Abstract:
:The use of adenovirus vectors for human gene therapy is limited by potent inflammatory responses that result in significant morbidity. In kidney-derived epithelial cells (REC), activation of extracellular signal-regulated kinase 1/2 (ERK) and p38 kinase (p38) pathways occurred within 20 min of transduction with the serotype 5 adenovirus vector AdCMV beta gal. Inhibition of ERK and p38 with U0126 and SB203580, respectively, reduced the expression of IP-10 mRNA following transduction with AdCMV beta gal. To determine the role of the coxsackievirus-adenovirus receptor (CAR) or alpha(v) integrins in the activation of ERK and p38 and the expression of IP-10, REC cells were transduced with the fiber-modified and RGD-deleted adenovirus vectors AdL.F(RAEK-HA) and AdL.PB(HA), respectively. Compared with the wild-type capsid vector Ad5Luc, transduction with AdL.F(RAEK-HA) and AdL.PB(HA) resulted in reduced ERK-p38 activation and less IP-10 mRNA expression. The decreased IP-10 expression induced by the tropism-modified vectors was due to diminished transduction, since increasing multiplicity of infection resulted in increased IP-10 expression. Inhibition of adenovirus penetration with bafilomycin A1 or ammonium chloride attenuated the activation of ERK-p38 and IP-10 mRNA expression following infection, suggesting that endosomal escape was required to trigger these pathways. In vivo, direct inhibition of ERK and p38 signaling pathways inhibited adenovirus vector-induced IP-10 expression in mouse liver 1 h following transduction. These results demonstrate the importance of signaling via ERK and p38 in the early host response to adenovirus vectors and will permit the development of novel strategies to improve the safety and efficacy of these agents in human gene therapy.
journal_name
J Viroljournal_title
Journal of virologyauthors
Tibbles LA,Spurrell JC,Bowen GP,Liu Q,Lam M,Zaiss AK,Robbins SM,Hollenberg MD,Wickham TJ,Muruve DAdoi
10.1128/jvi.76.4.1559-1568.2002subject
Has Abstractpub_date
2002-02-01 00:00:00pages
1559-68issue
4eissn
0022-538Xissn
1098-5514journal_volume
76pub_type
杂志文章abstract::Plasma from a small subset of subjects chronically infected with HIV-1 shows remarkable magnitude and breadth of neutralizing activity. From one of these individuals (CH0219), we isolated two broadly neutralizing antibodies (bnAbs), CH01 and VRC-CH31, from two clonal lineages of memory B cells with distinct specificit...
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pub_type: 杂志文章
doi:10.1128/JVI.07163-11
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.79.4.2079-2086.2005
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journal_title:Journal of virology
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doi:10.1128/JVI.75.15.7188-7192.2001
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abstract:UNLABELLED:Plasma microRNAs (miRNAs) change in abundance in response to disease and have been associated with liver fibrosis severity in chronic hepatitis C virus (HCV) infection. However, the early dynamics of miRNA release during acute HCV infection are poorly understood. In addition, circulating miRNA signatures hav...
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pub_type: 临床试验,杂志文章,多中心研究
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.72.2.1640-1646.1998
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pub_type: 杂志文章
doi:10.1128/JVI.02817-06
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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pub_type: 杂志文章
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doi:10.1128/JVI.78.21.12012-12021.2004
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journal_title:Journal of virology
pub_type: 杂志文章
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journal_title:Journal of virology
pub_type: 杂志文章
doi:10.1128/JVI.63.12.5037-5045.1989
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pub_type: 杂志文章
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