Adenovirus Early Region 4 and Viral DNA Synthesis

Reduced toxicity, attenuated immunogenicity and efficient mediation of human p53 gene expression in vivo by an adenovirus vector with deleted E1-E3 and inactivated E4 by GAL4-TATA promoter replacement

“…Our results are consistent with other researchers' observations that the replication incompetence of E1-deleted adenovirus could be overcome by adenoviral infection at a high MOI in non-E1-transformed cells. 6,18,31 Synthesis of the late viral hexon was dramatically reduced by E4 inactivation in both G4-transfected H1299 and A549 cells at MOI 10 and MOI 50, respectively, compared with those in BG-and WT-infected cells. The reduction in accumulation of the late viral protein hexon correlated with reduction in virus production.…”

“…[1][2][3][4][5] However, recent studies have demonstrated that the replication defect in E1-deleted adenoviruses could be overcome in cultured cells at high multiplicities of infection (MOI) 6,7 and that the early and late viral gene products can be expressed independently of E1a function following adenovirus-mediated gene transfer in vivo. [8][9][10] The expressed viral genes may elicit a host immune response in the transduced cells and lead to toxicity, 11,12 limit the duration of transgene expression, [13][14][15][16] and consequently hinder the application of these vectors for human gene therapy.…”

E4 gene function in adenovirus, adenovirus vector and adeno-associated virus infections.

“…Mutant viruses unable to make one or other protein show a modest reduction in DNA synthesis ; mutants unable to make either protein are substantially deficient in replication (Bridge & Ketner, 1989 ;Huang & Hearing, 1989 a). Although the replication defects of mutants unable to make any E4 proteins and those specifically impaired in both Orf3 and Orf6 appeared from these studies to be identical at moderate multiplicities of infection, it was later shown that Orf4 modulates these effects (Bridge et al, 1993 a). Viruses which retain Orf4 in the absence of Orf3 and Orf6 are severely defective in replication at multiplicities and times post-infection when total E4-deletion mutants produce close to normal levels of DNA ; supplying Orf4 either in cis or in trans to these latter infections inhibits replication.…”

“…Ad infection also results in a progressive redistribution of splicing factors in the nucleus (Bridge et al, 1993(Bridge et al, b, 1995. The relationship of this reorganization to the effect on PODs is not certain.…”

Les adénovirus non-humains

“…La plupart d'entre elles ont un rôle dans le contrôle de la réponse immunitaire de l'hôte. En particulier, la protéine gp19K se lie aux molécules du complexe majeur d'histocompatibilité de classe I (CMH I) [33], bloquant la réponse immunitaire cytotoxique dépendant des lymphocytes T. Enfin, la région E4 produit plusieurs protéines qui ont toutes un rôle essentiel dans la réplication du virus [34]. La protéine E4 ORF3 (E4 gene open reading frame 3 protein) forme un complexe avec E1B-55K et recrute des composants associés aux corps nucléaires PML (promyelocytic leukemia) [35] qui interviennent dans les processus de réparation de l'ADN, de réplication, de défense antivirale et au niveau de la transcription [36].…”