Differential interaction of retroviral vector with target cell: quantitative effect of cellular receptor, soluble proteoglycan, and cell type on gene delivery efficiency.
Retroviral vectors are powerful tools for gene therapy and stem cell engineering. To improve efficiency of retroviral gene delivery, quantitative understanding of interactions of a retroviral vector and a cell is crucial. Effects of nonspecific adsorption of retrovirus on a cell via proteoglycans and receptor-mediated binding of retrovirus to a cell on overall transduction efficiency were quantified by combining a mathematical model and experimental data. Results represented by transduction rate constant, a lumped parameter of overall transduction efficiency, delineated that chondroitin sulfate C (CSC) plays dual roles as either enhancer or inhibitor of retroviral transduction, depending on its concentrations in the retroviral supernatant. At the concentration of 20 microg/mL, CSC enhanced the transduction efficiency up to threefold but inhibited more than sevenfold at the concentration of 100 microg/mL. Transduction rate constants for amphotropic retroviral infection of NIH 3T3 cells under phosphate-depleted culture condition showed a proportional relationship between cellular receptor density on a cell and transduction efficiency. It was finally shown that amphotropic retrovirus transduced human fibroblast HT1080 cells more efficiently than NIH 3T3 cells. On the contrary, the transduction efficiency of NIH 3T3 cells by vesicular stomatitis virus G protein pseudotyped retroviruses was eightfold higher than that of HT1080 cells. This study implies usefulness of using quantitative analysis of retroviral transduction in understanding and optimizing retroviral gene delivery systems for therapeutic approaches to tissue engineering.
Kwon
Young Jik
YJ
Department of Chemical Engineering, University of Southern California, Los Angeles, California 92697, USA. kwonyj@uci.edu
Peng
Ching-An
CA
D000818:Animals; D001667:Binding, Competitive / Q000187:drug effects; D002460:Cell Line; D049109:Cell Proliferation / Q000187:drug effects; D048430:Cell Shape / Q000187:drug effects; D002809:Chondroitin Sulfates / Q000494:pharmacology; D005822:Genetic Vectors / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D041681:NIH 3T3 Cells; D010710:Phosphates / Q000494:pharmacology; D011509:Proteoglycans / Q000494:pharmacology; D011991:Receptors, Virus / Q000378:metabolism; D012190:Retroviridae / Q000235:genetics / Q000378:metabolism*; D014161:Transduction, Genetic / Q000379:methods*
D010710:Phosphates; D011509:Proteoglycans; D011991:Receptors, Virus; D002809:Chondroitin Sulfates