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Nucleic Acids Research Apr 2021A significant portion of human cancers are due to viruses integrating into human genomes. Therefore, accurately predicting virus integrations can help uncover the...
A significant portion of human cancers are due to viruses integrating into human genomes. Therefore, accurately predicting virus integrations can help uncover the mechanisms that lead to many devastating diseases. Virus integrations can be called by analysing second generation high-throughput sequencing datasets. Unfortunately, existing methods fail to report a significant portion of integrations, while predicting a large number of false positives. We observe that the inaccuracy is caused by incorrect alignment of reads in repetitive regions. False alignments create false positives, while missing alignments create false negatives. This paper proposes SurVirus, an improved virus integration caller that corrects the alignment of reads which are crucial for the discovery of integrations. We use publicly available datasets to show that existing methods predict hundreds of thousands of false positives; SurVirus, on the other hand, is significantly more precise while it also detects many novel integrations previously missed by other tools, most of which are in repetitive regions. We validate a subset of these novel integrations, and find that the majority are correct. Using SurVirus, we find that HPV and HBV integrations are enriched in LINE and Satellite regions which had been overlooked, as well as discover recurrent HBV and HPV breakpoints in human genome-virus fusion transcripts.
Topics: Algorithms; Alphapapillomavirus; Datasets as Topic; Genome, Human; Hepatitis B virus; Humans; Repetitive Sequences, Nucleic Acid; Sequence Analysis, RNA; Software; Virus Integration
PubMed: 33444454
DOI: 10.1093/nar/gkaa1237 -
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 -
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 -
Critical Reviews in Biochemistry and... Jun 2021Exogenous retroviruses are RNA viruses that require reverse transcription for their replication. Among these viruses, human immunodeficiency virus (HIV) is infectious to... (Review)
Review
Exogenous retroviruses are RNA viruses that require reverse transcription for their replication. Among these viruses, human immunodeficiency virus (HIV) is infectious to humans and causes the development of acquired immune deficiency syndrome (AIDS). There are also endogenous retroelements that require reverse transcription for their retrotransposition, among which the type 1 long interspersed element (LINE-1) is the only type of retroelement that can replicate autonomously. It was once believed that retroviruses like HIV and retroelements like LINE-1 share similarities in processes such as reverse transcription and integration. Accordingly, many HIV suppressors are also potent LINE-1 inhibitors. However, in many cases, one suppressor uses two or more distinct mechanisms to repress HIV and LINE-1. In this review, we discuss some of these suppressors, focusing on their alternative mechanisms opposing the replication of HIV and LINE-1. Based on the differences in HIV and LINE-1 activity, the subcellular localization of these suppressors, and the impact of LINE-1 retrotransposition on human cells, we propose possible reasons for the inhibition of HIV and LINE-1 through different pathways by these suppressors, with the hope of accelerating future studies in associated research fields.
Topics: Acquired Immunodeficiency Syndrome; Endogenous Retroviruses; HIV-1; Humans; Long Interspersed Nucleotide Elements; Reverse Transcription; Virus Integration
PubMed: 33648399
DOI: 10.1080/10409238.2021.1893640 -
Clinical Infectious Diseases : An... Feb 2023This study investigated the effect of nucleos(t)ide analogue (NUC) treatment on hepatitis B virus (HBV) DNA integration and hepatocyte clonal expansion, both of which...
BACKGROUND
This study investigated the effect of nucleos(t)ide analogue (NUC) treatment on hepatitis B virus (HBV) DNA integration and hepatocyte clonal expansion, both of which are implicated in hepatocellular carcinoma (HCC) in chronic hepatitis B.
METHODS
Twenty-eight patients receiving NUCs (11 lamivudine, 7 telbivudine, 10 entecavir) were included. All had liver biopsies at baseline and year 1, and 7 had a third biopsy at year 10. HBV DNA integration and hepatocyte clone size were assessed by inverse polymerase chain reaction.
RESULTS
All patients had detectable HBV integration at baseline, with a median integration frequency of 1.01 × 109 per liver and hepatocyte clone size of 2.41 × 105. Neither integration frequency nor hepatocyte clone size correlated with age and HBV virologic parameters. After 1 year of treatment, HBV integration was still detectable in all patients, with a median of 5.74 × 108 integration per liver (0.22 log reduction; P = .008) and hepatocyte clone size of 1.22 × 105 (0.40 log reduction; P = .002). HBV integration remained detectable at year 10 of treatment, with a median integration frequency of 4.84 × 107 integration per liver (0.93 log reduction from baseline) and hepatocyte clone size of 2.55 × 104 (1.02 log reduction from baseline). From baseline through year 1 to year 10, there was a decreasing trend in both integration frequency and hepatocyte clone size (P = .066 and.018, respectively).
CONCLUSIONS
NUCs reduced both HBV DNA integration and hepatocyte clonal expansion, suggesting another alternative pathway besides direct viral suppression to reduce HCC risk. Our findings supported the notion for a long-term NUC treatment to prevent HCC.
Topics: Humans; Hepatitis B virus; Antiviral Agents; Carcinoma, Hepatocellular; DNA, Viral; Liver Neoplasms; Hepatitis B, Chronic; Hepatocytes; Virus Integration; Hepatitis B
PubMed: 35594553
DOI: 10.1093/cid/ciac383 -
Microbiology Spectrum Aug 2022Moloney murine leukemia virus (MLV) infects BALB/c mice and induces T-cell lymphoma in mice. Retroviral integration is mediated by the interaction of the MLV integrase...
Moloney murine leukemia virus (MLV) infects BALB/c mice and induces T-cell lymphoma in mice. Retroviral integration is mediated by the interaction of the MLV integrase (IN) with members of the bromodomain and extraterminal motif (BET) protein family (BRD2, BRD3, and BRD4). The introduction of the W390A mutation into MLV IN abolishes the BET interaction. Here, we compared the replication of W390A MLV to that of wild-type (WT) MLV in adult BALB/c mice to study the role of BET proteins in replication, integration, and tumorigenesis . Comparing WT and W390A MLV infections revealed similar viral loads in the blood, thymus, and spleen cells. Interestingly, W390A MLV integration was retargeted away from GC-enriched genomic regions. However, both WT MLV- and W390A MLV-infected mice developed T-cell lymphoma after similar latencies represented by an enlarged thymus and spleen and multiorgan tumor infiltration. Integration site sequencing from splenic tumor cells revealed clonal expansion in all WT MLV- and W390A MLV-infected mice. However, the integration profiles of W390A MLV and WT MLV differed significantly. Integrations were enriched in enhancers and promoters, but compared to the WT, W390A MLV integrated less frequently into enhancers and more frequently into oncogene bodies such as and . We conclude that host factors direct MLV integration site selection. Although BET proteins target WT MLV integration preferentially toward enhancers and promoters, insertional lymphomagenesis can occur independently from BET, likely due to the intrinsically strong enhancer/promoter of the MLV long terminal repeat (LTR). In this study, we have shown that the replication of murine leukemia virus happens independently of BET proteins, which are key host determinants involved in retroviral integration site selection. This finding opens a new research line in the discovery of alternative viral or host factors that may complement the dominant host factor. In addition, our results show that BET-independent murine leukemia virus uncouples insertional mutagenesis from gene enhancers, although lymphomagenesis still occurs despite the lack of an interaction with BET proteins. Our findings also have implications for the engineering of BET-independent MLV-based vectors for gene therapy, which may not be a safe alternative.
Topics: Animals; Genomics; Integrases; Leukemia Virus, Murine; Lymphoma, T-Cell; Mice; Nuclear Proteins; Transcription Factors; Virus Integration
PubMed: 35852337
DOI: 10.1128/spectrum.01478-22 -
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 -
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 -
Viruses Jan 2021Hepatitis B Virus (HBV) is a globally-distributed pathogen and is a major cause of liver disease. HBV (or closely-related animal hepadnaviruses) can integrate into the... (Review)
Review
Hepatitis B Virus (HBV) is a globally-distributed pathogen and is a major cause of liver disease. HBV (or closely-related animal hepadnaviruses) can integrate into the host genome, but (unlike retroviruses) this integrated form is replication-defective. The specific role(s) of the integrated HBV DNA has been a long-standing topic of debate. Novel in vitro models of HBV infection combined with sensitive molecular assays now enable researchers to investigate this under-characterised phenomenon with greater ease and precision. This review covers the contributions these systems have made to understanding how HBV DNA integration induces liver cancer and facilitates viral persistence. We summarise the current findings into a working model of chronic HBV infection and discuss the clinical implications of this hypothetical framework on the upcoming therapeutic strategies used to curb HBV-associated pathogenesis.
Topics: Animals; Carcinoma, Hepatocellular; DNA, Viral; Hepatitis B Surface Antigens; Hepatitis B virus; Hepatitis B, Chronic; Humans; Liver Neoplasms; Models, Biological; Virus Integration
PubMed: 33530322
DOI: 10.3390/v13020180