2007
DOI: 10.1128/jvi.01584-07
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Fiber Shaft-Chimeric Adenovirus Vectors Lacking the KKTK Motif Efficiently Infect Liver Cells In Vivo

Abstract: The molecular mechanisms governing the infectivity of adenovirus (Ad) toward specific cell and tissue types in vivo remain poorly understood. The direct Ad binding to hepatic heparan sulfate proteoglycans via the KKTK motif within the fiber shaft domain was suggested to be the major mechanism of Ad liver cell infection in vivo. Here, we describe the generation and in vitro and in vivo infectivity studies of Ad5-based vectors possessing long Ad31-or Ad41-derived fiber shaft domains, which lack the KKTK motif. W… Show more

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Cited by 36 publications
(33 citation statements)
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References 48 publications
(92 reference statements)
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“…Also, it was postulated that the HSPG-binding KKTK motif in the third shaft repeat mediated liver transduction and a substitution to a GAGA motif dramatically reduced liver transduction in mice, rats, and nonhuman primates (Smith et al, 2003a,b). In contrast to this, Di Paolo and colleagues reported that the KKTK motif within the Ad5 fiber played a minimal role in hepatic cell transduction in vivo (Di Paolo et al, 2007). In our study we found that the RKSK mutation did not affect heparin inhibition and was thus not a true triple-ablated vector.…”
Section: Fig 7 Cross-sections Of Ad[zh/3]-treated Tumors For Detectcontrasting
confidence: 84%
“…Also, it was postulated that the HSPG-binding KKTK motif in the third shaft repeat mediated liver transduction and a substitution to a GAGA motif dramatically reduced liver transduction in mice, rats, and nonhuman primates (Smith et al, 2003a,b). In contrast to this, Di Paolo and colleagues reported that the KKTK motif within the Ad5 fiber played a minimal role in hepatic cell transduction in vivo (Di Paolo et al, 2007). In our study we found that the RKSK mutation did not affect heparin inhibition and was thus not a true triple-ablated vector.…”
Section: Fig 7 Cross-sections Of Ad[zh/3]-treated Tumors For Detectcontrasting
confidence: 84%
“…13,14 Indeed, mutation of the KKTK motif in the Ad5 fiber shaft renders the fiber inflexible and prevents internalization of Ad5 through steric hindrance. 15,16 However, in vitro and in vivo infectivity studies of Ad5-based vectors possessing long Ad31 (species A)-or Ad41 (species F)-derived fiber shaft domains that lack the KKTK motif have shown that these vectors transduce hepatocytes with similar efficiency compared with Ad5 vectors, 17 consistent with a noncritical role of the KKTK motif in hepatocyte transduction.…”
Section: In Vitro and In Vivo Transduction By Adenoviral Vectorsmentioning
confidence: 98%
“…Smith et al (2003b) examined the role of heparan sulfate proteoglycans (HSPGs) in liver adenovirus uptake in vivo by replacing a putative HSPG-binding motif (KKTK) in the fiber shaft with an irrelevant peptide sequence, and observed a reduction in liver transgene expression of 90 %. However, Di Paolo et al (2007) demonstrated recently that the KKTK motif plays only a minimal role in hepatic infectivity in vivo.…”
Section: Introductionmentioning
confidence: 99%