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Current Issues in Molecular Biology 2020Modern genomic sequencing and bioinformatics approaches have detected numerous examples of DNA sequences derived from DNA and RNA virus genomes integrated into both... (Review)
Review
Modern genomic sequencing and bioinformatics approaches have detected numerous examples of DNA sequences derived from DNA and RNA virus genomes integrated into both vertebrate and insect genomes. Retroviruses encode RNA-dependent DNA polymerases (reverse transcriptases) and integrases that convert their RNA viral genomes into DNA proviruses and facilitate proviral DNA integration into the host genome. Surprisingly, DNA sequences derived from RNA viruses that do not encode these enzymes also occur in host genomes. Non-retroviral integrated RNA virus sequences (NIRVS) occur at relatively high frequency in the genomes of the arboviral vectors and , are not distributed randomly and possibly contribute to mosquito antiviral immunity, suggesting these mosquitoes could serve as a model system for unravelling the function of NIRVS. Here we address the following questions: What drives DNA synthesis from the genomes of non-retroviral RNA viruses? How does integration of virus cDNA into host DNA occur, and what is its biological function (if any)? We review current knowledge of viral integrations in insect genomes, hypothesize mechanisms of NIRVS formation and their potential impact on insect biology, particularly antiviral immunity, and suggest directions for future research.
Topics: Aedes; Animals; Computational Biology; DNA Viruses; Endogenous Retroviruses; Genome, Insect; Genomics; Host-Pathogen Interactions; Insecta; Mosquito Vectors; RNA Viruses; RNA, Small Interfering; Retroelements; Virus Integration
PubMed: 31167954
DOI: 10.21775/cimb.034.013 -
Trends in Immunology Aug 2022Despite antiretroviral therapy (ART), HIV-1 persists as proviruses integrated into the genomic DNA of CD4 T cells. The mechanisms underlying the persistence and clonal... (Review)
Review
Despite antiretroviral therapy (ART), HIV-1 persists as proviruses integrated into the genomic DNA of CD4 T cells. The mechanisms underlying the persistence and clonal expansion of these cells remain incompletely understood. Cases have been described in which proviral integration can alter host gene expression to drive cellular proliferation. Here, we review observations from other genome-integrating human viruses to propose additional putative modalities by which HIV-1 integration may alter cellular function to favor persistence, such as by altering susceptibility to cytotoxicity in virus-expressing cells. We propose that signals implicating such mechanisms may have been masked thus far by the preponderance of defective and/or nonreactivatable HIV-1 proviruses, but could be revealed by focusing on the integration sites of intact proviruses with expression potential.
Topics: Anti-Retroviral Agents; CD4-Positive T-Lymphocytes; HIV Infections; HIV-1; Humans; Proviruses; Virus Integration
PubMed: 35817699
DOI: 10.1016/j.it.2022.06.001 -
Viruses Sep 2020The HIV-1 integrase enzyme (IN) plays a critical role in the viral life cycle by integrating the reverse-transcribed viral DNA into the host chromosome. This function of... (Review)
Review
The HIV-1 integrase enzyme (IN) plays a critical role in the viral life cycle by integrating the reverse-transcribed viral DNA into the host chromosome. This function of IN has been well studied, and the knowledge gained has informed the design of small molecule inhibitors that now form key components of antiretroviral therapy regimens. Recent discoveries unveiled that IN has an under-studied yet equally vital second function in human immunodeficiency virus type 1 (HIV-1) replication. This involves IN binding to the viral RNA genome in virions, which is necessary for proper virion maturation and morphogenesis. Inhibition of IN binding to the viral RNA genome results in mislocalization of the viral genome inside the virus particle, and its premature exposure and degradation in target cells. The roles of IN in integration and virion morphogenesis share a number of common elements, including interaction with viral nucleic acids and assembly of higher-order IN multimers. Herein we describe these two functions of IN within the context of the HIV-1 life cycle, how IN binding to the viral genome is coordinated by the major structural protein, Gag, and discuss the value of targeting the second role of IN in virion morphogenesis.
Topics: Animals; HIV Infections; HIV Integrase; HIV-1; Humans; Virion; Virus Integration
PubMed: 32916894
DOI: 10.3390/v12091005 -
Journal of Medical Virology May 2023Integration of human papilloma virus (HPV) DNA into the human genome may progressively contribute to cervical carcinogenesis. To explore how HPV integration affects gene...
Integration of human papilloma virus (HPV) DNA into the human genome may progressively contribute to cervical carcinogenesis. To explore how HPV integration affects gene expression by altering DNA methylation during carcinogenesis, we analyzed a multiomics dataset for cervical cancer. We obtained multiomics data by HPV-capture sequencing, RNA sequencing, and Whole Genome Bisulfite Sequencing from 50 patients with cervical cancer. We detected 985 and 485 HPV-integration sites in matched tumor and adjacent paratumor tissues. Of these, LINC00486 (n = 19), LINC02425 (n = 11), LLPH (n = 11), PROS1 (n = 5), KLF5 (n = 4), LINC00392 (n = 3), MIR205HG (n = 3) and NRG1 (n = 3) were identified as high-frequency HPV-integrated genes, including five novel recurrent genes. Patients at clinical stage II had the highest number of HPV integrations. E6 and E7 genes of HPV16 but not HPV18 showed significantly fewer breakpoints than random distribution. HPV integrations occurring in exons were associated with altered gene expression in tumor tissues but not in paratumor tissues. A list of HPV-integrated genes regulated at transcriptomic or epigenetic level was reported. We also carefully checked the candidate genes with regulation pattern correlated in both levels. HPV fragments integrated at MIR205HG mainly came from the L1 gene of HPV16. RNA expression of PROS1 was downregulated when HPV integrated in its upstream region. RNA expression of MIR205HG was elevated when HPV integrated into its enhancer. The promoter methylation levels of PROS1 and MIR205HG were all negatively correlated with their gene expressions. Further experimental validations proved that upregulation of MIR205HG could promote the proliferative and migrative abilities of cervical cancer cells. Our data provides a new atlas for epigenetic and transcriptomic regulations regarding HPV integrations in cervical cancer genome. We demonstrate that HPV integration may affect gene expression by altering methylation levels of MIR205HG and PROS1. Our study provides novel biological and clinical insights into HPV-induced cervical cancer.
Topics: Female; Humans; Human Papillomavirus Viruses; Uterine Cervical Neoplasms; Transcriptome; Multiomics; Epigenomics; Cell Transformation, Neoplastic; Carcinogenesis; Human papillomavirus 16; RNA; Papillomavirus Infections; Oncogene Proteins, Viral; Virus Integration
PubMed: 37212325
DOI: 10.1002/jmv.28789 -
International Journal of Cancer Oct 2020Hepatitis B virus (HBV) infection has been reported to be associated with non-Hodgkin lymphoma (NHL). However, the evidence is limited to the seroepidemiological study....
Hepatitis B virus (HBV) infection has been reported to be associated with non-Hodgkin lymphoma (NHL). However, the evidence is limited to the seroepidemiological study. There is a lack of evidence showing the HBV infection and integration in NHL cells. Here, we reported that in the Shanghai area, the positive rates of serum HBsAg (OR: 3.11; 95% CI: 2.20-4.41) and HBeAg (OR: 3.99; 95% CI: 1.73-9.91) were significantly higher in patients with NHL. HBsAg, HBcAg and HBV DNA were detected in 34.4%, 45.2% and 47.0% of the NHL tissues, respectively. Furthermore, by using a high-throughput viral integration detection approach (HIVID), integrated HBV DNA was identified from 50% (6/12) HBV-related NHL tissues. There were a total of 313 HBV integration sites isolated from the NHL tissues, among which four protein-coding genes (FAT2, SETX, ITGA10 and CD63) were interrupted by HBV DNA in their exons. Seven HBV preferential target genes (ANKS1B, HDAC4, EGFLAM, MAN1C1, XKR6, ZBTB38 and CCDC91) showed significantly altered expression levels in NHL, suggesting a potential role of these genes in NHL development. Taken together, HBV integration is a common phenomenon in NHL. This finding opens up a new direction of research into the mechanistic link between HBV infection and NHL.
Topics: China; DNA, Viral; Exons; Female; Hepatitis B; Hepatitis B Surface Antigens; Hepatitis B virus; Humans; Lymphoma, Non-Hodgkin; Male; Middle Aged; Virus Integration
PubMed: 32350851
DOI: 10.1002/ijc.33027 -
Hepatology (Baltimore, Md.) Apr 2022Despite the epidemiological association between intrahepatic cholangiocarcinoma (iCCA) and HBV infection, little is known about the relevant oncogenic effects. We sought...
BACKGROUND AND AIMS
Despite the epidemiological association between intrahepatic cholangiocarcinoma (iCCA) and HBV infection, little is known about the relevant oncogenic effects. We sought to identify the landscape and mechanism of HBV integration, along with the genomic architecture of HBV-infected iCCA (HBV-iCCA) tumors.
APPROACH AND RESULTS
We profiled a cohort of 108 HBV-iCCAs using whole-genome sequencing, deep sequencing, and RNA sequencing, together with preconstructed data sets of HBV-infected HCC (HBV-HCC; n = 167) and combined hepatocellular cholangiocarcinoma (HBV-cHCC/CCA; n = 59), and conventional (n = 154) and fluke-related iCCAs (n = 16). Platforms based on primary iCCA cell lines to evaluate the functional effects of chimeric transcripts were also used. We found that HBV had inserted at multiple sites in the iCCA genomes in 45 (41.7%) of the tumors. Recurrent viral integration breakpoints were found at nine different sites. The most common insertional hotspot (7 tumors) was in the TERT (telomerase reverse transcriptase) promoter, where insertions and mutations (11 tumors) were mutually exclusive, and were accompanied by promoter hyperactivity. Recurrent HBV integration events (5 tumors) were also detected in FAT2 (FAT atypical cadherin 2), and were associated with enrichment of epithelial-mesenchymal transition-related genes. A distinctive intergenic insertion (chr9p21.3), between DMRTA1 (DMRT like family A1) and LINC01239 (long intergenic non-protein coding RNA 1239), had oncogenic effects through activation of the mammalian target of rapamycin (mTOR)/4EBP/S6K pathway. Regarding the mutational profiles of primary liver cancers, the overall landscape of HBV-iCCA was closer to that of nonviral conventional iCCA, than to HBV-HCC and HBV-cHCC/CCA.
CONCLUSIONS
Our findings provide insight into the behavior of iCCAs driven by various pathogenic mechanisms involving HBV integration events and associated genomic aberrations. This knowledge should be of use in managing HBV carriers.
Topics: Bile Duct Neoplasms; Bile Ducts, Intrahepatic; Carcinogenesis; Carcinoma, Hepatocellular; Cholangiocarcinoma; Genomics; Hepatitis B virus; Humans; Liver Neoplasms; Virus Integration
PubMed: 34478159
DOI: 10.1002/hep.32135 -
Journal of Medical Virology May 2024Human Papillomaviruses (HPV) are a diverse family of non-enveloped dsDNA viruses that infect the skin and mucosal epithelia. Persistent HPV infections can lead to cancer... (Review)
Review
Human Papillomaviruses (HPV) are a diverse family of non-enveloped dsDNA viruses that infect the skin and mucosal epithelia. Persistent HPV infections can lead to cancer frequently involving integration of the virus into the host genome, leading to sustained oncogene expression and loss of capsid and genome maintenance proteins. Microhomology-mediated double-strand break repair, a DNA double-stranded breaks repair pathway present in many organisms, was initially thought to be a backup but it's now seen as vital, especially in homologous recombination-deficient contexts. Increasing evidence has identified microhomology (MH) near HPV integration junctions, suggesting MH-mediated repair pathways drive integration. In this comprehensive review, we present a detailed summary of both the mechanisms underlying MH-mediated repair and the evidence for its involvement in HPV integration in cancer. Lastly, we highlight the involvement of these processes in the integration of other DNA viruses and the broader implications on virus lifecycles and host innate immune response.
Topics: Humans; Papillomaviridae; Carcinogenesis; Papillomavirus Infections; Virus Integration; DNA Repair; DNA Breaks, Double-Stranded; DNA, Viral
PubMed: 38757834
DOI: 10.1002/jmv.29674 -
Open Biology Sep 2021The canonical lytic-lysogenic binary has been challenged in recent years, as more evidence has emerged on alternative bacteriophage infection strategies. These infection... (Review)
Review
The canonical lytic-lysogenic binary has been challenged in recent years, as more evidence has emerged on alternative bacteriophage infection strategies. These infection modes are little studied, and yet they appear to be more abundant and ubiquitous in nature than previously recognized, and can play a significant role in the ecology and evolution of their bacterial hosts. In this review, we discuss the extent, causes and consequences of alternative phage lifestyles, and clarify conceptual and terminological confusion to facilitate research progress. We propose distinct definitions for the terms 'pseudolysogeny' and 'productive or non-productive chronic infection', and distinguish them from the carrier state life cycle, which describes a population-level phenomenon. Our review also finds that phages may change their infection modes in response to environmental conditions or the physiological state of the host cell. We outline known molecular mechanisms underlying the alternative phage-host interactions, including specific genetic pathways and their considerable biotechnological potential. Moreover, we discuss potential implications of the alternative phage lifestyles for microbial biology and ecosystem functioning, as well as applied topics such as phage therapy.
Topics: Bacteria; Bacteriophages; Ecosystem; Lysogeny; Persistent Infection
PubMed: 34520699
DOI: 10.1098/rsob.210188 -
Virology Journal Jan 2020Despite antiretroviral therapy (ART) which halts HIV-1 replication and reduces plasma viral load to clinically undetectable levels, viral rebound inevitably occurs once... (Review)
Review
Despite antiretroviral therapy (ART) which halts HIV-1 replication and reduces plasma viral load to clinically undetectable levels, viral rebound inevitably occurs once ART is interrupted. HIV-1-infected cells can undergo clonal expansion, and these clonally expanded cells increase over time. Over 50% of latent reservoirs are maintained through clonal expansion. The clonally expanding HIV-1-infected cells, both in the blood and in the lymphoid tissues, contribute to viral rebound. The major drivers of clonal expansion of HIV-1-infected cells include antigen-driven proliferation, homeostatic proliferation and HIV-1 integration site-dependent proliferation. Here, we reviewed how viral, immunologic and genomic factors contribute to clonal expansion of HIV-1-infected cells, and how clonal expansion shapes the HIV-1 latent reservoir. Antigen-specific CD4 T cells specific for different pathogens have different clonal expansion dynamics, depending on antigen exposure, cytokine profiles and exhaustion phenotypes. Homeostatic proliferation replenishes the HIV-1 latent reservoir without inducing viral expression and immune clearance. Integration site-dependent proliferation, a mechanism also deployed by other retroviruses, leads to slow but steady increase of HIV-1-infected cells harboring HIV-1 proviruses integrated in the same orientation at specific sites of certain cancer-related genes. Targeting clonally expanding HIV-1 latent reservoir without disrupting CD4 T cell function is a top priority for HIV-1 eradication.
Topics: CD4-Positive T-Lymphocytes; HIV Infections; HIV-1; Humans; Proviruses; Viral Load; Virus Integration; Virus Latency; Virus Replication
PubMed: 31910871
DOI: 10.1186/s12985-019-1276-8 -
Cancer Medicine Aug 2020Human T-lymphotropic virus-1 (HTLV-1) Hodgkin lymphoma (HL) is difficult to differentiate from adult T-cell leukemia/lymphoma (ATLL) with HL-like histology (HL-like...
BACKGROUND
Human T-lymphotropic virus-1 (HTLV-1) Hodgkin lymphoma (HL) is difficult to differentiate from adult T-cell leukemia/lymphoma (ATLL) with HL-like histology (HL-like ATLL).
METHODS
Cytological and immunohistological features, HTLV-1 proviral DNA integration, and rearrangements of the T-cell receptor (TCR) Cβ1 gene were examined in 11 HTLV-1 patients with HL-like disease.
RESULTS
Six patients were classified as HTLV-1 HL and five as HL-like ATLL in accordance with genetic findings of HTLV-1 proviral DNA integration and rearrangements of the TCR Cβ1 gene. Small ordinary looking lymphocytes with round nuclei were detected in the background of six patients with HTLV-1 HL, which were immunohistochemically negative for CD25 and CC chemokine receptor (CCR)4 and had a low MIB1 labeling index (mean: 28.3%). In the HL-like ATLL specimens, small- and medium-sized atypical lymphocytes with indented and irregular-shaped nuclei were found, and were diffusely positive for CD25 and CCR4, with high MIB1 labeling (mean: 76%). Both groups had scattered CD30 and CD15 Hodgkin and Reed Sternberg (RS) giant cells, with or without CD20 expression and Epstein-Barr virus infection. The 50% overall survival period was significantly longer for the HTLV-1 HL group (180 months) than for the HL-like ATLL group (7.8 months; P = .004).
CONCLUSIONS
HTLV-1 HL showed typical small lymphoid cells with a low MIB1 labeling index in a background of Hodgkin and RS cells, with some scattered CD25 and CCR4 lymphocytes. In HTLV-1 endemic areas, distinguishing HTLV-1 HL from HL-like ATLL is important because of their differing treatment strategies and prognoses.
Topics: Adult; Aged; Antigens, CD20; Cell Size; DNA, Viral; Epstein-Barr Virus Infections; Female; Gene Rearrangement, beta-Chain T-Cell Antigen Receptor; Genes, T-Cell Receptor beta; Hodgkin Disease; Human T-lymphotropic virus 1; Humans; Leukemia-Lymphoma, Adult T-Cell; Lymphocytes, Tumor-Infiltrating; Male; Middle Aged; Reed-Sternberg Cells; Virus Integration
PubMed: 32597011
DOI: 10.1002/cam4.3139