ABSTRACT Adenovirus (Ad) infection triggers a cell-specific antiviral response following exposure of viral DNA to the intracellular compartment. A variety sensors (DAI, AIM2, DDx41, RNA polymerase [Pol] III, and IFI16 [p204]) have been identified in recent years; however, sensor involved detection adenovirus has not established. Cyclic GMP-AMP synthase (cGAS), that produces cyclic guanine-adenine dinucleotide (cGAMP) inducer STING, examined determine its role generating an antiadenoviral...

To optimize the use of modified adenoviruses as vectors for gene delivery to myocardium, we have characterized infection cultured fetal and adult rat cardiac myocytes in vitro vivo by using a replication-defective adenovirus carrying chloramphenicol acetyltransferase (CAT) reporter driven cytomegalovirus promoter (AdCMVCATgD). In vitro, virtually all or cardiocytes express CAT when infected with 1 plaque-forming unit virus per cell. enzymatic activity can be detected these cells early 4 hr...

Sequence elements within the mouse beta maj-globin transcription unit required for efficient termination of by RNA polymerase II have been delineated. To facilitate nascent-chain analysis termination, DNA segment in which ceases was introduced into adenovirus chromosome its E1A unit. Two beta-globin were to effect termination: an upstream sequence that includes two poly(A) addition signals and a downstream region previously shown be where synthesis stops. The role established introduction...

The efficient uptake of adenovirus into a target cell is function capsid proteins and their interaction with the host cell. protein fiber mediates high-affinity attachment to Although cellular receptor(s) for unknown, evidence indicates that single receptor does not as site each 49 different serotypes adenovirus. Sequence variation ligand, particularly in C- terminal knob domain, associated serotype-specific binding specificity. Additionally, this domain functions major serotype determinant....

Recombinant, replication-deficient adenovirus (Ad) vectors have been successfully used to transfer and express the normal human cystic fibrosis transmembrane conductance regulator (CFTR) cDNA in vivo respiratory epithelium of experimental animals humans with (CF). Since Ad-directed gene expression wanes over time, repeat administration is necessary achieve an effective treatment for CF. A major hurdle such a strategy possibility that anti-Ad humoral immunity may prevent individuals...

Infection with adenovirus vectors (AdV) results in rapid activation of innate immunity, which serves the dual purpose stimulating inflammatory antiviral host defenses and adaptive immune system. Viral recognition by macrophages, dendritic cells, other cell types requires an ability to sense presence a foreign molecular pattern "pattern receptors." The nature adenoviral sensor, target ligand downstream signaling response triggered virus infection have not been defined for this nonenveloped...

Tumor necrosis factor-alpha (TNF-alpha) is well recognized for its role in mediating innate immune responses. However, the mechanisms of TNF-alpha that influence adaptive response to virus infections are not understood. In this study, we have investigated activating cellular and humoral responses systemic viral challenge with recombinant replication-defective adenovirus (rAd). Evaluation T cell function TNF-alpha-deficient (TNFKO) mice revealed impaired virus-specific proliferation cells...

ABSTRACT Following receptor binding and internalization, intracellular trafficking of adenovirus (Ad) among subgroups B C is different, with significant amounts Ad serotype 7 (Ad7) (subgroup B) virions found in cytoplasm during the initial hours infection while Ad5 C) rapidly translocate to nucleus. To evaluate role fiber these differences, we examined Ad5, Ad7, Ad5f7 (a chimeric vector composed capsid replaced by Ad7 fiber) conjugating capsids directly Cy3 fluorescent dye, permitting be...

Adenovirus (Ad) gene transfer vectors are rapidly cleared from infected hepatocytes in mice. To determine which effector mechanisms responsible for elimination of the Ad vectors, we mice that were genetically compromised immune pathways [perforin, Fas, or tumor necrosis factor α (TNF-α)] with vector, Ad5-chloramphenicol acetyl transferase (CAT). Mice sacrificed at 7–60 days postinfection, and levels CAT expression liver determined by a quantitative enzymatic assay. When livers harvested 28...

Systemic administration of adenovirus and vectors induces a robust innate adaptive immune response in variety animal models. In tumor necrosis factor (TNF) -/- mice, diminished to (Ad) infection has been attributed compromised dendritic cell (DC) maturation. this report, we investigated the mechanisms responsible for Ad-mediated activation maturation DC. Ad induced high levels TNF-α expression by murine bone marrow-derived DC, comparable observed with lipopolysaccharide exposure. Ad-induced...

ABSTRACT This study has used the strategy of gene replacement to characterize contribution adenovirus (Ad) capsid protein hexon serotype definition. By replacing Ad type 5 (Ad5) with sequences from Ad2, we have changed specificity chimeric virus. The type-determining epitopes are primarily associated loop 1 and, a much lesser degree, 2. In spite distinctiveness viruses, epitope similarity between vectors resulted in low level cross-reactive neutralizing antibody, which combination activated...

Journal Article Transcription termination occurs within a 1000 base pair region downstream from the poly(A) site of mouse β-globin (major) gene Get access Bruce Citron, Citron The Rockefeller UniversityNew York, NY 10021, USA Search for other works by this author on: Oxford Academic PubMed Google Scholar Erik Falck-Pedersen, Falck-Pedersen Marianne Salditt-Georgieff, Salditt-Georgieff James E. Darnell, Jr. Nucleic Acids Research, Volume 12, Issue 22, 26 November 1984, Pages 8723–8731,...

Adenoviruses invading the organism via normal digestive or respiratory routes require Coxsackie-adenovirus receptor (CAR) to infect epithelial barrier cells. Because CAR is a component of tight junctions and basolateral membrane normally excluded from apical membrane, most epithelia are resistant adenoviruses. However, we discovered that specialized epithelium, retinal pigment epithelium (RPE), anomalously expressed at surface was highly susceptible adenovirus infection. These properties RPE...

ABSTRACT We have used the RAW 264.7 murine macrophage-like cell line as a platform to characterize recognition and early signaling response recombinant adenoviral vectors (rAdV). Infection of cells triggers an (2 6 h postinfection) that includes phosphorylation interferon (IFN) factor 3 (IRF3) transcription factor, upregulation IRF3 primary genes (interferon-stimulated gene 56 [ISG56], beta IFN [IFN-β]), subsequent type I secondary (STAT1/2 phosphorylation). Using short hairpin RNA (shRNA)...

ABSTRACT Infection by adenovirus, a nonenveloped DNA virus, induces antiviral innate and adaptive immune responses. Studies of transformed human murine cell lines using short hairpin RNA (shRNA) knockdown strategies identified cyclic guanine adenine synthase (cGAS) as pattern recognition receptor (PRR) that contributes to the antiadenovirus response. Here we demonstrate how cGAS/STING cascade influences responses in knockout model. Using bone marrow-derived dendritic cells (BMDCs)...

Adeno-associated virus (AAV) undergoes site-specific integration into human chromosome 19 through a deletion-substitution mechanism at the well characterized AAVS1 site. We have shown previously that cis element within left end of AAV genome enhances efficiency Rep-mediated when present in inverted terminal repeat-containing recombinant (rAAV) plasmids. now demonstrate 138-bp element, p5 (p5IEE), mediates efficient integration. The p5IEE is not only required for integration, it also...

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In several mammalian transcription units, a termination mechanism in which efficient is dependent on the presence of an intact 3' RNA processing site has been identified. The mouse beta maj-globin unit one such example, poly(A) required for termination. It now evident that mRNA sites are not always processed with same efficiency. this study, we characterized pre-mRNAs as substrates reaction cleavage and polyadenylation. We then determined whether vary efficiency support site-dependent event....

We have investigated the mechanisms involved in early-to-late RNA-processing switch which regulates mRNA species generated from adenovirus major late transcription unit (MLTU). In particular, polyadenylation choice were characterized by using a reconstructed E1A gene as site for insertion of MLTU poly(A) regulation signals (L1 and L3). Adenovirus constructs containing variant recognition elements used to compare signal utilization with wild-type L5) utilization. both early stages infection,...

ABSTRACT Viral integrations are important in human biology, yet genome-wide integration profiles have not been determined for many viruses. Adeno-associated virus (AAV) infects most of the population and is a prevalent gene therapy vector. AAV integrates into genome with preference single locus, termed AAVS1. However, has defined, principles underlying this recombination remain unclear. Using novel high-throughput approach, integrant capture sequencing, nearly 12 million junctions were...

The cGAS/STING DNA sensing complex has recently been established as a predominant pathogen recognition receptor (PRR) for DNA-directed type I interferon (IFN) innate immune activation. Using replication-defective adenovirus vectors and replication-competent wild-type adenovirus, we have modeled the influence of cascade in permissive human cell lines (A549, HeLa, ARPE19, THP1). Wild-type induced efficient early activation cell-specific manner. In all responsive lines, short hairpin RNA...