-
Viruses Apr 2017Chronic infection with the Hepatitis B Virus (HBV) is a major cause of liver-related morbidity and mortality. One peculiar observation in cells infected with HBV (or... (Review)
Review
Chronic infection with the Hepatitis B Virus (HBV) is a major cause of liver-related morbidity and mortality. One peculiar observation in cells infected with HBV (or with closely‑related animal hepadnaviruses) is the presence of viral DNA integration in the host cell genome, despite this form being a replicative dead-end for the virus. The frequent finding of somatic integration of viral DNA suggests an evolutionary benefit for the virus; however, the mechanism of integration, its functions, and the clinical implications remain unknown. Here we review the current body of knowledge of HBV DNA integration, with particular focus on the molecular mechanisms and its clinical implications (including the possible consequences of replication-independent antigen expression and its possible role in hepatocellular carcinoma). HBV DNA integration is likely to influence HBV replication, persistence, and pathogenesis, and so deserves greater attention in future studies.
Topics: Animals; DNA, Viral; Hepatitis B virus; Humans; Recombination, Genetic; Virus Integration
PubMed: 28394272
DOI: 10.3390/v9040075 -
Med (New York, N.Y.) Jun 2023The majority of oncogenic viruses are capable of integrating into the host genome, posing significant challenges to clinical control. Recent conceptual and technological...
The majority of oncogenic viruses are capable of integrating into the host genome, posing significant challenges to clinical control. Recent conceptual and technological advances, however, offer promising clinical applications. Here, we summarize the advances in our understanding of oncogenic viral integration, their clinical relevance, and the future perspectives.
Topics: Oncogenic Viruses; Genome; Virus Integration
PubMed: 37301195
DOI: 10.1016/j.medj.2023.04.007 -
Current Opinion in Molecular... Aug 2009Adeno-associated virus (AAV) vectors efficiently transduce various cell types and can produce long-term expression of transgenes in vivo. Although AAV vector genomes can... (Review)
Review
Adeno-associated virus (AAV) vectors efficiently transduce various cell types and can produce long-term expression of transgenes in vivo. Although AAV vector genomes can persist within cells as episomes, vector integration has been observed in various experimental settings, either at non-homologous sites where DNA damage may have occurred or by homologous recombination. In some cases, integration is essential for the therapeutic or experimental efficacy of AAV vectors. Recently, insertional mutagenesis resulting from the integration of AAV vectors was associated with tumorigenesis in mice, a consideration that may have relevance for certain clinical applications.
Topics: Animals; Cell Nucleus; Dependovirus; Genetic Vectors; Genome, Viral; Humans; Recombination, Genetic; Virus Integration
PubMed: 19649989
DOI: No ID Found -
BMC Medical Genomics Jan 2019Since tumor often has a high level of intra-tumor heterogeneity, multiple tumor samples from the same patient at different locations or different time points are often...
BACKGROUND
Since tumor often has a high level of intra-tumor heterogeneity, multiple tumor samples from the same patient at different locations or different time points are often sequenced to study tumor intra-heterogeneity or tumor evolution. In virus-related tumors such as human papillomavirus- and Hepatitis B Virus-related tumors, virus genome integrations can be critical driving events. It is thus important to investigate the integration sites of the virus genomes. Currently, a few algorithms for detecting virus integration sites based on high-throughput sequencing have been developed, but their insufficient performance in their sensitivity, specificity and computational complexity hinders their applications in multiple related tumor sequencing.
RESULTS
We develop VirTect for detecting virus integration sites simultaneously from multiple related-sample data. This algorithm is mainly based on the joint analysis of short reads spanning breakpoints of integration sites from multiple samples. To achieve high specificity and breakpoint accuracy, a local precise sandwich alignment algorithm is used. Simulation and real data analyses show that, compared with other algorithms, VirTect is significantly more sensitive and has a similar or lower false discovery rate.
CONCLUSIONS
VirTect can provide more accurate breakpoint position and is computationally much more efficient in terms both memory requirement and computational time.
Topics: Algorithms; Genome, Human; Genomics; High-Throughput Nucleotide Sequencing; Humans; Virus Integration; Workflow
PubMed: 30704462
DOI: 10.1186/s12920-018-0461-8 -
Current HIV/AIDS Reports Mar 2015The persistence of human immunodeficiency virus type 1 (HIV-1) in latent reservoirs is a major barrier to HIV cure. Reservoir establishment depends on low viral... (Review)
Review
The persistence of human immunodeficiency virus type 1 (HIV-1) in latent reservoirs is a major barrier to HIV cure. Reservoir establishment depends on low viral expression that may be related to provirus integration sites (IS). In vitro, in cell lines and primary T cells, latency is associated with specific IS through reduced viral expression mediated by transcriptional interference by host cellular promoters, reverse orientation, and the presence of specific epigenetic modifiers. In primary T cell models of latency, specific IS are associated with intracellular viral antigen expression that is not directly related to cell activation. In contrast, in patient CD4+ T cells, there is enrichment for IS in genes controlling cell cycle and survival and in some clonally expanded T cell subpopulations. Multiple insertion sites within some specific genes may suggest that integrated HIV can increase the host's T cell survival.
Topics: Disease Reservoirs; HIV Infections; HIV-1; Humans; Virus Integration; Virus Latency
PubMed: 25573791
DOI: 10.1007/s11904-014-0241-9 -
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 -
Clinical Microbiology and Infection :... Apr 2016Retroviruses, including the human immunodeficiency virus (HIV), are notorious for two essential steps of their viral replication: reverse transcription and integration.... (Review)
Review
Retroviruses, including the human immunodeficiency virus (HIV), are notorious for two essential steps of their viral replication: reverse transcription and integration. This latter property is considered to be essential for productive replication and ensures the stable long-term insertion of the viral genome sequence in the host chromatin, thereby leading to the life-long association of the virus with the infected cell. Using HIV as a prototypic example, the present review aims to provide an overview of how and where integration occurs, as well as presenting general consequences for both the virus and the infected host.
Topics: Host-Pathogen Interactions; Humans; Retroviridae; Virus Integration
PubMed: 27107301
DOI: 10.1016/j.cmi.2016.02.013 -
BMC Genomics Nov 2021Engineered versions of adeno-associated virus (AAV) are commonly used in gene therapy but evidence revealing a potential oncogenic role of natural AAV in hepatocellular...
BACKGROUND
Engineered versions of adeno-associated virus (AAV) are commonly used in gene therapy but evidence revealing a potential oncogenic role of natural AAV in hepatocellular carcinoma (HCC) has raised concerns. The frequency of potentially oncogenic integrations has been reported in only a few populations. AAV infection and host genome integration in another type of liver cancer, cholangiocarcinoma (CCA), has been studied only in one cohort. All reported oncogenic AAV integrations in HCC come from strains resembling the fully sequenced AAV2 and partly sequenced AAV13. When AAV integration occurs, only a fragment of the AAV genome is detectable in later DNA or RNA sequencing. The integrated fragment is typically from the 3' end of the AAV genome, and this positional bias has been only partly explained. Three research groups searched for evidence of AAV integration in HCC RNAseq samples in the Cancer Genome Atlas (TCGA) but reported conflicting results.
RESULTS
We collected and analyzed whole transcriptome and viral capture DNA sequencing in paired tumor and non-tumor samples from two liver cancer Asian cohorts from Thailand (N = 147, 47 HCC and 100 intrahepatic cholangiocarcinoma (iCCA)) and Mongolia (N = 70, all HCC). We found only one HCC patient with a potentially oncogenic integration of AAV, in contrast to higher frequency reported in European patients. There were no oncogenic AAV integrations in iCCA patients. AAV genomic segments are present preferentially in the non-tumor samples of Thai patients. By analyzing the AAV genome positions of oncogenic and non-oncogenic integrated fragments, we found that almost all the putative oncogenic integrations overlap the X gene, which is present and functional only in the strain AAV2 among all fully sequenced strains. This gene content difference could explain why putative oncogenic integrations from other AAV strains have not been reported. We resolved the discrepancies in previous analyses of AAV presence in TCGA HCC samples and extended it to CCA. There are 12 TCGA samples with an AAV segment and none are in Asian patients. AAV segments are present in preferentially in TCGA non-tumor samples, like what we observed in the Thai patients.
CONCLUSIONS
Our findings suggest a minimal AAV risk of hepatocarcinogenesis in Asian liver cancer patients. The partial genome presence and positional bias of AAV integrations into the human genome has complicated analysis of possible roles of AAV in liver cancer.
Topics: Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinogenesis; Carcinoma, Hepatocellular; Dependovirus; Hepatitis B virus; Humans; Liver Neoplasms; Thailand; Virus Integration
PubMed: 34763675
DOI: 10.1186/s12864-021-08098-9 -
Journal of Virology Mar 2004It had been suggested that during integration of spumaretroviruses (foamy viruses) the right (U5) end of the cDNA is processed, while the left (U3) remains uncleaved. We...
It had been suggested that during integration of spumaretroviruses (foamy viruses) the right (U5) end of the cDNA is processed, while the left (U3) remains uncleaved. We confirmed this hypothesis by sequencing two-long terminal repeat (LTR) circle junctions of unintegrated DNA. Based on an infectious foamy virus molecular clone, a set of constructs harboring mutations at the 5' end of the U3 region in the 3' LTR was analyzed for particle export, reverse transcription, and replication. Following transient transfection some mutants were severely impaired in generating infectious virus, while others replicated almost like the wild type. The replication competence of the mutants was unrelated to the cleavability of the newly created U3 end. This became obvious with two mutants both belonging to the high-titer type. One mutant containing a dinucleotide artificially transferred from the right to the left end was trimmed upon integration, while another one with an unrelated dinucleotide in that place was not. The latter construct in particular showed that the canonical TG motif at the beginning of the provirus is not essential for foamy virus integration.
Topics: Animals; Base Sequence; Cell Line; Cricetinae; Genetic Vectors; Humans; Mutation; Proviruses; Recombination, Genetic; Spumavirus; Terminal Repeat Sequences; Virus Integration; Virus Replication
PubMed: 14963145
DOI: 10.1128/jvi.78.5.2472-2477.2004 -
Arteriosclerosis, Thrombosis, and... Mar 2020
PIM1 (Provirus Integration Site For Moloney Murine Leukemia Virus) as a Novel Biomarker and Therapeutic Target in Pulmonary Arterial Hypertension: Another Evidence for Cancer Theory.
Topics: Animals; Biomarkers; DNA Damage; Leukemia; Mice; Moloney murine leukemia virus; Neoplasms; Pulmonary Arterial Hypertension; Signal Transduction; Virus Integration
PubMed: 32101474
DOI: 10.1161/ATVBAHA.120.313975