlying Rab11a viral hijacking remained unknown. Here, we provide the first comprehensive characterization of the interaction between RSV vRNPs and Rab11a using immunoprecipitation, immunofluorescence colocalization, GST pull-down assays, and biolayer interferometry. We demonstrate that the viral polymerase L is the sole vRNPs component responsible for Rab11a recognition: immunoprecipitation of L specifically co-precipitates HA-tagged Rab11a, whereas other vRNPs proteins show no interaction. In vitro binding studies confirm that L interacts directly and specifically with the active, GTP-bound form of Rab11a with sub-micromolar affinity. Domain mapping using truncated constructs reveals that this interaction requires the C-terminal methyltransferase and CTD domains of L (residues 1756-2165) and depends on Rab11a's Switch I region, known to mediate interactions with cellular Rab11a partners. Mutagenesis further highlights leucine 1860 in the L polymerase as critical for Rab11a binding. Competitive inhibition of the interaction between Rab11a and L using the minimal Rab11a-binding domain significantly impairs vRNP dynamics during infection, indicating that Rab11a-L binding is involved in the transport of vRNPs. Together, these findings establish RSV polymerase L as the key mediator of Rab11a engagement, define the molecular interface of their interaction, and reveal a potentially conserved viral strategy for genome transport. Targeting the L-Rab11a interaction could therefore be a promising strategy for the development of RSV-specific or broad-spectrum antiviral therapies.

rab GTP-Binding Proteins↗
PubMed1977

Rifampin and vaccinia DNA.

The effect of rifampin on the replication of vaccinia DNA was studied in mouse L cells by a cytochemical techinque and by alkaline sucrose sedimentation analysis of newly synthesized viral DNA molecules. By the use of a fluorescent DNA-binding compound (Hoechst 33258), the sequential appearance, size, and location of the viral "factories" in rifampin-treated, virus-infected cells were found to be indistinguishable from those observed in untreated, infected cells. Sedimentation analysis in alkaline scurose gradients of the viral DNA molecules labeled in pulse-chase experiments showed that formation of small fragments, elongation into "intermediate"-sized molecules, and maturation into full-length viral DNA and, finally, into cross-linked viral DNA molecules occurred in the absence or presence of rifampin. The results support the view that the primary effect of the drug is related to assembly or morphogenesis.

DNA Replication↗
PubMed2026

Infection cycles of viruses of the phylum Nucleocytoviricota.

The phylum Nucleocytoviricota, formerly known as nucleocytoplasmic large DNA viruses (NCLDVs), comprises evolutionarily related viruses with remarkably diverse genome sizes, coding capacities and virion morphologies. These viruses infect hosts across the eukaryotic tree of life, from protists to humans, and are believed to have emerged during the early stages of eukaryotic evolution. How the basic aspects of virus-host interaction have evolved in different lineages and whether they share a conserved infection cycle remain unclear. In this Review, we synthesize the information on the infection cycles of model representatives from the major orders within the phylum, revealing both shared traits and lineage-specific innovations. We compare the information available for the extensively studied poxviruses, asfiviruses, iridoviruses and chloroviruses with insights from the rapidly expanding literature on the mimiviruses, pandoraviruses, marseilleviruses and pithoviruses. We provide an overview of the molecular details underlying the key stages of Nucleocytoviricota infection cycles: entry via membrane fusion, formation of viral factories organized via phase separation, genome replication, virion morphogenesis through a crescent intermediate, and egress. We highlight outstanding questions in the field, unify concepts across traditionally separated research areas, and provide a conceptual framework to guide future cell biology studies on large double-stranded DNA viruses.

DNA Viruses↗
PubMed1979

Species specificity of interferon action: maintenance and establishment of the antiviral state in the presence of a heterospecific nucleus.

The expression of the interferon-induced antiviral state was studied in heterokaryons and cytoplasmic hybrids (cybrids). An autoradiographic assay for the antiviral state, in which the percentage of cells containing vaccinia viral DNA factories was determined, was used. The expression of the antiviral state was dominant in homokaryons and heterokaryons formed by fusion of interferon-treated cells with untreated cells. Cytoplasts derived from treated cells conferred resistance to virus growth on cybrids formed by fusing such cytoplasts with untreated cells. Treatment of L cell x HeLa cell heterokaryons with human interferon or mouse interferon was much less effective in inducing a detectable antiviral state than was similar treatment of parental cells with homospecific interferon. The antiviral state was fully induced when heterokaryons were treated simultaneously with both types of interferon. Cybrids formed by fusing L cell cytoplasts with HeLa cells or HeLa cytoplasts with L cells did not enter a detectable antiviral state after treatment with interferon specific for the cell type of the enucleated parent. However, treatment of cybrids with interferon specific for the cell type of the nucleated parent was effective in inducing a detectable antiviral state.

Animals↗
PubMed2025

Chromatin assembly by the histone chaperone HIRA facilitates Human Papillomavirus replication.

The circular, double-stranded DNA genomes of Human papillomaviruses (HPV) exist in a nucleosomal state throughout the infectious cycle and rely on host histone epigenetic modifications and chromatin assembly processes to promote various phases of the viral life cycle. Here, we show that the histone H3.3 chaperone HIRA and its associated complex members are recruited to HPV replication factories during the late phase of the HPV life cycle. HIRA is also recruited to HPV replication factories generated by amplification of a replicon with a minimal origin and expression of the viral replication proteins E1 and E2, demonstrating that the E1 and E2 proteins are sufficient for HIRA recruitment. Downregulation of HIRA expression reduces HPV31 DNA amplification and viral transcription in differentiated keratinocytes. Histone H3.3 that is highly phosphorylated on serine residue 31 is also enriched at sites of HPV replication and this modification links the DNA damage response to chromatin that supports rapid gene activation. We propose that deposition of histone H3.3 generates viral minichromosomes that are highly primed to support the late stages of the HPV life cycle.

H3.3 phosphorylation↗
PubMedDate not supplied

Multidimensional statistical data analysis of viral hepatitis report records.

The internal connections between the variables defined by the data obtained from viral hepatitis (VH) report records completed ih a Romanian county durihg 1973 are analysed. The mathematical model for linear factorial analysis allowed a simultaneous processing of all variables and the distinction of representative factors. The conclusions of the study suggest new possible approaches by the introduction of supplementary questions in the VH report records.

Factor Analysis, Statistical↗
PubMed2025

Optimized GMP-grade production of non-viral Sleeping Beauty-generated CARCIK cells for enhanced fitness and clinical scalability.

BACKGROUND: Strict adherence to GMP guidelines and regulatory compliance is crucial when transitioning from research to clinical-grade production of ATMPs like CAR T cells. The success of CAR T cell therapy in treating hematological malignancies highlights the need for closed or automated systems to ensure quality and efficacy. Recent evidence also suggests that ex vivo culture conditions can significantly impact CAR T cell functionality. METHODS: We present our optimized methodology for expanding Sleeping Beauty transposon-engineered Chimeric Antigen Receptor-Cytokine-Induced Killer (CARCIK) cells using G-Rex devices and evaluate its impact on CARCIK cell phenotype and T cell fitness. RESULTS: Building on our previously validated protocol, we introduced key simplifications to optimize the CARCIK differentiation process. Delaying the nucleofection step eliminated the need for feeder cells while maintaining efficient CAR expression and high cell viability. Transitioning from T-flasks to G-Rex bioreactors reduced operator hands-on time from 21 to 28 days to 14-17 days and resulted in a less differentiated CARCIK cell product. Metabolic and transcriptional analyses showed that the novel protocol improves CARCIK cell fitness and in vivo efficacy against B-cell lymphoma. The novel method was validated in Good Manufacturing Practices (GMP) conditions at our two Cell Factories and yielded enough numbers of CARCIK-CD19 cells for clinical use. CONCLUSIONS: Optimizing non-viral CARCIK cell production using G-Rex bioreactors and refined timing adjustments has streamlined the workflow, enhanced cell fitness, and resulted in a highly effective therapeutic product with demonstrated in vivo efficacy in mice. These improvements reduced manipulation and contamination risks, while optimizing logistics and space efficiency, facilitating allogeneic CARCIK generation for a current phase I/II clinical trial (NCT05869279) in patients with R/R CD19 + non-Hodgkin Lymphoma (B-cell NHL) and Chronic Lymphocytic Leukemia (CLL), confirming the approach's scalability and clinical potential.

Humans↗
PubMed1977

Ultrastructural study of cell cultures infected with swinepox and orf viruses.

Monolayer cells of a porcine kidney cell line were infected with the PP-1 strain of swinepox virus, while secondary or third subcultured monolayer cells of African green monkey kidney were inoculated with the Iwate BT-9 strain of orf virus. Those infected cells were fixed when CPE became remarkable in the monolayers and examined by electron microscope. In the cytoplasm of cells infected with both viruses, various immature forms of viral particles in different developmental stages were observed. Micells were detected very close to the opening of immature particles. Mature particles asssociated with a double membrane were frequently observed. From those observations it was suggested that the developmental sequence of both viruses is essentially the same as that of vaccinia (Dales, 1973). Besides various virus forms as well as factories, the following ultrastructural changes were noted in swinepox infected cells, i.e. 1) intranuclear inclusions which consist of very fine filaments, 2) fibrillar structures with cross striations located in the nuclear inclusions, and 3) similar striated fibrillar structures in or just adjacent to virus factories (B type inclusions) in the cytoplasm. Those observations made with in vitro cells are in good accordance with the descriptions by previous investigators on in vivo materials. Accordingly those ultrastructural changes characterize the swinepox infection.

Animals↗
PubMed2025

Dysregulation of lung epithelial cell homeostasis and immunity contributes to Middle East respiratory syndrome coronavirus disease severity.

Coronaviruses (CoV) emerge suddenly from animal reservoirs to cause novel diseases in new hosts. Discovered in 2012, the Middle East respiratory syndrome coronavirus (MERS-CoV) is endemic in camels in the Middle East and is continually causing local outbreaks and epidemics. While all three newly emerging human CoVs from the past 20 years (SARS-CoV, SARS-CoV-2, and MERS-CoV) cause respiratory disease, each CoV has unique host interactions that drive differential pathogeneses. To better understand the virus and host interactions driving lethal MERS-CoV infection, we performed a longitudinal multi-omics analysis of sublethal and lethal MERS-CoV infection in mice. Significant differences were observed in body weight loss, virus titers, and acute lung injury among lethal and sub-lethal virus doses. Virus-induced apoptosis of type I and II alveolar epithelial cells suggests that loss or dysregulation of these key cell populations was a major driver of severe disease. Omics analysis suggested differential pathogenesis was multi-factorial with clear differences among innate and adaptive immune pathways as well as those that regulate lung epithelial homeostasis. Infection of mice lacking functional T and B cells showed that adaptive immunity was important in controlling viral replication but also increased pathogenesis. In summary, we provide a high-resolution host response atlas for MERS-CoV infection and disease severity. Multi-omics studies of viral pathogenesis offer a unique opportunity to not only better understand the molecular mechanisms of disease but also to identify genes and pathways that can be exploited for therapeutic intervention all of which is important for our future pandemic preparedness.IMPORTANCEEmerging coronaviruses like SARS-CoV, SARS-CoV-2, and MERS-CoV cause a range of disease outcomes in humans from an asymptomatic, moderate, and severe respiratory disease that can progress to death but the factors causing these disparate outcomes remain unclear. Understanding host responses to mild and life-threatening infections provides insight into virus-host networks within and across organ systems that contribute to disease outcomes. We used multi-omics approaches to comprehensively define the host response to moderate and severe MERS-CoV infection. Severe respiratory disease was associated with dysregulation of the immune response. Key lung epithelial cell populations that are essential for lung function get infected and die. Mice lacking key immune cell populations experienced greater virus replication but decreased disease severity implicating the immune system in both protective and pathogenic roles in response to MERS-CoV. These data could be utilized to design new therapeutic strategies targeting specific pathways that contribute to severe disease.

Animals↗
PubMed1992

Aplastic anaemia: a review of cases at the University College Hospital, Ibadan, Nigeria.

Thirty male and 27 female patients were treated at the University College Hospital, Ibadan, over a 20 year period (January, 1971 to December, 1990) for aplastic anaemia. Age range was three months to 52 years with a median of 19 years. In 26 patients the aplasia could not be linked with a particular cause. Most patients in this category were students in secondary and tertiary institutions, office workers and casual labourers. Nineteen patients were automobile and factory workers who are exposed to lead while two were dealers in petroleum products. In two patients aplasia was linked to chloramphenicol ingestion while in three, the aplasia linked to the use of hair dye. Another three linked the aplasia to a past history of viral hepatitis. One patient had congenital aplasia of the marrow and one was a radiographer. Treatment included oxymethalone 100 mg given three times daily (tds) or intramuscular (i.m.) Durabolin 500 mg weekly. When these drugs were unavailable prednisolone 60 mg daily was administered. No patient had the benefit of bone marrow transplantation (BMT) or the superior drugs, e.g. anti-thymocyte globulin and cyclosporin A. This might have contributed to the poor prognosis as revealed by the survival pattern in which 24 patients died within six months of diagnosis while 19 survived 12 months. Seven patients died within 18 months and four others died within three years. Three patients were alive five years after presentation. Death generally resulted from complications of the aplastic anaemia with gastro-intestinal bleeding, cerebro-vascular accidents and overwhelming infections.

Adolescent↗
PubMed2026

Refining a giant virus lineage: a novel order unifying Mamonoviridae and "Manesviridae," unveiled by the discovery of furtivovirus.

UNLABELLED: The evolutionary origins and taxonomic framework of giant viruses related to the family Mamonoviridae and its relative group, including clandestinovirus, remain unclassified due to gaps in genome size and host range between these two groups. This study aimed to address this gap by integrating our newly isolated virus with publicly available metagenome-assembled genomes (MAGs) to construct a more robust phylogenetic framework. Here, we report the isolation and characterization of a new giant virus, furtivovirus, using the unicellular amoeba Vermamoeba vermiformis as a host. Furtivovirus has a genome of approximately 560 kbp and shares key features with its closest relative, clandestinovirus. Ultrastructural analysis revealed a unique host-nucleus-dependent replication strategy characterized by the breakdown of the nuclear membrane and the packaging of nascent virions directly within the nucleoplasm, distinguishing it from canonical cytoplasmic virion factories. Comprehensive phylogenetic and comparative genomic analyses of shared orthologous groups and nucleocytovirus marker proteins revealed that furtivovirus, clandestinovirus, ushikuvirus, and usurpativirus form a distinct monophyletic clade, for which we propose a new family, "Manesviridae." Further analysis using amino acid-based similarity metrics of Nucleocytoviricota viral genomes, including established MAGs, demonstrated that this new family is robustly placed as a sister group to the family Mamonoviridae. This study elucidated the evolutionary relationships between viruses with large and small genomes that possess similar virion sizes within this lineage. Based on this cumulative evidence, we propose the establishment of a new order to unify these two families, thereby expanding their diversity and clarifying the evolutionary history of this branch within Nucleocytoviricota. IMPORTANCE: Giant viruses challenge our traditional understanding of viral evolution, raising the question of how a single related group can diverge to infect different hosts while evolving into vastly different genome sizes and replication strategies. The family Mamonoviridae and its relatives epitomize this evolutionary divergence: one group possesses massive genomes, whereas the other has genomes that are less than half their size. The discovery of furtivovirus and its unique nucleoplasm-dependent replication cycle provides a critical biological context for this genomic disparity. Through deep comparative genomic analysis, we demonstrated that these seemingly disparate lineages share a cohesive evolutionary origin that is distinct from other established orders. This finding highlights the complexity of genome evolution, demonstrating that giant viruses can expand their overall genome size to adapt to uncertain environments while reducing their core essential genes, thereby providing new insights into the evolutionary pressures that shape the diversity of the virosphere.

Giant Viruses↗
PubMed1978

Ebola haemorrhagic fever in Sudan, 1976. Report of a WHO/International Study Team.

A large outbreak of haemorrhagic fever (subsequently named Ebola haemorrhagic fever) occurred in southern Sudan between June and November 1976. There was a total of 284 cases; 67 in the source town of Nzara, 213 in Maridi, 3 in Tembura, and 1 in Juba. The outbreak in Nzara appears to have originated in the workers of a cotton factory. The disease in Maridi was amplified by transmission in a large, active hospital. Transmission of the disease required close contact with an acute case and was usually associated with the act of nursing a patient. The incubation period was between 7 and 14 days. Although the link was not well established, it appears that Nzara could have been the source of infection for a similar outbreak in the Bumba Zone of Zaire.In this outbreak Ebola haemorrhagic fever was a unique clinical disease with a high mortality rate (53% overall) and a prolonged recovery period in those who survived. Beginning with an influenza-like syndrome, including fever, headache, and joint and muscle pains, the disease soon caused diarrhoea (81%), vomiting (59%), chest pain (83%), pain and dryness of the throat (63%), and rash (52%). Haemorrhagic manifestations were common (71%), being present in half of the recovered cases and in almost all the fatal cases.Two post mortems were carried out on patients in November 1976. The histopathological findings resembled those of an acute viral infection and although the features were characteristic they were not exclusively diagnostic. They closely resembled the features described in Marburg virus infection, with focal eosinophilic necrosis in the liver and destruction of lymphocytes and their replacement by plasma cells. One case had evidence of renal tubular necrosis.Two strains of Ebola virus were isolated from acute phase sera collected from acutely ill patients in Maridi hospital during the investigation in November 1976. Antibodies to Ebola virus were detected by immunofluorescence in 42 of 48 patients in Maridi who had been diagnosed clinically, but in only 6 of 31 patients in Nzara. The possibility of the indirect immunofluorescent test not being sufficiently sensitive is discussed.Of Maridi case contacts, in hospital and in the local community, 19% had antibodies. Very few of them gave any history of illness, indicating that Ebola virus can cause mild or even subclinical infections. Of the cloth room workers in the Nzara cotton factory, 37% appeared to have been infected, suggesting that the factory may have been the prime source of infection.

Adolescent↗
PubMed2026

The factory enters the fray: how mitochondrial protein trafficking shapes the host response to infection.

Beyond textbook functions in homeostatic metabolism, mitochondria are now recognized as central coordinators of cell-intrinsic and cell-extrinsic immune responses to infection. Directed trafficking of proteins and other molecules between mitochondria and the rest of the cell underlies a growing catalog of these activities. Some are pro-host; others are antagonized by viral effectors or co-opted by viruses entirely. How host and viral factors rewire the mitochondrial proteome during infection to shape these outcomes remains incompletely understood. The evolutionary history of this system adds another dimension: mitochondria retain biochemical signatures of their α-proteobacterial endosymbiotic origin, and ongoing co-evolution between viral, host, and mitochondrial genomes continues to shape the proteins that traffic to and from the organelle. Using published examples, we highlight general principles, mechanisms, and consequences of host and viral protein localization to and from the mitochondria. To support discovery, we present integrated gene lists identifying host mitochondrial factors with evidence for type I interferon stimulation, interactions with viral proteins, and signatures of positive selection. Together, these resources and the principles within offer a framework for understanding mitochondria not as passive metabolic machinery but as actively contested cellular territory whose protein composition is continuously negotiated between the host and the pathogen.

adaptation↗
PubMed1979

Avian pox virus. An ultrastructural study on a cherrug falcon. Brief report.

The ultrastructure and maturation of avian pox particles is described in the rare case of a naturally infected hawk (Falco cherrug). As in other cells infected by fowlpox virus two types of inclusion bodies are encountered in the cytoplasm: firstly assemblies of fluffy filamentous material apparently giving rise to immature virions. They are thought to present virus factories (inclusion body B). Secondly mature virus particles budded into extensive groupings (Bollinger bodies, inclusion body A) which display a fine structure identical to other strains of fowlpox virus.

Animals↗