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At least 19 recordsLinked to original sources
PubMed1992

Complete nucleotide sequence of the cloned infectious genome of Junonia coenia densovirus reveals an organization unique among parvoviruses.

We previously constructed a recombinant plasmid, pBRJ, encompassing an infectious Junonia coenia densovirus (JcDNV) genome (M. Jourdan et al. (1990). Virology 179, 403-409). We report here the complete viral sequence of pBRJ. The genome, 5908 nucleotides (nt) long, consists of an internal unique sequence flanked by long (517 nt) inverted terminal repeats. The first 96 bases of one extremity can fold into a typical Y-shaped hairpin structure. The opposite extremity is incomplete, lacking 88 nt. These terminal structures, similar to those of dependoviruses, human parvovirus B19 and Bombyx mori densovirus (BmDNV), strongly suggest a common mechanism of DNA replication for these parvoviruses. JcDNV genomic organization is unique among parvoviruses in that coding sequences are evenly distributed in the 5' half of both strands. On one strand, the major open reading frame (ORF1) encodes the four structural proteins. On the complementary strand, ORF2, ORF3 (included in ORF2), and ORF4 probably encode nonstructural proteins. JcDNV genome has little DNA homology with vertebrate parvoviruses and surprisingly even less with the two densoviruses presently sequenced. ORF1 contains the highly conserved PGY and G-rich regions and ORF2 the NTP-binding domain common to most structural and to all nonstructural vertebrate parvoviral ORFs, respectively. The single homology between JcDNV and BmDNV is unexpectedly located in JcDNV NTP-binding domain and BmDNV ORF2 assumed to encode structural polypeptides. Only a weak homology exists between JcDNV and Aedes DNV in their NTP-binding domain.

Amino Acid Sequence↗
PubMed2022

Endothelial Retargeting of AAV9 In Vivo.

Adeno-associated viruses (AAVs) are frequently used for gene transfer and gene editing in vivo, except for endothelial cells, which are remarkably resistant to unmodified AAV-transduction. AAVs are retargeted here toward endothelial cells by coating with second-generation polyamidoamine dendrimers (G2) linked to endothelial-affine peptides (CNN). G2CNN AAV9-Cre (encoding Cre recombinase) are injected into mTmG-mice or mTmG-pigs, cell-specifically converting red to green fluorescence upon Cre-activity. Three endothelial-specific functions are assessed: in vivo quantification of adherent leukocytes after systemic injection of - G2CNN AAV9 encoding 1) an artificial adhesion molecule (S1FG) in wildtype mice (day 10) or 2) anti-inflammatory Annexin A1 (Anxa1) in ApoE-/- mice (day 28). Moreover, 3) in Cas9-transgenic mice, blood pressure is monitored till day 56 after systemic application of G2CNN AAV9-gRNAs, targeting exons 6-10 of endothelial nitric oxide synthase (eNOS), a vasodilatory enzyme. G2CNN AAV9-Cre transduces microvascular endothelial cells in mTmG-mice or mTmG-pigs. Functionally, G2CNN AAV9-S1FG mediates S1FG-leukocyte adhesion, whereas G2CNN AAV9-Anxa1-application reduces long-term leukocyte recruitment. Moreover, blood pressure increases in Cas9-expressing mice subjected to G2CNN AAV9-gRNAeNOS . Therefore, G2CNN AAV9 may enable gene transfer in vascular and atherosclerosis models.

Animals↗
PubMed2024

Adeno-Associated Virus Type 5 Infection via PDGFRα Is Associated With Interstitial Lung Disease in Systemic Sclerosis and Generates Composite Peptides and Epitopes Recognized by the Agonistic Immunoglobulins Present in Patients With Systemic Sclerosis.

OBJECTIVE: The etiopathogenesis of systemic sclerosis (SSc) is unknown. Platelet-derived growth factor receptors (PDGFRs) are overexpressed in patients with SSc. Because PDGFR&#x3b1; is targeted by the adeno-associated virus type 5 (AAV5), we investigated whether AAV5 forms a complex with PDGFR&#x3b1; exposing epitopes that may induce the immune responses to the virus-PDGFR&#x3b1; complex. METHODS: The binding of monomeric human PDGFR&#x3b1; to the AAV5 capsid was analyzed by in silico molecular docking, surface plasmon resonance (SPR), and genome editing of the PDGFR&#x3b1; locus. AAV5 was detected in SSc lungs by in situ hybridization, immunohistochemistry, confocal microscopy, and molecular analysis of bronchoalveolar lavage (BAL) fluid. Immune responses to AAV5 and PDGFR&#x3b1; were evaluated by SPR using SSc monoclonal anti-PDGFR&#x3b1; antibodies and immunoaffinity-purified anti-PDGFR&#x3b1; antibodies from sera of patients with SSc. RESULTS: AAV5 was detected in the BAL fluid of 41 of 66 patients with SSc with interstitial lung disease (62.1%) and in 17 of 66 controls (25.75%) (P <&#x2009;0.001). In SSc lungs, AAV5 localized&#x2009;in type II pneumocytes and in interstitial cells. A molecular complex formed of spatially contiguous epitopes of the AAV5 capsid and of PDGFR&#x3b1; was identified and characterized. In silico molecular docking analysis and binding to the agonistic anti-PDGFR&#x3b1; antibodies identified spatially contiguous epitopes derived from PDGFR&#x3b1; and AAV5 that interacted with SSc agonistic antibodies to PDGFR&#x3b1;. These peptides were also able to bind total IgG isolated from patients with SSc, not from healthy controls. CONCLUSION: These data link AVV5 with the immune reactivity to endogenous antigens in SSc and provide a novel element in the pathogenesis of SSc.

Humans↗
PubMed1992

Characterization of a preferred site on human chromosome 19q for integration of adeno-associated virus DNA by non-homologous recombination.

The human parvovirus, adeno-associated virus (AAV), has been shown to integrate preferentially into human chromosome 19 q13.3-qter. The human target sequence for AAV integration (AAVS1) was cloned and sequenced. By analysis of the proviral junctions it was determined that integration of the AAV DNA occurred via a non-homologous recombination pathway although there were either four or five identical nucleotides at the junctions. Integration was a multistep, concerted process that resulted in cellular sequence rearrangements. The sequence of the integration locus was analyzed for possible recombination signals. Direct repeats at a much greater than random occurrence were found distributed non-uniformly throughout the AAVS1 sequence. A CpG island containing transcription factor binding site elements is suggestive of a TATA-less promoter. Evidence for transcriptional activity was provided by PCR amplification of reverse transcribed RNA.

Base Sequence↗
PubMed2016

Controlling AAV Tropism in the Nervous System with Natural and Engineered Capsids.

More than one hundred naturally occurring variants of adeno-associated virus (AAV) have been identified, and this library has been further expanded by an array of techniques for modification of the viral capsid. AAV capsid variants possess unique antigenic profiles and demonstrate distinct cellular tropisms driven by differences in receptor binding. AAV capsids can be chemically modified to alter tropism, can be produced as hybrid vectors that combine the properties of multiple serotypes, and can carry peptide insertions that introduce novel receptor-binding activity. Furthermore, directed evolution of shuffled genome libraries can identify engineered variants with unique properties, and rational modification of the viral capsid can alter tropism, reduce blockage by neutralizing antibodies, or enhance transduction efficiency. This large number of AAV variants and engineered capsids provides a varied toolkit for gene delivery to the CNS and retina, with specialized vectors available for many applications, but selecting a capsid variant from the array of available vectors can be difficult. This chapter describes the unique properties of a range of AAV variants and engineered capsids, and provides a guide for selecting the appropriate vector for specific applications in the CNS and retina.

Animals↗
PubMed1979

Isolation of an adeno associated virus from sheep. Brief report.

An adenovirus and a spherical virus 20--24 nm diameter were isolated from ovine faeces. The small virus replicated in the nucleus, and was associated especially with the nucleolus. It haemagglutinated guinea pig and human erythrocytes, was thermostable and required an adenovirus for replication. It is concluded that this represents the first recorded isolate of an ovine AAV.

Animals↗
PubMed2009

Directed evolution of adeno-associated virus for glioma cell transduction.

Glioblastoma multiforme (GBM) is a serious form of brain cancer for which there is currently no effective treatment. Alternative strategies such as adeno-associated virus (AAV) vector mediated-genetic modification of brain tumor cells with genes encoding anti-tumor proteins have shown promising results in preclinical models of GBM, although the transduction efficiency of these tumors is often low. As higher transduction efficiency of tumor cells should lead to enhanced therapeutic efficacy, a means to rapidly engineer AAV vectors with improved transduction efficiency for individual tumors is an attractive strategy. Here we tested the possibility of identifying high-efficiency AAV vectors for human U87 glioma cells by selection in culture of a newly constructed chimeric AAV capsid library generated by DNA shuffling of six different AAV cap genes (AAV1, AAV2, AAV5, AAVrh.8, AAV9, AAVrh.10). After seven rounds of selection, we obtained a chimeric AAV capsid that transduces U87 cells at high efficiency (97% at a dose of 10(4) genome copies/cell), and at low doses it was 1.45-1.6-fold better than AAV2, which proved to be the most efficient parental capsid. Interestingly, the new AAV capsid displayed robust gene delivery properties to all glioma cells tested (including primary glioma cells) with relative fluorescence indices ranging from 1- to 14-fold higher than AAV2. The selected vector should be useful for in vitro glioma research when efficient transduction of several cell lines is required, and provides proof-of-concept that an AAV library can be used to generate AAV vectors with enhanced transduction efficiency of glioma cells.

Capsid Proteins↗
PubMed2014

A needleless liquid jet injection delivery method for cardiac gene therapy: a comparative evaluation versus standard routes of delivery reveals enhanced therapeutic retention and cardiac specific gene expression.

This study evaluates needleless liquid jet method and compares it with three common experimental methods: (1) intramuscular injection (IM), (2) left ventricular intracavitary infusion (LVIC), and (3) LV intracavitary infusion with aortic and pulmonary occlusion (LVIC-OCCL). Two protocols were executed. First (n&#x2009;=&#x2009;24 rats), retention of dye was evaluated 10&#xa0;min after delivery in an acute model. The acute study revealed the following: significantly higher dye retention (expressed as % myocardial cross-section area) in the left ventricle in both the liquid jet [52&#x2009;&#xb1;&#x2009;4] % and LVIC-OCCL [58&#x2009;&#xb1;&#x2009;3] % groups p&#x2009;<&#x2009;0.05 compared with IM [31&#x2009;&#xb1;&#x2009;8] % and LVIC [35&#x2009;&#xb1;&#x2009;4] %. In the second (n&#x2009;=&#x2009;16 rats), each animal received adeno-associated virus encoding green fluorescent protein (AAV.EGFP) at a single dose with terminal 6-week endpoint. In the second phase with AAV.EGFP at 6&#xa0;weeks post-delivery, a similar trend was found with liquid jet [54&#x2009;&#xb1;&#x2009;5] % and LVIC-OCCL [60&#x2009;&#xb1;&#x2009;8] % featuring more LV expression as compared with IM [30&#x2009;&#xb1;&#x2009;9] % and LVIC [23&#x2009;&#xb1;&#x2009;9] %. The IM and LVIC-OCCL cross sections revealed myocardial fibrosis. With more detailed development in future model studies, needleless liquid jet delivery offers a promising strategy to improve direct myocardial delivery.

Animals↗
PubMed1992

Adenovirus containing a deletion of the early region 2A gene allows growth of adeno-associated virus with decreased efficiency.

Efficient growth of adeno-associated virus (AAV) requires helper functions provided by a coinfecting adenovirus or herpesvirus. Earlier studies using adenoviruses having temperature-sensitive lesions in the early region 2A gene (E2A) produced contradictory evidence regarding the role of the E2A 72-kDa DNA-binding protein (DBP) in allowing efficient AAV growth. These disparate results may reflect varying levels of residual function in the temperature-sensitive DBP. We examined this issue using an adenovirus type 5 mutant (Add/802) that fails to produce any detectable DBP or any fragment of it. Our experiments show that AAV can carry out a full growth cycle in the complete absence of DBP. However, AAV DNA replication and rep and capsid protein synthesis were reduced several fold and the yield of infectious AAV was reduced by an order of magnitude. This appears to reflect mainly decreased post-transcriptional expression of AAV rep and capsid protein genes.

Adenoviridae↗
PubMed1992

Replication of adeno-associated virus type 2 in human lymphocytic cells and interaction with HIV-1.

Adeno-associated virus (AAV) is a nonpathogenic parvovirus which normally requires helper adenovirus or herpes-virus for replication. We examined the growth of AAV type 2 in human lymphocytes and its possible interaction with HIV-1. Three B cell lines (CK-B, HS-2, and UC729) and four T cell lines (Molt-4, Jurkat, HUT78, and HUT78+HIV, which is persistently infected with HIV-1) were infected with AAV either in the presence or in the absence of adenovirus. AAV DNA was found in cells of all the lines following incubation with the virus, indicating absorption. AAV DNA replication occurred in most cell lines without particular preference for B or T cells, but only in the presence of helper virus, either adenovirus or Epstein-Barr virus. Expression of AAV proteins was examined by immunoblotting and ELISA, using sera specific for AAV Rep or capsid proteins. The level of AAV protein synthesis correlated with the efficiency of AAV DNA replication, and both varied between cell lines. The yield of infectious AAV was low in most cases, except in one T4 line (Jurkat), where AAV replication and protein synthesis in the presence of adenovirus were very extensive. In HUT78+HIV cells both adenovirus and AAV (in the presence of Ad2) replicated efficiently. The effects of adenovirus plus AAV coinfections on HIV-1 replication, measured by reverse-transcriptase (RT) activity, were mild. Infection with adenovirus or AAV alone resulted in a 60-70% increase in RT activity, while infection with AAV plus adenovirus resulted in a 20% decrease in RT activity. The yield of infectious AAV in this cell line was very low.

Adenoviridae Infections↗
PubMed1992

Inhibition of bovine papillomavirus plasmid DNA replication by adeno-associated virus.

The helper-dependent human parvovirus adeno-associated virus type 2 (AAV) inhibits both the oncogenic transforming abilities and the DNA replication of its helper viruses, adenovirus (Ad), and herpes simplex virus (HSV). As AAV-2 also inhibits the transforming ability of bovine papillomavirus type 1 (BPV), AAV-2 was assayed for its ability to inhibit BPV plasmid DNA replication. Here we find that the AAV-2 Rep78 gene is able to trans-inhibit BPV plasmid DNA replication and that the AAV-2 terminal repeats (TR) are also cis-required for the full inhibitory effect of AAV-2. When both the AAV-2 Rep78 open reading frame and TRs are present the inhibition of BPV plasmid DNA replication is very strong.

Animals↗