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Viruses Sep 2021Papillomaviruses cause persistent, and usually self-limiting, infections in the mucosal and cutaneous surfaces of the host epithelium. However, in some cases, infection... (Review)
Review
Papillomaviruses cause persistent, and usually self-limiting, infections in the mucosal and cutaneous surfaces of the host epithelium. However, in some cases, infection with an oncogenic HPV can lead to cancer. The viral genome is a small, double-stranded circular DNA molecule that is assembled into nucleosomes at all stages of infection. The viral minichromosome replicates at a low copy number in the nucleus of persistently infected cells using the cellular replication machinery. When the infected cells differentiate, the virus hijacks the host DNA damage and repair pathways to replicate viral DNA to a high copy number to generate progeny virions. This strategy is highly effective and requires a close association between viral and host chromatin, as well as cellular processes associated with DNA replication, repair, and transcription. However, this association can lead to accidental integration of the viral genome into host DNA, and under certain circumstances integration can promote oncogenesis. Here we describe the fate of viral DNA at each stage of the viral life cycle and how this might facilitate accidental integration and subsequent carcinogenesis.
Topics: Alphapapillomavirus; Carcinogenesis; Cell Differentiation; Cell Proliferation; Chromosomes, Human; DNA, Viral; Genome, Viral; Humans; Mitosis; Papillomavirus Infections; Promyelocytic Leukemia Nuclear Bodies; Viral Proteins; Virus Integration; Virus Replication
PubMed: 34578427
DOI: 10.3390/v13091846 -
Viruses Jan 2021Human hepatitis B virus (HBV) can cause chronic, lifelong infection of the liver that may lead to persistent or episodic immune-mediated inflammation against... (Review)
Review
Human hepatitis B virus (HBV) can cause chronic, lifelong infection of the liver that may lead to persistent or episodic immune-mediated inflammation against virus-infected hepatocytes. This immune response results in elevated rates of killing of virus-infected hepatocytes, which may extend over many years or decades, lead to fibrosis and cirrhosis, and play a role in the high incidence of hepatocellular carcinoma (HCC) in HBV carriers. Immune-mediated inflammation appears to cause oxidative DNA damage to hepatocytes, which may also play a major role in hepatocarcinogenesis. An additional DNA damaging feature of chronic infections is random integration of HBV DNA into the chromosomal DNA of hepatocytes. While HBV DNA integration does not have a role in virus replication it may alter gene expression of the host cell. Indeed, most HCCs that arise in HBV carriers contain integrated HBV DNA and, in many, the integrant appears to have played a role in hepatocarcinogenesis. Clonal expansion of hepatocytes, which is a natural feature of liver biology, occurs because the hepatocyte population is self-renewing and therefore loses complexity due to random hepatocyte death and replacement by proliferation of surviving hepatocytes. This process may also represent a risk factor for the development of HCC. Interestingly, during chronic HBV infection, hepatocyte clones detected using integrated HBV DNA as lineage-specific markers, emerge that are larger than those expected to occur by random death and proliferation of hepatocytes. The emergence of these larger hepatocyte clones may reflect a survival advantage that could be explained by an ability to avoid the host immune response. While most of these larger hepatocyte clones are probably not preneoplastic, some may have already acquired preneoplastic changes. Thus, chronic inflammation in the HBV-infected liver may be responsible, at least in part, for both initiation of HCC via oxidative DNA damage and promotion of HCC via stimulation of hepatocyte proliferation through immune-mediated killing and compensatory division.
Topics: Animals; DNA, Viral; Hepatitis B virus; Hepatitis B, Chronic; Hepatocytes; Humans; Liver; Virus Integration
PubMed: 33573130
DOI: 10.3390/v13020210 -
Nature Microbiology Apr 2021Early events of the human immunodeficiency virus 1 (HIV-1) lifecycle, such as post-entry virus trafficking, uncoating and nuclear import, are poorly characterized...
Early events of the human immunodeficiency virus 1 (HIV-1) lifecycle, such as post-entry virus trafficking, uncoating and nuclear import, are poorly characterized because of limited understanding of virus-host interactions. Here, we used mass spectrometry-based proteomics to delineate cellular binding partners of curved HIV-1 capsid lattices and identified Sec24C as an HIV-1 host dependency factor. Gene deletion and complementation in Jurkat cells revealed that Sec24C facilitates infection and markedly enhances HIV-1 spreading infection. Downregulation of Sec24C in HeLa cells substantially reduced HIV-1 core stability and adversely affected reverse transcription, nuclear import and infectivity. Live-cell microscopy showed that Sec24C co-trafficked with HIV-1 cores in the cytoplasm during virus ingress. Biochemical assays demonstrated that Sec24C directly and specifically interacted with hexameric capsid lattices. A 2.3-Å resolution crystal structure of Sec24C in the complex with a capsid hexamer revealed that the Sec24C FG-motif bound to a pocket comprised of two adjoining capsid subunits. Combined with previous data, our findings indicate that a capsid-binding FG-motif is conserved in unrelated proteins present in the cytoplasm (Sec24C), the nuclear pore (Nup153; refs. ) and the nucleus (CPSF6; refs. ). We propose that these virus-host interactions during HIV-1 trafficking across different cellular compartments are crucial for productive infection of target cells.
Topics: Active Transport, Cell Nucleus; Amino Acid Motifs; Binding Sites; Capsid; Cell Nucleus; Cytoplasm; HIV-1; Host-Pathogen Interactions; Humans; Lentiviruses, Primate; Nuclear Pore; Protein Binding; Reverse Transcription; Structure-Activity Relationship; Vesicular Transport Proteins; Virus Integration; Virus Replication
PubMed: 33649557
DOI: 10.1038/s41564-021-00868-1 -
Microbiology Spectrum Sep 2019Most isolates carry multiple bacteriophages in their genome, which provide the pathogen with traits important for niche adaptation. Such temperate phages often encode... (Review)
Review
Most isolates carry multiple bacteriophages in their genome, which provide the pathogen with traits important for niche adaptation. Such temperate phages often encode a variety of accessory factors that influence virulence, immune evasion and host preference of the bacterial lysogen. Moreover, transducing phages are primary vehicles for horizontal gene transfer. Wall teichoic acid (WTA) acts as a common phage receptor for staphylococcal phages and structural variations of WTA govern phage-host specificity thereby shaping gene transfer across clonal lineages and even species. Thus, bacteriophages are central for the success of as a human pathogen.
Topics: Animals; Gene Transfer, Horizontal; Host Specificity; Host-Pathogen Interactions; Humans; Immune Evasion; Podoviridae; Staphylococcal Infections; Staphylococcus Phages; Staphylococcus aureus; Teichoic Acids; Transduction, Genetic; Virulence; Virulence Factors; Virus Integration
PubMed: 31562736
DOI: 10.1128/microbiolspec.GPP3-0058-2018 -
Nature Jul 2020Bats possess extraordinary adaptations, including flight, echolocation, extreme longevity and unique immunity. High-quality genomes are crucial for understanding the...
Bats possess extraordinary adaptations, including flight, echolocation, extreme longevity and unique immunity. High-quality genomes are crucial for understanding the molecular basis and evolution of these traits. Here we incorporated long-read sequencing and state-of-the-art scaffolding protocols to generate, to our knowledge, the first reference-quality genomes of six bat species (Rhinolophus ferrumequinum, Rousettus aegyptiacus, Phyllostomus discolor, Myotis myotis, Pipistrellus kuhlii and Molossus molossus). We integrated gene projections from our 'Tool to infer Orthologs from Genome Alignments' (TOGA) software with de novo and homology gene predictions as well as short- and long-read transcriptomics to generate highly complete gene annotations. To resolve the phylogenetic position of bats within Laurasiatheria, we applied several phylogenetic methods to comprehensive sets of orthologous protein-coding and noncoding regions of the genome, and identified a basal origin for bats within Scrotifera. Our genome-wide screens revealed positive selection on hearing-related genes in the ancestral branch of bats, which is indicative of laryngeal echolocation being an ancestral trait in this clade. We found selection and loss of immunity-related genes (including pro-inflammatory NF-κB regulators) and expansions of anti-viral APOBEC3 genes, which highlights molecular mechanisms that may contribute to the exceptional immunity of bats. Genomic integrations of diverse viruses provide a genomic record of historical tolerance to viral infection in bats. Finally, we found and experimentally validated bat-specific variation in microRNAs, which may regulate bat-specific gene-expression programs. Our reference-quality bat genomes provide the resources required to uncover and validate the genomic basis of adaptations of bats, and stimulate new avenues of research that are directly relevant to human health and disease.
Topics: Adaptation, Physiological; Animals; Chiroptera; DNA Transposable Elements; Evolution, Molecular; Genome; Genomics; Immunity; Molecular Sequence Annotation; Phylogeny; RNA, Untranslated; Reference Standards; Reproducibility of Results; Virus Integration; Viruses
PubMed: 32699395
DOI: 10.1038/s41586-020-2486-3 -
International Journal of Molecular... Jul 2022Human papillomavirus (HPV) integration within the host genome may contribute to carcinogenesis through various disruptive mechanisms. With next-generation sequencing...
Human papillomavirus (HPV) integration within the host genome may contribute to carcinogenesis through various disruptive mechanisms. With next-generation sequencing (NGS), identification of viral and host genomic breakpoints and chimeric sequences are now possible. However, a simple, streamlined bioinformatics workflow has been non-existent until recently. Here, we tested two new, automated workflows in CLC Microbial Genomics, i.e., Viral Hybrid Capture (VHC) Data Analysis and Viral Integration Site (VIS) Identification for software performance and efficiency. The workflows embedded with HPV and human reference genomes were used to analyze a publicly available NGS dataset derived from pre- and cancerous HPV+ cervical cytology of 21 Gabonese women. The VHC and VIS workflow median runtimes were 19 and 7 min per sample, respectively. The VIS dynamic graphical outputs included read mappings, virus-host genomic breakpoints, and virus-host integration circular plots. Key findings, including disrupted and nearby genes, were summarized in an auto-generated report. Overall, the VHC and VIS workflows proved to be a rapid and accurate means of localizing viral-host integration site(s) and identifying disrupted and neighboring human genes. Applying HPV VIS-mapping to pre- or invasive tumors will advance our understanding of viral oncogenesis and facilitate the discovery of prognostic biomarkers and therapeutic targets.
Topics: Alphapapillomavirus; DNA, Viral; Female; Genomics; Humans; Papillomaviridae; Papillomavirus Infections; Uterine Cervical Neoplasms; Virus Integration; Workflow
PubMed: 35897706
DOI: 10.3390/ijms23158132 -
The Saudi Dental Journal Oct 2019Head and neck squamous cell carcinomas (HNSCCs) arise in the mucosal linings of the upper aerodigestive tract and are heterogeneous in nature. Risk factors for HNSCCs... (Review)
Review
Head and neck squamous cell carcinomas (HNSCCs) arise in the mucosal linings of the upper aerodigestive tract and are heterogeneous in nature. Risk factors for HNSCCs are smoking, excessive alcohol consumption, and the human papilloma virus. Conventional treatments are surgery, radiotherapy, chemotherapy, or a combined modality; however, no international standard mode of therapy exists. In contrast to the conventional model of clonal evolution in tumor development, there is a newly proposed theory based on the activity of cancer stem cells (CSCs) as the model for carcinogenesis. This "CSC hypothesis" may explain the high mortality rate, low response to treatments, and tendency to develop multiple tumors for HNSCC patients. We review current knowledge on HNSCC etiology and treatment, with a focus on CSCs, including their origins, identifications, and effects on therapeutic options.
PubMed: 31700218
DOI: 10.1016/j.sdentj.2019.05.010 -
Exploration of Targeted Anti-tumor... 2023Medulloblastoma (MB) is the commonest primary malignant brain cancer. The current treatment of MB is usually surgical resection combined with radiotherapy or... (Review)
Review
Medulloblastoma (MB) is the commonest primary malignant brain cancer. The current treatment of MB is usually surgical resection combined with radiotherapy or chemotherapy. Although great progress has been made in the clinical management of MB, tumor metastasis and recurrence are still the main cause of death. Therefore, definitive and timely diagnosis is of great importance for improving therapeutic effects on MB. In 2016, the World Health Organization (WHO) divided MB into four subtypes: wingless-type mouse mammary tumor virus integration site (WNT), sonic hedgehog (SHH), non-WNT/non-SHH group 3, and group 4. Each subtype of MB has a unique profile in copy number variation, DNA alteration, gene transcription, or post-transcriptional/translational modification, all of which are associated with different biological manifestations, clinical features, and prognosis. This article reviewed the research progress of different molecular pathology markers in MB and summarized some targeted drugs against these molecular markers, hoping to stimulate the clinical application of these molecular markers in the classification, diagnosis, and treatment of MB.
PubMed: 36937322
DOI: 10.37349/etat.2023.00126 -
Microbiome Jan 2021Polintons are large mobile genetic elements found in the genomes of eukaryotic organisms that are considered the ancient ancestors of most eukaryotic dsDNA viruses....
BACKGROUND
Polintons are large mobile genetic elements found in the genomes of eukaryotic organisms that are considered the ancient ancestors of most eukaryotic dsDNA viruses. Originally considered as transposons, they have been found to encode virus capsid genes, suggesting they may actually be integrated viruses; however, an extracellular form has yet to be detected. Recently, circa 25 Polinton-like viruses have been discovered in environmental metagenomes and algal genomes, which shared distantly related genes to both Polintons and virophages (Lavidaviridae). These entities could be the first members of a major class of ancient eukaryotic viruses; however, owing to the lack of available genomes for analysis, information on their global diversity, evolutionary relationships, eukaryotic hosts, and status as free virus particles is limited.
RESULTS
Here, we analysed the metaviromes of an alpine lake to show that Polinton-like virus genome sequences are abundant in the water column. We identify major capsid protein genes belonging to 82 new Polinton-like viruses and use these to interrogate publicly available metagenomic datasets, identifying 543 genomes and a further 16 integrated into eukaryotic genomes. Using an analysis of shared gene content and major capsid protein phylogeny, we define large groups of Polinton-like viruses and link them to diverse eukaryotic hosts, including a new group of viruses, which possess all the core genes of virophages and infect oomycetes and Chrysophyceae.
CONCLUSIONS
Our study increased the number of known Polinton-like viruses by 25-fold, identifying five major new groups of eukaryotic viruses, which until now have been hidden in metagenomic datasets. The large enrichment (> 100-fold) of Polinton-like virus sequences in the virus-sized fraction of this alpine lake and the fact that their viral major capsid proteins are found in eukaryotic host transcriptomes support the hypothesis that Polintons in unicellular eukaryotes are viruses. In summary, our data reveals a diverse assemblage of globally distributed viruses, associated with a wide range of unicellular eukaryotic hosts. We anticipate that the methods we have developed for Polinton-like virus detection and the database of over 20,000 genes we present will allow for continued discovery and analysis of these new viral groups. Video abstract.
Topics: Aquatic Organisms; DNA Viruses; DNA, Viral; Ecosystem; Eukaryota; Genome, Viral; Lakes; Phylogeny; Virophages; Virus Integration
PubMed: 33436089
DOI: 10.1186/s40168-020-00956-0 -
Nucleic Acids Research Jan 2022Molecular mechanisms of virus-related diseases involve multiple factors, including viral mutation accumulation and integration of a viral genome into the host DNA. With...
Molecular mechanisms of virus-related diseases involve multiple factors, including viral mutation accumulation and integration of a viral genome into the host DNA. With increasing attention being paid to virus-mediated pathogenesis and the development of many useful technologies to identify virus mutations (VMs) and viral integration sites (VISs), much research on these topics is available in PubMed. However, knowledge of VMs and VISs is widely scattered in numerous published papers which lack standardization, integration and curation. To address these challenges, we built a pilot database of human disease-related Virus Mutations, Integration sites and Cis-effects (ViMIC), which specializes in three features: virus mutation sites, viral integration sites and target genes. In total, the ViMIC provides information on 31 712 VMs entries, 105 624 VISs, 16 310 viral target genes and 1 110 015 virus sequences of eight viruses in 77 human diseases obtained from the public domain. Furthermore, in ViMIC users are allowed to explore the cis-effects of virus-host interactions by surveying 78 histone modifications, binding of 1358 transcription regulators and chromatin accessibility on these VISs. We believe ViMIC will become a valuable resource for the virus research community. The database is available at http://bmtongji.cn/ViMIC/index.php.
Topics: Chromatin; Data Mining; Databases, Factual; Gene Expression Regulation; Genome, Viral; Histones; Host-Pathogen Interactions; Humans; Internet; Mutation; Signal Transduction; Software; Transcription Factors; Viral Proteins; Virus Diseases; Virus Integration; Viruses
PubMed: 34500462
DOI: 10.1093/nar/gkab779