Targeted integration by adeno-associated virus.
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Base Sequence↗
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[Inhibition of integration of human immunodeficiency virus DNA, modified by oligonucleotides].
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Base Sequence↗
[Integration of hepatitis B virus DNA in liver tissues from patients with hepatocellular carcinoma and liver cirrhosis].
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Carcinoma, Hepatocellular↗
How infections with non-retroviral RNA viruses may be involved in the development of neoplasia.
There have been reports of associations of infections with non-retroviral RNA viruses and tumour development. A hypothesis is proposed as to how non-retroviral RNA viruses may play a role in the development of neoplasia. It is based on a recent report of the detection of complementary DNA (cDNA) of the RNA virus lymphocytic choriomeningitis virus in mouse and hamster cells. This lends credence to the claim made in 1975 of the detection of cDNA copies of genomic DNA of three non-retroviral RNA viruses integrated into the DNA of host cells. Briefly, the hypothesis proposes that at least one cDNA fragment of a non-retroviral RNA virus is synthesized and integrated into the genome of the host cell in a way that could lead or contribute to tumour development. General approaches for testing the hypothesis are outlined.
Animals↗
Large scaled analysis of hepatitis B virus (HBV) DNA integration in HBV related hepatocellular carcinomas.
BACKGROUND AND AIMS: Hepatitis B virus (HBV) DNA integration into or close to cellular genes is frequently detected in HBV positive hepatocellular carcinomas (HCC). We have previously shown that viral integration can lead to aberrant target gene transcription. In this study, we attempted to investigate common pathways to hepatocarcinogenesis. METHODS: By using a modified Alu-polymerase chain reaction approach, we analysed 50 HCCs along with 10 previously published cases. RESULTS: Sixty eight cellular flanking sequences (seven repetitive or unidentified sequences, 42 cellular genes, and 19 sequences potentially coding for unknown proteins) were obtained. Fifteen cancer related genes and 25 cellular genes were identified. HBV integration recurrently targeted the human telomerase reverse transcriptase gene (three cases) and genes belonging to distinct pathways: calcium signalling related genes, 60s ribosomal protein encoding genes, and platelet derived growth factor and mixed lineage leukaemia encoding genes. Two tumour suppressor genes and five genes involved in the control of apoptosis were also found at the integration site. The viral insertion site was distributed over all chromosomes except 13, X, and Y. CONCLUSIONS: In 61/68 (89.7%) cases, HBV DNA was integrated into cellular genes potentially providing cell growth advantage. Identification of recurrent viral integration sites into genes of the same family allows recognition of common cell signalling pathways activated in hepatocarcinogenesis.
Adolescent↗
Chromosomal sites of integration of simian virus 40 DNA sequences mapped by in situ hybridization in two transformed hybrid cell lines.
Simian virus 40 DNA sequences, integrated on human chromosome 7 in two transformed human-mouse hybrid somatic cell lines, were mapped to a specific chromosomal locus by in situ hybridization. To detect the integrated viral DNA by in situ hybridization, we increased the sensitivity of the technique by using as a probe 125I-labeled simian virus 40 cRNA (2 X 10(9) to 3 X 10(9) dpm/micrograms) prepared by in vitro transcription of simian virus 40 DNA with high-specific-radioactivity [125I]CTP. Although the viral nucleic acid was shown by blot hybridization in the two cell lines to be integrated in different restriction fragments, it was shown by in situ hybridization in the two cell lines to map to the same position, q31, on the long arm of human chromosome 7. The viral DNA integration sites were localized with a precision of +/- 1 silver grain diameter, equivalent to about 6.2 X 10(7) nucleotide pairs in the human genome. The procedures we describe may be adapted for localization of any gene on diploid chromosomes that can be cloned in a recombinant DNA vector.
Animals↗
Transcriptionally active genome regions are preferred targets for retrovirus integration.
We have analyzed the transcriptional activity of cellular target sequences for Moloney murine leukemia virus integration in mouse fibroblasts. At least five of the nine random, unselected integration target sequences studied showed direct evidence for transcriptional activity by hybridization to nuclear run-on transcripts prepared from uninfected cells. At least four of the sequences contained multiple recognition sites for several restriction enzymes that cut preferentially in CpG-rich islands, indicating integration into 5' or 3' ends or flanking regions of genes. Assuming that only a minor fraction (less than 20%) of the genome is transcribed in mammalian cells, we calculated the probability that this association of retroviral integration sites with transcribed sequences is due to chance to be very low (1.6 x 10(-2]. Thus, our results strongly suggest that transcriptionally active genome regions are preferred targets for retrovirus integration.
Animals↗
Sites of integration of reticuloendotheliosis virus DNA in chicken DNA.
The pattern of integration of spleen necrosis virus (SNV) DNA in DNA from a large population of SNV-infected chicken cells was studied by nucleic acid hybridization with iodinated viral RNA by the blotting technique of Southern. SNV DNA was found to be integrated at multiple sites in acutely infected chicken cells. Concomitant with the transition from acute to chronic infection, a shift in the pattern of integration was observed. The majority of integrated SNV DNA found in acutely infected cells was absent from chronically infected cells. This result is consistent with the hypothesis that the cell death that occurs after infection of avian cells with reticuloendotheliosis viruses is a consequence of the multiple integrations of the provirus. Viral DNA was also integrated at multiple sites in chronically infected cells. However, infectious viral DNA molecules in chronically infected cells migrated in a uniform manner in agarose gel electrophoresis after EcoRI digestion (which does not cut viral DNA), indicating that not all integrated SNV copies are equally infectious.
Acute Disease↗
Potyviruses, chaos or order?
At first potyviruses were easily distinguished by biological and serological properties because only a few were known and information on their host ranges was limited. The first evidence of serological cross reaction between two of these viruses was reported in 1951 and was further corroborated for three obviously distinct members of the group in 1960. In 1968 attention was drawn to the fact that some legume and non-legume potyviruses have much wider host ranges than previously known and that within the potyvirus group there is as much biological variation within viruses and overlap between viruses as there is in serology. The concept of continuity within the group was soon supported by others and became known as the "continuum hypothesis." Results with highly sensitive serological methods using polyclonal antisera were conflicting, and nucleic acid hybridization techniques did not unambiguously discriminate between potyviruses. Recent results, obtained with antibodies directed toward epitopes located in the N-termini of the coat proteins of potyviruses, suggest that there are ways to more definitely group strains of one potyvirus and distinguish them from other potyviruses. However, there are exceptions to this rule, as in the case of bean yellow mosaic virus and clover yellow vein virus which are clearly distinct in host range, inclusion bodies, and migration velocity of coat protein, but which still react with antibodies to the N-terminal epitopes of one virus. So the question remains of whether coat-protein properties, especially the serological reactivity of N-termini, which do not alter overall virus integrity when lost, sufficiently represent the genome of a pathogenic virus entity as a single criterion for classification.
Capsid↗
Increased sarcoma virus RNA in cells transformed by leukemia viruses: model for leukemogenesis.
A morphologically flat revertant of mink cells nonproductively infected with Moloney sarcoma virus exhibited contact inhibition and lacked detectable sarcoma virus RNA. Superinfection by usually nontransforming type C mammalian leukemia-causing viruses induced transformation and increased sarcoma virus RNA. The results suggest a model for leukemogenesis in animals by increasing, during replication of usually nontransforming leukemia viruses, the levels of RNA from potentially oncogenic cell or integrated virus transforming genes.
Cell Transformation, Neoplastic↗
Localization of proviral integration sites (Mlvi-1, Mlvi-2, and Pvt-1) and the alpha-globin pseudogene, Hba-3ps, on murine chromosome 15.
In situ hybridization was applied to map different proviral integration sites on murine chromosome 15. The Moloney murine leukemia virus integration site 1, Mlvi-1, was assigned to 15D2, Mlvi-2 to 15A2-B1, and the plasmacytoma variant translocation site 1, Pvt-1, to 15D2-3. The alpha-globin pseudogene, Hba-3ps, was mapped in close proximity to Mlvi-1 in 15D2.
Animals↗
In situ expression of helper-free avian leukosis virus (ALV)-based retrovirus vectors in early chick embryos.
Defective avian leukosis-based vectors expressing the bacterial lacZ gene were used as helper-free preparations to infect early stage Brown-Leghorn embryos. Both in toto X-gal staining and DNA analysis using Southern blot technique were applied to detect virus integration and expression. Our results demonstrate a low efficiency of in vitro infection in early stages of embryonic development. Southern blot analysis reveals that only 1% of embryonic cells integrate the vector genome after infection using 2 to 12 virus particle per embryonic cell. In situ expression of the lacZ marker gene was detected in only 0.06% of embryonic cells. These results lead us to conclude that only 6% of infected cells express efficiently the lacZ marker gene. This low level of expression could result from avian leukosis virus LTRs inhibition in chicken embryonic cells at an early stage of development. In spite of the low efficiency of infection, no evidence for tissue restrictive expression was observed. However, vector containing LTRs from RAV-2 virus allows preferential expression of provirus vector in neural tube tissue, whereas cardiac localization of the preferential expression was observed using vector containing the RAV-1 LTRs. The chronological analysis of the marker gene expression in terms of location of expression foci and sizes of these foci, lead us to hypothesize the putative regulation of retrovirus expression linked to embryonic development.
Animals↗
Analysis of hematopoietic and lymphopoietic tissue during a regenerative aplastic crisis induced by avian retrovirus MAV-2(O).
Infection of 10-day-old chickens with an avian osteopetrosis virus resulted in a severe regenerative aplastic crisis. Hematopoietic and lymphopoietic tissues of chickens infected with myeloblastosis-associated virus (of subgroup B, inducing osteopetrosis, MAV-2(O] were analyzed for integrated and unintegrated viral DNA sequences, cell population shifts, weight changes, and morphological alterations. By 6 days postinfection (p.i.), DNA from bone marrow cells and peripheral blood leukocytes (PBL) contained between 0.50 and 0.70 copies of viral DNA per haploid genome. Erythrocytes and splenic leukocytes contained less than 0.10 copies/haploid genome. Granulocytes and precursor mesomyelocytes were absent from bone marrow, but numbers of erythrocytes, erythroblasts, and reticulocytes were normal. By 9 days p.i., bone marrow was severely hypoplastic and both granulopoietic and erythropoietic colonies were depleted. By 12 days p.i., erythrocytes and granulocytes were maximally depressed in peripheral blood and the amount of integrated virus in bone marrow and PBL decreased to less than 0.20 copies/haploid genome. In contrast, erythrocytes contained integrated viral DNA of up to 0.30 copies/haploid genome, indicating infection of erythrocyte precursors. At 18 days p.i., viral DNA was detected only in erythrocytes. Unintegrated viral DNA was not detected in any organs. Anemia was accompanied by splenomegaly and erythrophagocytosis. Viral DNA was never detected in thymus or bursa. Differential counting and flow cytometry of cells from bursa, thymus, and spleen, and of blood lymphocytes did not detect significant population shifts. These results suggest that MAV-2(O) infection of immunocompetent chickens occurs primarily in myelopoietic tissues, and tissues are selectively infected.
Anemia, Aplastic↗
Integration status of virus DNA and p53 codon 72 polymorphism in human papillomavirus type 16 positive cervical cancers.
BACKGROUND: The aim of this study was to determine the physical state of HPV16 DNA and to reveal any association between the physical state of virus DNA and pathologic or prognostic factors in HPV16 positive cervical cancers. The other aim was to estimate the role of p53 codon 72 polymorphism in disease progression. MATERIALS AND METHODS: The presence and physical state of HPV16 DNA was analysed by Southern blot hybridisation and E1-E2 specific PCRs in the primary tumours and pelvic lymph nodes of 85 cervical carcinoma patients. Results Integrated HPV16 DNA was found in 32 out of 41 (78%) primary tumours and 2 out of 22 (95%) lymph nodes carrying HPV16 DNA. No significant association was found between integration of virus DNA and course of the disease. There was a trend towards an association between disease recurrence and the presence of the p53 codon 72 arginine homozygous genotype (OR = 3.41, p = 0.23). CONCLUSION: The physical state of HPV16 DNA does not seem to play a major role as a prognostic indicator in Hungarian cervical cancer patients, while the p53 codon 72 genotype may have an impact on the clinical outcome of the disease.
Adult↗
The terminal nucleotides of retrovirus DNA are required for integration but not virus production.
Deletion of specific nucleotides at either end of the long terminal repeat of the avian retrovirus, spleen necrosis virus, results in replication-competent but integration-defective virus. This result supports two conclusions: (1) the 5-base pair terminal inverted repeats and three to seven adjacent nucleotides are required for integration; (2) integration of retrovirus DNA is not required for retrovirus gene expression.
Cell Nucleus↗
HMG protein family members stimulate human immunodeficiency virus type 1 and avian sarcoma virus concerted DNA integration in vitro.
We have reconstituted concerted human immunodeficiency virus type 1 (HIV-1) integration in vitro with specially designed mini-donor HIV-1 DNA, a supercoiled plasmid acceptor, purified bacterium-derived HIV-1 integrase (IN), and host HMG protein family members. This system is comparable to one previously described for avian sarcoma virus (ASV) (A. Aiyar et al., J. Virol. 70:3571-3580, 1996) that was stimulated by the presence of HMG-1. Sequence analyses of individual HIV-1 integrants showed loss of 2 bp from the ends of the donor DNA and almost exclusive 5-bp duplications of the acceptor DNA at the site of integration. All of the integrants sequenced were inserted into different sites in the acceptor. These are the features associated with integration of viral DNA in vivo. We have used the ASV and HIV-1 reconstituted systems to compare the mechanism of concerted DNA integration and examine the role of different HMG proteins in the reaction. Of the three HMG proteins examined, HMG-1, HMG-2, and HMG-I(Y), the products formed in the presence of HMG-I(Y) for both systems most closely match those observed in vivo. Further analysis of HMG-I(Y) mutants demonstrates that the stimulation of integration requires an HMG-I(Y) domain involved in DNA binding. While complexes containing HMG-I(Y), ASV IN, and donor DNA can be detected in gel shift experiments, coprecipitation experiments failed to demonstrate stable interactions between HMG-I(Y) and ASV IN or between HMG-I(Y) and HIV-1 IN.
Animals↗
[Current clinico-pathogenetic aspects of chronic hepatitis B].
The author analyzes the results of clinical morphologic and immunologic studies carried out in 55 patients (78.2 percent of these with chronic active hepatitis, 12.7 percent with chronic latent hepatitis, and 9.1 percent with chronic passive hepatitis) with the virus replication phase serum markers and in 57 patients (82.5 percent with chronic passive and 17.2 percent with chronic active condition) with the hepatitis B virus integration phase markers. Histologic examination of the liver has revealed hepatocyte necroses, lobular necroses predominating in the patients with the replication phase markers (90.9 percent) and periportal necroses in those with the integration phase markers (17.5 percent). Clinical symptoms and laboratory findings, irrespective of the stage of hepatitis B virus, were not representative. Chronic hepatitis associated with the viral replication stage, was characterized by a reduction of T lymphocyte functional activity, elevation of T suppressor count, and reduced immunologic regulation index. In-Chronic hepatitis associated with viral integration phase the immunologic parameters did not much differ from those in the controls. The results evidence that the dialogic cycle of hepatitis B virus development plays the major role in the pathogenesis of chronic hepatitis; active stage of the disease is associated with the replicative phase of viral development and regressive stage and arrest of the condition with the integration phase.
Biomarkers↗
Metagenomic analysis reveals global landscape of viruses in biogeochemical cycles and microbial resistance in paddy soils and wetlands.
Paddy soils and wetlands form a critical soil-water interface that supports global crop production and biogeochemical cycling. Understanding the role of viruses in these ecosystems is vital for predicting ecosystem resilience. Considering the significance of viruses in microbial community structure and environmental pollution, we analyzed 163 metagenomes from 18 countries in Asia, Europe, America, and Australia. We characterized the global distribution and potential ecological functions of viruses through viral auxiliary metabolic genes (vAMGs), antibiotic resistance genes (vARGs), and metal(loid) resistance genes (vMRGs). We found viruses with globally consistent compositions and host profiles, characterized by high richness and a dominance of lysogenic families. We identified 497 vAMGs associated with carbon, phosphorus, nitrogen, and sulfur cycling, and detected 279 vARGs (conferring resistance to 10 antibiotic) and 141 vMRGs (against 7 metal(loids)). These genes exhibited strong co-localization and co-selection patterns, and their transduction can promote the emergence of multi-resistant microbes, reshaping microbial communities. Therefore, viruses are key mobile vectors for the environmental spread of these genes. By quantifying these pathways, we provide a crucial advancement for ecological risk identification and assessment. This meta-analysis provides a comprehensive overview of virus-mediated biogeochemical processes and resistance gene propagation. We demonstrate that viruses can disseminate antibiotic and metal(loid) resistance, a pollution-driven process that poses potential health risks. Furthermore, by regulating key metabolic pathways, viruses can influence greenhouse gas fluxes. Our findings underscore the necessity of integrating viruses into climate models, pollution mitigation strategies, and One Health policies to assess ecological risks and to protect ecosystem and public health.
Wetlands↗