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1.
EMBO J. 1991 Dec;10(12):3941-50.

Targeted integration of adeno-associated virus (AAV) into human chromosome 19.

Author information

  • 1Department of Biological Sciences, University of Pittsburgh, PA 15260.

Erratum in

  • EMBO J 1992 Mar;11(3):1228.

Abstract

A key feature in adeno-associated virus (AAV) replication is efficient integration of the viral genome into host cell DNA to establish latency when helper virus is absent. The steps involved in this process remain largely uncharacterized, even though AAV integration was first documented 20 years ago. Using a protein--DNA binding method we isolated AAV--cellular junction DNA sequences. The cellular component hybridized to a single restriction fragment in the virus-free parental cell line, and also co-migrated with AAV-specific sequences in numerous latently infected cell lines. Analysis of somatic cell hybrids indicated that this cellular sequence maps to the distal portion of the q arm of human chromosome 19. In situ hybridization of AAV DNA to chromosomes from latently infected cells confirms the physical location of AAV integrations to be q13.4-ter of chromosome 19. Sequence analysis of several independent integration sites shows breakpoints occurring within a 100 bp cellular region. This non-pathogenic parvovirus thus appears to establish viral latency by integrating its DNA specifically into one chromosomal region. Such specific integration is so far unique among the eukaryotic DNA viruses. The incorporation of site-specific integration into AAV vector schemes should make this vector system attractive for human gene therapy approaches.

PMID:
1657596
PMCID:
PMC453134
[PubMed - indexed for MEDLINE]
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2.
Science. 2009 Jan 16;323(5912):393-6. doi: 10.1126/science.1167375.

Recombination of retrotransposon and exogenous RNA virus results in nonretroviral cDNA integration.

Author information

  • 1Institute of Experimental Immunology, University Hospital Zürich, Schmelzbergstrasse 12, 8091 Zürich, Switzerland. geuking@mcmaster.ca

Abstract

Retroviruses have the potential to acquire host cell-derived genetic material during reverse transcription and can integrate into the genomes of larger, more complex DNA viruses. In contrast, RNA viruses were believed not to integrate into the host's genome under any circumstances. We found that illegitimate recombination between an exogenous nonretroviral RNA virus, lymphocytic choriomeningitis virus, and the endogenous intracisternal A-type particle (IAP) retrotransposon occurred and led to reverse transcription of exogenous viral RNA. The resulting complementary DNA was integrated into the host's genome with an IAP element. Thus, RNA viruses should be closely scrutinized for any capacity to interact with endogenous retroviral elements before their approval for therapeutic use in humans.

PMID:
19150848
DOI:
10.1126/science.1167375
[PubMed - indexed for MEDLINE]
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3.
J Virol. 2010 Nov;84(22):11876-87. doi: 10.1128/JVI.00955-10. Epub 2010 Sep 1.

Widespread horizontal gene transfer from double-stranded RNA viruses to eukaryotic nuclear genomes.

Author information

  • 1College of Plant Science and Technology, Huazhong Agricultural University, Hubei Province, People's Republic of China.

Abstract

Horizontal gene transfer commonly occurs from cells to viruses but rarely occurs from viruses to their host cells, with the exception of retroviruses and some DNA viruses. However, extensive sequence similarity searches in public genome databases for various organisms showed that the capsid protein and RNA-dependent RNA polymerase genes from totiviruses and partitiviruses have widespread homologs in the nuclear genomes of eukaryotic organisms, including plants, arthropods, fungi, nematodes, and protozoa. PCR amplification and sequencing as well as comparative evidence of junction coverage between virus and host sequences support the conclusion that these viral homologs are real and occur in eukaryotic genomes. Sequence comparison and phylogenetic analysis suggest that these genes were likely transferred horizontally from viruses to eukaryotic genomes. Furthermore, we present evidence showing that some of the transferred genes are conserved and expressed in eukaryotic organisms and suggesting that these viral genes are also functional in the recipient genomes. Our findings imply that horizontal transfer of double-stranded RNA viral genes is widespread among eukaryotes and may give rise to functionally important new genes, thus entailing that RNA viruses may play significant roles in the evolution of eukaryotes.

PMID:
20810725
PMCID:
PMC2977895
DOI:
10.1128/JVI.00955-10
[PubMed - indexed for MEDLINE]
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4.
Biologics. 2010 May 25;4:75-81.

Hepatitis B virus and Homo sapiens proteome-wide analysis: A profusion of viral peptide overlaps in neuron-specific human proteins.

Author information

  • 1Department of Pathological Anatomy.

Abstract

The primary amino acid sequence of the hepatitis B virus (HBV) proteome was searched for identity spots in the human proteome by using the Protein Information Resource database. We find that the HBV polyprotein shares sixty-five heptapeptides, one octapeptide, and one nonapeptide with the human proteins. The viral matches are disseminated among fundamental human proteins such as adhesion molecules, leukocyte differentiation antigens, enzymes, proteins associated with spermatogenesis, and transcription factors. As a datum of special interest, a number of peptide motifs are shared between the virus- and brain-specific antigens involved in neuronal protection. This study may help to evaluate the potential cross reactions and side effects of HBV antigen-based vaccines.

KEYWORDS:

HBV proteome; human proteome; similarity analysis; vaccine-related cross-reactions; viral versus human proteome overlapping

PMID:
20531967
PMCID:
PMC2880343
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5.
Biologics. 2010 Sep 13;4:245-61.

Describing the hexapeptide identity platform between the influenza A H5N1 and Homo sapiens proteomes.

Author information

  • 1Department of Biochemistry and Molecular Biology, University of Bari, Italy.

Abstract

We searched the primary sequence of influenza A H5N1 polyprotein for hexamer amino acid sequences shared with human proteins using the Protein International Resource database and the exact peptide matching analysis program. We find that the viral polyprotein shares numerous hexapeptides with the human proteome. The human proteins involved in the viral overlap are represented by antigens associated with basic cell functions such as proliferation, development, and differentiation. Of special importance, many human proteins that share peptide sequences with influenza A polyprotein are antigens such as reelin, neurexin I-α, myosin-IXa, Bardet-Biedl syndrome 10 protein, Williams syndrome transcription factor, disrupted in schizophrenia 1 protein, amyotrophic lateral sclerosis 2 chromosomal region candidate gene 17 protein, fragile X mental retardation 2 protein, and jouberin. That is, the viral-vs-human overlap involves human proteins that, when altered, have been reported to be potentially associated with multiple neurological disorders that can include autism, epilepsy, obesity, dystonia, ataxia-telangiectasia, amyotrophic lateral sclerosis, sensorineural deafness, sudden infant death syndrome, Charcot-Marie-Tooth disease, and myelination. The present data are discussed as a possible molecular basis for understanding influenza A viral escape from immunosurveillance and for defining anti-influenza immune-therapeutic approaches devoid of collateral adverse events.

KEYWORDS:

host-pathogen relationships; neurological disorders; peptide sharing; viral escape from immunosurveillance

PMID:
20859452
PMCID:
PMC2943197
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6.
Peptides. 2008 Oct;29(10):1755-66. doi: 10.1016/j.peptides.2008.05.022. Epub 2008 Jun 5.

Massive peptide sharing between viral and human proteomes.

Author information

  • 1Department of Biochemistry and Molecular Biology, University of Bari, Bari 70126, Italy. d.kanduc@biologia.uniba.it

Abstract

Thirty viral proteomes were examined for amino acid sequence similarity to the human proteome, and, in parallel, a control of 30 sets of human proteins was analyzed for internal human overlapping. We find that all of the analyzed 30 viral proteomes, independently of their structural or pathogenic characteristics, present a high number of pentapeptide overlaps to the human proteome. Among the examined viruses, human T-lymphotropic virus 1, Rubella virus, and hepatitis C virus present the highest number of viral overlaps to the human proteome. The widespread and ample distribution of viral amino acid sequences through the human proteome indicates that viral and human proteins are formed of common peptide backbone units and suggests a fluid compositional chimerism in phylogenetic entities canonically classified distantly as viruses and Homo sapiens. Importantly, the massive viral to human peptide overlapping calls into question the possibility of a direct causal association between virus-host sharing of amino acid sequences and incitement to autoimmune reactions through molecular recognition of common motifs.

PMID:
18582510
DOI:
10.1016/j.peptides.2008.05.022
[PubMed - indexed for MEDLINE]
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7.
Peptides. 2007 Jun;28(6):1260-7. Epub 2007 Apr 8.

Widespread and ample peptide overlapping between HCV and Homo sapiens proteomes.

Author information

  • 1Department of Computer Science, University of Saskatchewan, Saskatoon, Canada.

Abstract

Alignment of protein sequences is fundamental in analyzing homology, evolutionary events and functional relationships. Searching for the epitopic peptide platform underlying hepatitis C virus (HCV) infection and autoimmune phenomena, we have used sequence-sequence peptide matching to compare the HCV polyprotein sequence to the human proteome. The following results were obtained: (1) pentamers from HCV polyprotein have a widespread and high level of similarity to a large number of human proteins (19,605 human proteins, that is 57.6% of the human proteome); (2) remarkable similarity between the two proteomes persists even using longer peptide motifs as probes for identity scanning; (3) only a limited number of HCV pentameric fragments have no similarity to the human host, so representing molecular sequence signatures of the virus. We conclude that the widespread sharing of numerous perfect exact matches between HCV and human proteomes might explain HCV persistence in humans.

PMID:
17485143
DOI:
10.1016/j.peptides.2007.04.001
[PubMed - indexed for MEDLINE]
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8.
PLoS Genet. 2010 Nov 18;6(11):e1001191. doi: 10.1371/journal.pgen.1001191.

Endogenous viral elements in animal genomes.

Author information

  • 1Department of Zoology, University of Oxford, Oxford, UK. rgifford@adarc.org

Abstract

Integration into the nuclear genome of germ line cells can lead to vertical inheritance of retroviral genes as host alleles. For other viruses, germ line integration has only rarely been documented. Nonetheless, we identified endogenous viral elements (EVEs) derived from ten non-retroviral families by systematic in silico screening of animal genomes, including the first endogenous representatives of double-stranded RNA, reverse-transcribing DNA, and segmented RNA viruses, and the first endogenous DNA viruses in mammalian genomes. Phylogenetic and genomic analysis of EVEs across multiple host species revealed novel information about the origin and evolution of diverse virus groups. Furthermore, several of the elements identified here encode intact open reading frames or are expressed as mRNA. For one element in the primate lineage, we provide statistically robust evidence for exaptation. Our findings establish that genetic material derived from all known viral genome types and replication strategies can enter the animal germ line, greatly broadening the scope of paleovirological studies and indicating a more significant evolutionary role for gene flow from virus to animal genomes than has previously been recognized.

PMID:
21124940
PMCID:
PMC2987831
DOI:
10.1371/journal.pgen.1001191
[PubMed - indexed for MEDLINE]
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9.
Nature. 2010 Jan 7;463(7277):84-7. doi: 10.1038/nature08695.

Endogenous non-retroviral RNA virus elements in mammalian genomes.

Author information

  • 1Department of Virology, Research Institute for Microbial Diseases (BIKEN), Osaka University, Osaka 565-0871, Japan.

Abstract

Retroviruses are the only group of viruses known to have left a fossil record, in the form of endogenous proviruses, and approximately 8% of the human genome is made up of these elements. Although many other viruses, including non-retroviral RNA viruses, are known to generate DNA forms of their own genomes during replication, none has been found as DNA in the germline of animals. Bornaviruses, a genus of non-segmented, negative-sense RNA virus, are unique among RNA viruses in that they establish persistent infection in the cell nucleus. Here we show that elements homologous to the nucleoprotein (N) gene of bornavirus exist in the genomes of several mammalian species, including humans, non-human primates, rodents and elephants. These sequences have been designated endogenous Borna-like N (EBLN) elements. Some of the primate EBLNs contain an intact open reading frame (ORF) and are expressed as mRNA. Phylogenetic analyses showed that EBLNs seem to have been generated by different insertional events in each specific animal family. Furthermore, the EBLN of a ground squirrel was formed by a recent integration event, whereas those in primates must have been formed more than 40 million years ago. We also show that the N mRNA of a current mammalian bornavirus, Borna disease virus (BDV), can form EBLN-like elements in the genomes of persistently infected cultured cells. Our results provide the first evidence for endogenization of non-retroviral virus-derived elements in mammalian genomes and give novel insights not only into generation of endogenous elements, but also into a role of bornavirus as a source of genetic novelty in its host.

PMID:
20054395
PMCID:
PMC2818285
DOI:
10.1038/nature08695
[PubMed - indexed for MEDLINE]
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10.
Int J Alzheimers Dis. 2010 Dec 29;2010:140539. doi: 10.4061/2010/140539.

Alzheimer's disease: a pathogenetic autoimmune disorder caused by herpes simplex in a gene-dependent manner.

Author information

  • 1Polygenic Pathways, Flat 4, 20 Upper Maze Hill, Saint Leonard's on Sea, East Sussex TN38 OLG, UK.

Abstract

Herpes simplex is implicated in Alzheimer's disease and viral infection produces Alzheimer's disease like pathology in mice. The virus expresses proteins containing short contiguous amino acid stretches (5-9aa "vatches" = viralmatches) homologous to APOE4, clusterin, PICALM, and complement receptor 1, and to over 100 other gene products relevant to Alzheimer's disease, which are also homologous to proteins expressed by other pathogens implicated in Alzheimer's disease. Such homology, reiterated at the DNA level, suggests that gene association studies have been tracking infection, as well as identifying key genes, demonstrating a role for pathogens as causative agents. Vatches may interfere with the function of their human counterparts, acting as dummy ligands, decoy receptors, or via interactome interference. They are often immunogenic, and antibodies generated in response to infection may target their human counterparts, producing protein knockdown, or generating autoimmune responses that may kill the neurones in which the human homologue resides, a scenario supported by immune activation in Alzheimer's disease. These data may classify Alzheimer's disease as an autoimmune disorder created by pathogen mimicry of key Alzheimer's disease-related proteins. It may well be prevented by vaccination and regular pathogen detection and elimination, and perhaps stemmed by immunosuppression or antibody adsorption-related therapies.

11.
Proc Natl Acad Sci U S A. 2010 Mar 23;107(12):5563-8. doi: 10.1073/pnas.0913586107. Epub 2010 Mar 8.

The latent human herpesvirus-6A genome specifically integrates in telomeres of human chromosomes in vivo and in vitro.

Author information

  • 1Department of Molecular Medicine, University of South Florida College of Medicine, Tampa, FL 33612, USA.

Abstract

Previous research has suggested that human herpesvirus-6 (HHV-6) may integrate into host cell chromosomes and be vertically transmitted in the germ line, but the evidence--primarily fluorescence in situ hybridization (FISH)--is indirect. We sought, first, to definitively test these two hypotheses. Peripheral blood mononuclear cells (PBMCs) were isolated from families in which several members, including at least one parent and child, had unusually high copy numbers of HHV-6 DNA per milliliter of blood. FISH confirmed that HHV-6 DNA colocalized with telomeric regions of one allele on chromosomes 17p13.3, 18q23, and 22q13.3, and that the integration site was identical among members of the same family. Integration of the HHV-6 genome into TTAGGG telomere repeats was confirmed by additional methods and sequencing of the integration site. Partial sequencing of the viral genome identified the same integrated HHV-6A strain within members of families, confirming vertical transmission of the viral genome. We next asked whether HHV-6A infection of naïve cell lines could lead to integration. Following infection of naïve Jjhan and HEK-293 cell lines by HHV-6, the virus integrated into telomeres. Reactivation of integrated HHV-6A virus from individuals' PBMCs as well as cell lines was successfully accomplished by compounds known to induce latent herpesvirus replication. Finally, no circular episomal forms were detected even by PCR. Taken together, the data suggest that HHV-6 is unique among human herpesviruses: it specifically and efficiently integrates into telomeres of chromosomes during latency rather than forming episomes, and the integrated viral genome is capable of producing virions.

PMID:
20212114
PMCID:
PMC2851814
DOI:
10.1073/pnas.0913586107
[PubMed - indexed for MEDLINE]
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