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Viruses Jul 2017Human herpesvirus-6A (HHV-6A) and human herpesvirus-6B (HHV-6B) are two closely related viruses that infect T-cells. Both HHV-6A and HHV-6B possess telomere-like repeats... (Review)
Review
Human herpesvirus-6A (HHV-6A) and human herpesvirus-6B (HHV-6B) are two closely related viruses that infect T-cells. Both HHV-6A and HHV-6B possess telomere-like repeats at the terminal regions of their genomes that facilitate latency by integration into the host telomeres, rather than by episome formation. In about 1% of the human population, human herpes virus-6 (HHV-6) integration into germline cells allows the viral genome to be passed down from one generation to the other; this condition is called inherited chromosomally integrated HHV-6 (iciHHV-6). This review will cover the history of HHV-6 and recent works that define the biological differences between HHV-6A and HHV-6B. Additionally, HHV-6 integration and inheritance, the capacity for reactivation and superinfection of iciHHV-6 individuals with a second strain of HHV-6, and the role of hypomethylation of human chromosomes during integration are discussed. Overall, the data suggest that integration of HHV-6 in telomeres represent a unique mechanism of viral latency and offers a novel tool to study not only HHV-6 pathogenesis, but also telomere biology. Paradoxically, the integrated viral genome is often defective especially as seen in iciHHV-6 harboring individuals. Finally, gaps in the field of HHV-6 research are presented and future studies are proposed.
Topics: Chromosomes, Human; DNA Methylation; DNA, Viral; Genome, Viral; Herpesvirus 6, Human; Humans; Plasmids; Roseolovirus Infections; Telomere; Virus Activation; Virus Integration; Virus Latency
PubMed: 28737715
DOI: 10.3390/v9070194 -
Advanced Science (Weinheim,... May 2021Approximately 15% of human cancers are estimated to be attributed to viruses. Virus sequences can be integrated into the host genome, leading to genomic instability and...
Approximately 15% of human cancers are estimated to be attributed to viruses. Virus sequences can be integrated into the host genome, leading to genomic instability and carcinogenesis. Here, a new deep convolutional neural network (CNN) model is developed with attention architecture, namely DeepVISP, for accurately predicting oncogenic virus integration sites (VISs) in the human genome. Using the curated benchmark integration data of three viruses, hepatitis B virus (HBV), human herpesvirus (HPV), and Epstein-Barr virus (EBV), DeepVISP achieves high accuracy and robust performance for all three viruses through automatically learning informative features and essential genomic positions only from the DNA sequences. In comparison, DeepVISP outperforms conventional machine learning methods by 8.43-34.33% measured by area under curve (AUC) value enhancement in three viruses. Moreover, DeepVISP can decode -regulatory factors that are potentially involved in virus integration and tumorigenesis, such as HOXB7, IKZF1, and LHX6. These findings are supported by multiple lines of evidence in literature. The clustering analysis of the informative motifs reveales that the representative k-mers in clusters could help guide virus recognition of the host genes. A user-friendly web server is developed for predicting putative oncogenic VISs in the human genome using DeepVISP.
Topics: Cluster Analysis; Deep Learning; Genome, Human; Genomic Instability; Hepatitis B virus; Herpesvirus 1, Human; Herpesvirus 4, Human; Humans; Neoplasms; Oncogenic Viruses; Reproducibility of Results; Virus Integration
PubMed: 33977077
DOI: 10.1002/advs.202004958 -
Cell Host & Microbe May 2016Viral latency can be considered a metastable, nonproductive infection state that is capable of subsequent reactivation to repeat the infection cycle. Viral latent... (Review)
Review
Viral latency can be considered a metastable, nonproductive infection state that is capable of subsequent reactivation to repeat the infection cycle. Viral latent infections have numerous associated pathologies, including cancer, birth defects, neuropathy, cardiovascular disease, chronic inflammation, and immunological dysfunctions. The mechanisms controlling the establishment, maintenance, and reactivation from latency are complex and diversified among virus families, species, and strains. Yet, as examined in this review, common properties of latent viral infections can be defined. Eradicating latent virus has become an important but elusive challenge and will require a more complete understanding of the mechanisms controlling these processes.
Topics: Animals; DNA Viruses; Epigenesis, Genetic; Genes, Viral; Herpesvirus 1, Human; Humans; Virus Diseases; Virus Integration; Virus Latency; Virus Physiological Phenomena; Virus Replication
PubMed: 27173930
DOI: 10.1016/j.chom.2016.04.008 -
Communications Biology Jul 2023Hepatitis B virus (HBV) may integrate into the genome of infected cells and contribute to hepatocarcinogenesis. However, the role of HBV integration in hepatocellular...
Hepatitis B virus (HBV) may integrate into the genome of infected cells and contribute to hepatocarcinogenesis. However, the role of HBV integration in hepatocellular carcinoma (HCC) development remains unclear. In this study, we apply a high-throughput HBV integration sequencing approach that allows sensitive identification of HBV integration sites and enumeration of integration clones. We identify 3339 HBV integration sites in paired tumour and non-tumour tissue samples from 7 patients with HCC. We detect 2107 clonally expanded integrations (1817 in tumour and 290 in non-tumour tissues), and a significant enrichment of clonal HBV integrations in mitochondrial DNA (mtDNA) preferentially occurring in the oxidative phosphorylation genes (OXPHOS) and D-loop region. We also find that HBV RNA sequences are imported into the mitochondria of hepatoma cells with the involvement of polynucleotide phosphorylase (PNPASE), and that HBV RNA might have a role in the process of HBV integration into mtDNA. Our results suggest a potential mechanism by which HBV integration may contribute to HCC development.
Topics: Humans; Hepatitis B virus; Carcinoma, Hepatocellular; Liver Neoplasms; DNA, Mitochondrial; Virus Integration; Mitochondria
PubMed: 37400627
DOI: 10.1038/s42003-023-05017-4 -
Molecular Therapy : the Journal of the... Dec 2021
Topics: Dependovirus; Genetic Vectors; HeLa Cells; Humans; Virus Integration
PubMed: 34758291
DOI: 10.1016/j.ymthe.2021.10.024 -
Infection, Genetics and Evolution :... Jul 2018Cervical cancer is one of the main causes of female cancer death worldwide, and human papilloma virus (HPV) its causal agent. To investigate viral oncogenesis several... (Review)
Review
Cervical cancer is one of the main causes of female cancer death worldwide, and human papilloma virus (HPV) its causal agent. To investigate viral oncogenesis several studies have focused on the effects of HPV oncoproteins E6 and E7 and the mechanisms by which these proteins stimulate the cellular transformation process. However, phenomena such as the physical state of the viral genome (episomal or integrated) and the effects of this integration on cell proliferation contribute new clues to understand how HPV infection causes carcinogenesis. New molecular technologies are currently facilitating these discoveries. This paper reviews the tumor development process initiated by HPV, recent findings on the process of viral integration into the host genome, new methods to detect HPV integration, and derived associated effects.
Topics: Disease Progression; Female; Host-Pathogen Interactions; Humans; Oncogene Proteins, Viral; Papillomaviridae; Papillomavirus Infections; Uterine Cervical Neoplasms; Virus Integration
PubMed: 29518579
DOI: 10.1016/j.meegid.2018.03.003 -
Microbiology Spectrum Oct 2014Transposable phage Mu has played a major role in elucidating the mechanism of movement of mobile DNA elements. The high efficiency of Mu transposition has facilitated a... (Review)
Review
Transposable phage Mu has played a major role in elucidating the mechanism of movement of mobile DNA elements. The high efficiency of Mu transposition has facilitated a detailed biochemical dissection of the reaction mechanism, as well as of protein and DNA elements that regulate transpososome assembly and function. The deduced phosphotransfer mechanism involves in-line orientation of metal ion-activated hydroxyl groups for nucleophilic attack on reactive diester bonds, a mechanism that appears to be used by all transposable elements examined to date. A crystal structure of the Mu transpososome is available. Mu differs from all other transposable elements in encoding unique adaptations that promote its viral lifestyle. These adaptations include multiple DNA (enhancer, SGS) and protein (MuB, HU, IHF) elements that enable efficient Mu end synapsis, efficient target capture, low target specificity, immunity to transposition near or into itself, and efficient mechanisms for recruiting host repair and replication machineries to resolve transposition intermediates. MuB has multiple functions, including target capture and immunity. The SGS element promotes gyrase-mediated Mu end synapsis, and the enhancer, aided by HU and IHF, participates in directing a unique topological architecture of the Mu synapse. The function of these DNA and protein elements is important during both lysogenic and lytic phases. Enhancer properties have been exploited in the design of mini-Mu vectors for genetic engineering. Mu ends assembled into active transpososomes have been delivered directly into bacterial, yeast, and human genomes, where they integrate efficiently, and may prove useful for gene therapy.
Topics: Bacteriophage mu; DNA Transposable Elements; DNA, Viral; Recombination, Genetic; Viral Proteins; Virus Integration
PubMed: 26104374
DOI: 10.1128/microbiolspec.MDNA3-0007-2014 -
Advances in Experimental Medicine and... 2018Upon infection and depending on the infected cell type, human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) can replicate or enter a state of latency. HHV-6A and HHV-6B can... (Review)
Review
Upon infection and depending on the infected cell type, human herpesvirus 6A (HHV-6A) and 6B (HHV-6B) can replicate or enter a state of latency. HHV-6A and HHV-6B can integrate their genomes into host chromosomes as one way to establish latency. Viral integration takes place near the subtelomeric/telomeric junction of chromosomes. When HHV-6 infection and integration occur in gametes, the virus can be genetically transmitted. Inherited chromosomally integrated HHV-6 (iciHHV-6)-positive individuals carry one integrated HHV-6 copy per somatic cell. The prevalence of iciHHV-6 individuals varies between 0.6% and 2%, depending on the geographical region sampled. In this chapter, the mechanisms leading to viral integration and reactivation from latency, as well as some of the biological and medical consequences associated with iciHHV-6, were discussed.
Topics: Animals; Chromosomes, Human; DNA, Viral; Herpesvirus 6, Human; Humans; Roseolovirus Infections; Telomere; Virus Integration
PubMed: 29896669
DOI: 10.1007/978-981-10-7230-7_10 -
Current Opinion in Cell Biology Jun 2015Viruses encounter and manipulate almost all aspects of cell structure and metabolism. The nuclear envelope (NE), with central roles in cell structure and genome... (Review)
Review
Viruses encounter and manipulate almost all aspects of cell structure and metabolism. The nuclear envelope (NE), with central roles in cell structure and genome function, acts and is usurped in diverse ways by different viruses. It can act as a physical barrier to infection that must be overcome, as a functional barrier that restricts infection by various mechanisms and must be counteracted or indeed as a positive niche, important or even essential for virus infection or production of progeny virions. This review summarizes virus-host interactions at the NE, highlighting progress in understanding the replication of viruses including HIV-1, Influenza, Herpes Simplex, Adenovirus and Ebola, and molecular insights into hitherto unknown functional pathways at the NE.
Topics: Animals; Humans; Nuclear Envelope; Simplexvirus; Spinal Cord Dorsal Horn; Virus Integration; Virus Replication
PubMed: 26121672
DOI: 10.1016/j.ceb.2015.06.002 -
European Journal of Cancer (Oxford,... Jul 2016Fifteen percent of cancers are driven by oncogenic human viruses. Four of those viruses, hepatitis B virus, human papillomavirus, Merkel cell polyomavirus, and human... (Review)
Review
Fifteen percent of cancers are driven by oncogenic human viruses. Four of those viruses, hepatitis B virus, human papillomavirus, Merkel cell polyomavirus, and human T-cell lymphotropic virus, integrate the host genome. Viral oncogenesis is the result of epigenetic and genetic alterations that happen during viral integration. So far, little data have been available regarding integration mechanisms and modifications in the host genome. However, the emergence of high-throughput sequencing and bioinformatic tools enables researchers to establish the landscape of genomic alterations and predict the events that follow viral integration. Cooperative working groups are currently investigating these factors in large data sets. Herein, we provide novel insights into the initiating events of cancer onset during infection with integrative viruses. Although much remains to be discovered, many improvements are expected from the clinical point of view, from better prognosis classifications to better therapeutic strategies.
Topics: Computational Biology; Genome, Viral; Genomics; High-Throughput Nucleotide Sequencing; Humans; Neoplasms; Oncogenic Viruses; Virus Diseases; Virus Integration
PubMed: 27156225
DOI: 10.1016/j.ejca.2016.03.086