CELL-CYCLE DEPENDENCE OF RETROVIRAL TRANSDUCTION - AN ISSUE OF OVERLAPPING TIME SCALES

Recombinant retroviruses are currently used as gene delivery vehicles for the purpose of gene therapy. It is generally believed that the eff iciency of retroviral transduction depends on the cell cycle status of the target cells. However, it has been reported that this Is not the case for the transduction of human and murine fibroblasts, in contrast to other cell types such as lymphocytes. The predictions of a mathema tical model that we constructed, offer an explanation of this contradi ction, based on the dynamics of the underlying processes of target cel l growth and the intracellular decay of retroviral vectors. The model suggests that the utility of synchronization experiments, that are usu ally employed to study cell cycle specificity, is severely limited whe n the time scales of the above kinetic events are comparable to each o ther. The predictions of the model also suggest the use of retroviral vectors as cell cycle markers, as an alternative way to detect cell cy cle dependence of retroviral transduction. This method obviates the ne ed for cell synchronization and therefore, it does not perturb the cel l cycle or interfere with the life cycle of retroviral vectors. Moreov er, it does not depend on the intracellular stability of retroviral ve ctors. Our results show that in contrast: to previously reported resul ts, transduction of murine fibroblasts is cell cycle dependent, and th ey are consistent with the current notion that mitosis is the phase th at confers transduction susceptibility. (C) 1998 John Wiley & Sons, In c.