Improved gene delivery to B lymphocytes using a modified adenovirus vector targeting CD21.
Gene transfer by adenoviruses, which are widely used for gene therapy, may provide an alternative approach to treatment of several hematopoietic malignancies. However, a major limitation of adenovirus 5-based gene therapy lies in the natural tropism of the virus for the widely expressed hCAR receptor. The efficacy of adenoviral vectors could be improved if viral vectors that exhibit tissue-specific gene delivery were developed. For efficient gene transfer it is essential that every step from binding of virus to target cells to transgene expression is successfully accomplished. We developed a specific vector targeting the CD21 receptor, by inserting a CD21 binding sequence, derived from the EBV GP350/220 protein, into the HI loop of the HAdV5 fiber protein. This vector, HAdV5-CD21HIloop, binds specifically to CD21-positive cells and results in enhanced expression of the transgene in these cells and reduced expression in CD21-negative cells. Viral infection is highly correlated with the presence of CD21 receptors. Taken together, these results demonstrate that HAdV5-CD21HIloop is able to transduce CD21-positive cells specifically with reduced infection of nontarget cells. This is the result of the maintenance of the intracellular trafficking of the genetically modified adenovirus without vesicular retention, leading to enhanced nuclear transfer.
Mailly
Laurent
L
INSERM, Unité 817, IMPRT, University of Lille 2, 1 Place de Verdun, 59045 Lille Cedex, France.
Renaut
Laurence
L
Rogée
Sophie
S
Grellier
Elodie
E
D'Halluin
Jean-Claude
JC
Colin
Morvane
M
D000256:Adenoviridae / Q000235:genetics*; D001402:B-Lymphocytes / Q000821:virology; D036022:Capsid Proteins / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D004705:Endocytosis; D018014:Gene Transfer Techniques; D005822:Genetic Vectors; D006801:Humans; D017464:Receptors, Complement 3d / Q000235:genetics* / Q000378:metabolism
D036022:Capsid Proteins; D017464:Receptors, Complement 3d; C018315:hexon capsid protein, Adenovirus